ASSESSMENT OF ALLERGIC IMMUNE RESPONSES TO INDOOR AIR FUNGAL CONTAMINANTS

EPA Science Inventory

We are using a mouse model to assess immune and inflammatory responses as well as changes in respiratory function and pathology characteristic of allergic asthma to fungal extracts M. anisopliae (MACA), S. chartarum (SCE), and P. chrysogenum (PCE). This model will be useful to a...

Assessment of hypoxia and TNF-alpha response by a vector with HRE and NF-kappaB response elements.

PubMed

Chen, Zhilin; Eadie, Ashley L; Hall, Sean R; Ballantyne, Laurel; Ademidun, David; Tse, M Yat; Pang, Stephen C; Melo, Luis G; Ward, Christopher A; Brunt, Keith R

2017-01-01

Hypoxia and inflammatory cytokine activation (H&I) are common processes in many acute and chronic diseases. Thus, a single vector that responds to both hypoxia and inflammatory cytokines, such as TNF-alpha, is useful for assesing the severity of such diseases. Adaptation to hypoxia is regulated primarily by hypoxia inducible transcription factor (HIF alpha) nuclear proteins that engage genes containing a hypoxia response element (HRE). Inflammation activates a multitude of cytokines, including TNF-alpha, that invariably modulate activation of the nuclear factor kappa B (NF-kB) transcription factor. We constructed a vector that encompassed both a hypoxia response element (HRE), and a NF-kappaB responsive element. We show that this vector was functionally responsive to both hypoxia and TNF-alpha, in vitro and in vivo . Thus, this vector might be suitable for the detection and assessment of hypoxia or TNF-alpha.

Periodontal disease as a potential factor for systemic inflammatory response in the dog.

PubMed

Kouki, M I; Papadimitriou, S A; Kazakos, G M; Savas, I; Bitchava, D

2013-01-01

Periodontal disease is an inflammatory disease that has numerous consequences both locally and systemically The aim of this study was to assess whether periodontal disease causes systemic inflammatory response in otherwise healthy, adult dogs. We estimated the total mouth periodontal score (TMPS), measured the concentration of C-reactive protein (CRP), hematocrit, and albumin, and determined the white blood cell (WBC) and polymorphonuclear cell (PMN) counts in client-owned dogs. There was a statistically significant relationship between the gingival bleeding index (TMPS-G) and CRP concentration, and WBC and PMN counts, possibly during the active periods of periodontal tissue destruction. No correlation was found between the periodontal destruction index (TMPS-P) and the measured blood parameters. We conclude that chronic periodontal disease does not cause anemia or a reduction in serum albumin. However, active periods of periodontal inflammation may be associated with laboratory values suggestive of a systemic inflammatory response.

Inflammatory bowel disease imaging: Current practice and future directions.

PubMed

Kilcoyne, Aoife; Kaplan, Jess L; Gee, Michael S

2016-01-21

The purpose of this paper is to evaluate the role of imaging in inflammatory bowel disease (IBD), including detection of extraluminal complications and extraintestinal manifestations of IBD, assessment of disease activity and treatment response, and discrimination of inflammatory from fibrotic strictures. IBD is a chronic idiopathic disease affecting the gastrointestinal tract that is comprised of two separate, but related intestinal disorders; Crohn's disease and ulcerative colitis. The paper discusses, in detail the pros and cons of the different IBD imaging modalities that need to be considered in order to optimize the imaging and clinical evaluation of patients with IBD. Historically, IBD evaluation of the bowel has included imaging to assess the portions of the small bowel that are inaccessible to optical endoscopic visualization. This traditionally was performed using barium fluoroscopic techniques; however, cross-sectional imaging techniques (computed tomography and magnetic resonance imaging) are being increasingly utilized for IBD evaluation because they can simultaneously assess mural and extramural IBD manifestations. Recent advances in imaging technology, that continue to improve the ability of imaging to noninvasively follow disease activity and treatment response, are also discussed. This review article summarizes the current imaging approach in inflammatory bowel disease as well as the role of emerging imaging modalities.

Evaluation of Complete Blood Count Indices (NLR, PLR, MPV/PLT, and PLCRi) in Healthy Dogs, Dogs With Periodontitis, and Dogs With Oropharyngeal Tumors as Potential Biomarkers of Systemic Inflammatory Response.

PubMed

Rejec, Ana; Butinar, Janos; Gawor, Jerzy; Petelin, Milan

2017-12-01

The aim of the study was to retrospectively assess complete blood count (CBC) indices of dogs with periodontitis (PD; n = 73) and dogs with oropharyngeal tumors (OT; n = 92) in comparison to CBC indices of healthy dogs (HD; n = 71). Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio, mean platelet volume to platelet ratio, and platelet large cell ratio index (PLCRi) were evaluated as biomarkers of systemic inflammatory response provoked by PD and OT. Results of multivariable polytomous logistic regression analysis indicated no significant associations between CBC indices and PD. Both NLR and PLCRi were significantly higher in dogs with OT when compared to HD and dogs with PD and could, therefore, indicate a tumor-associated systemic inflammatory response. Additional studies of CBC indices, along with other biomarkers of systemic inflammatory response, are recommended to validate them as reliable indicators of clinical disease activity.

Asian Dust Particles Induce Macrophage Inflammatory Responses via Mitogen-Activated Protein Kinase Activation and Reactive Oxygen Species Production

PubMed Central

Higashisaka, Kazuma; Fujimura, Maho; Taira, Mayu; Yoshida, Tokuyuki; Tsunoda, Shin-ichi; Baba, Takashi; Yamaguchi, Nobuyasu; Nabeshi, Hiromi; Yoshikawa, Tomoaki; Nasu, Masao; Tsutsumi, Yasuo

2014-01-01

Asian dust is a springtime meteorological phenomenon that originates in the deserts of China and Mongolia. The dust is carried by prevailing winds across East Asia where it causes serious health problems. Most of the information available on the impact of Asian dust on human health is based on epidemiological investigations, so from a biological standpoint little is known of its effects. To clarify the effects of Asian dust on human health, it is essential to assess inflammatory responses to the dust and to evaluate the involvement of these responses in the pathogenesis or aggravation of disease. Here, we investigated the induction of inflammatory responses by Asian dust particles in macrophages. Treatment with Asian dust particles induced greater production of inflammatory cytokines interleukin-6 and tumor necrosis factor-α (TNF-α) compared with treatment with soil dust. Furthermore, a soil dust sample containing only particles ≤10 μm in diameter provoked a greater inflammatory response than soil dust samples containing particles >10 μm. In addition, Asian dust particles-induced TNF-α production was dependent on endocytosis, the production of reactive oxygen species, and the activation of nuclear factor-κB and mitogen-activated protein kinases. Together, these results suggest that Asian dust particles induce inflammatory disease through the activation of macrophages. PMID:24987712

HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luo, Ying; Li, Shu-Jun; Yang, Jian

Highlights: •Mechanisms of inflammatory response induced by HMGB1 are incompletely understood. •We found that endoplasmic reticulum stress mediate the inflammatory response induced by HMGB1. •RAGE-mediated ERS pathways are involved in those processes. •We reported a new mechanism for HMGB1 induced inflammatory response. -- Abstract: The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulummore » stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01–1 μg/ml) for 24 h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway.« less

Endotoxin molecule lipopolysaccharide-induced zebrafish inflammation model: a novel screening method for anti-inflammatory drugs.

PubMed

Yang, Li-Ling; Wang, Guo-Quan; Yang, Li-Mei; Huang, Zhi-Bing; Zhang, Wen-Qing; Yu, Lin-Zhong

2014-02-21

Lipopolysaccharide (LPS), an endotoxin molecule, has been used to induce inflammatory responses. In this study, LPS was used to establish an in vivo inflammation model in zebrafish for drug screening. We present an experimental method that conveniently and rapidly assesses the anti-inflammatory properties of drugs. The yolks of 3-day post-fertilization (dpf) larvae were injected with 0.5 mg/mL LPS to induce fatal inflammation. After LPS stimulation, macrophages were tracked by NR and SB staining and neutrophil migration was observed using the MPO:GFP line. Larval mortality was used as the primary end-point. Expression levels of key cytokines involved in the inflammatory response including IL-1β, IL-6, and TNF-α, were measured using quantitative reverse transcription polymerase chain reaction (RT-PCR). Macrophages and neutrophils were both recruited to the LPS-injected site during the inflammatory response. Mortality was increased by LPS in a dose-dependent manner within 48 h. Analyses of IL-1β, IL-6, and TNF-α expression levels revealed the upregulation of the inflammatory response in the LPS-injected larvae. Further, the anti-inflammatory activity of chlorogenic acid (CA) was evaluated in this zebrafish model to screen for anti-inflammatory drugs. A preliminary result showed that CA revealed a similar effect as the corticosteroid dexamethasone (DEX), which was used as a positive control, by inhibiting macrophage and neutrophil recruitment to the LPS site and improving survival. Our results suggest that this zebrafish screening model could be applied to study inflammation-mediated diseases. Moreover, the Traditional Chinese Medicine CA displays potential anti-inflammatory activity.

Immunopathologic effects of scorpion venom on hepato-renal tissues: Involvement of lipid derived inflammatory mediators.

PubMed

Lamraoui, Amal; Adi-Bessalem, Sonia; Laraba-Djebari, Fatima

2015-10-01

Scorpion venoms are known to cause different inflammatory disorders through complex mechanisms in various tissues. In the study here, the involvement of phospholipase A2 (PLA2) and cyclo-oxygenase (COX)-derived metabolites in hepatic and renal inflammation responses were examined. Mice were envenomed with Androctonus australis hector scorpion venom in the absence or presence of inhibitors that can interfere with lipid inflammatory mediator synthesis, i.e., dexamethasone (PLA2 inhibitor), indomethacin (non-selective COX-1/COX-2 inhibitor), or celecoxib (selective COX-2 inhibitor). The inflammatory response was assessed by evaluating vascular permeability changes, inflammatory cell infiltration, oxidative/nitrosative stress marker levels, and by histologic and functional analyses of the liver and kidney. Results revealed that the venom alone induced an inflammatory response in this tissues marked by increased microvascular permeability and inflammatory cell infiltration, increases in levels of nitric oxide and lipid peroxidation, and decreases in antioxidant defense. Moreover, significant alterations in the histological architecture of these organs were associated with increased serum levels of some metabolic enzymes, as well as urea and uric acid. Pre-treatment of mice with dexamethasone led to significant decreases of the inflammatory disorders in the hepatic parenchyma; celecoxib pre-treatment seemed to be more effective against renal inflammation. Indomethacin pre-treatment only slightly reduced the inflammatory disorders in the tissues. These results suggest that the induced inflammation response in liver was mediated mainly by PLA2 activation, while the renal inflammatory process was mediated by prostaglandin formation by COX-2. These findings provide additional insight toward the understanding of activated pathways and related mechanisms involved in scorpion envenoming syndrome.

Unrepaired DNA damage in macrophages causes elevation of particulate matter- induced airway inflammatory response.

PubMed

Luo, Man; Bao, Zhengqiang; Xu, Feng; Wang, Xiaohui; Li, Fei; Li, Wen; Chen, Zhihua; Ying, Songmin; Shen, Huahao

2018-04-14

The inflammatory cascade can be initiated with the recognition of damaged DNA. Macrophages play an essential role in particulate matter (PM)-induced airway inflammation. In this study, we aim to explore the PM induced DNA damage response of macrophages and its function in airway inflammation. The DNA damage response and inflammatory response were assessed using bone marrow-derived macrophages following PM treatment and mouse model instilled intratracheally with PM. We found that PM induced significant DNA damage both in vitro and in vivo and simultaneously triggered a rapid DNA damage response, represented by nuclear RPA, 53BP1 and γH2AX foci formation. Genetic ablation or chemical inhibition of the DNA damage response sensor amplified the production of cytokines including Cxcl1, Cxcl2 and Ifn-γ after PM stimulation in bone marrow-derived macrophages. Similar to that seen in vitro , mice with myeloid-specific deletion of RAD50 showed higher levels of airway inflammation in response to the PM challenge, suggesting a protective role of DNA damage sensor during inflammation. These data demonstrate that PM exposure induces DNA damage and activation of DNA damage response sensor MRN complex in macrophages. Disruption of MRN complex lead to persistent, unrepaired DNA damage that causes elevated inflammatory response.

Chronic Systemic Immune Dysfunction in African-Americans with Small Vessel-Type Ischemic Stroke.

PubMed

Brown, Candice M; Bushnell, Cheryl D; Samsa, Gregory P; Goldstein, Larry B; Colton, Carol A

2015-12-01

The incidence of small vessel-type (lacunar) ischemic strokes is greater in African-Americans compared to whites. The chronic inflammatory changes that result from lacunar stroke are poorly understood. To elucidate these changes, we measured serum inflammatory and thrombotic biomarkers in African-Americans at least 6 weeks post-stroke compared to control individuals. Cases were African-Americans with lacunar stroke (n = 30), and controls were age-matched African-Americans with no history of stroke or other major neurologic disease (n = 37). Blood was obtained >6 weeks post-stroke and was analyzed for inflammatory biomarkers. Freshly isolated peripheral blood mononuclear cells were stimulated with lipopolysaccharide (LPS) to assess immune responsiveness in a subset of cases (n = 5) and controls (n = 4). After adjustment for covariates, the pro-inflammatory biomarkers, soluble vascular cadherin adhesion molecule-1 (sVCAM-1) and thrombin anti-thrombin (TAT), were independently associated with lacunar stroke. Immune responsiveness to LPS challenge was abnormal in cases compared to controls. African-Americans with lacunar stroke had elevated blood levels of VCAM-1 and TAT and an abnormal response to acute immune challenge >6 weeks post-stroke, suggesting a chronically compromised systemic inflammatory response.

Potential Use of Salivary Markers for Longitudinal Monitoring of Inflammatory Immune Responses to Vaccination

PubMed Central

Garssen, Johan; Sandalova, Elena

2016-01-01

Vaccination, designed to trigger a protective immune response against infection, is a trigger for mild inflammatory responses. Vaccination studies can address the question of inflammation initiation, levels, and resolution as well as its regulation for respective studied pathogens. Such studies largely based on analyzing the blood components including specific antibodies and cytokines were usually constrained by number of participants and volume of collected blood sample. Hence, blood-based studies may not be able to cover the full dynamic range of inflammation responses induced by vaccination. In this review, the potential of using saliva in addition to blood for studying the kinetics of inflammatory response studies was assessed. Saliva sampling is noninvasive and has a great potential to be used for studies aimed at analysing the magnitude, time course, and variance in immune responses, including inflammation after vaccination. Based on a literature survey of inflammatory biomarkers that can be determined in saliva and an analysis of how these biomarkers could help to understand the mechanisms and dynamics of immune reactivity and inflammation, we propose that the saliva-based approach might have potential to add substantial value to clinical studies, particularly in vulnerable populations such as infants, toddlers, and ill individuals. PMID:27022211

Effects of Cholinergic Stimulation with Pyridostigmine Bromide on Chronic Chagasic Cardiomyopathic Mice

PubMed Central

de Cuba, Marília Beatriz; Ribeiro Machado, Marcus Paulo; Farnesi, Thais Soares; Alves, Angelica Cristina; Martins, Livia Alves; de Oliveira, Lucas Felipe; Capitelli, Caroline Santos; Leite, Camila Ferreira; Vinícius Silva, Marcos; Machado, Juliana Reis; Kappel, Henrique Borges; Sales de Campos, Helioswilton; Paiva, Luciano; da Silva Gomes, Natália Lins; Guimarães Faleiros, Ana Carolina; Britto, Constança Felicia de Paoli de Carvalho; Savino, Wilson; Moreira, Otacílio Cruz; Rodrigues Jr., Virmondes; Montano, Nicola; Lages-Silva, Eliane; Ramirez, Luis Eduardo; Dias da Silva, Valdo Jose

2014-01-01

The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) with Trypanosoma cruzi (chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice. PMID:25221388

Effects of cholinergic stimulation with pyridostigmine bromide on chronic chagasic cardiomyopathic mice.

PubMed

de Cuba, Marília Beatriz; Machado, Marcus Paulo Ribeiro; Farnesi, Thais Soares; Alves, Angelica Cristina; Martins, Livia Alves; de Oliveira, Lucas Felipe; Capitelli, Caroline Santos; Leite, Camila Ferreira; Silva, Marcos Vinícius; Machado, Juliana Reis; Kappel, Henrique Borges; de Campos, Helioswilton Sales; Paiva, Luciano; Gomes, Natália Lins da Silva; Faleiros, Ana Carolina Guimarães; Britto, Constança Felicia de Paoli de Carvalho; Savino, Wilson; Moreira, Otacílio Cruz; Rodrigues, Virmondes; Montano, Nicola; Lages-Silva, Eliane; Ramirez, Luis Eduardo; da Silva, Valdo Jose Dias

2014-01-01

The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido), on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con) or chronically infected (5 months) with Trypanosoma cruzi (chagasic:Chg) were treated or not (NT) with Pyrido for one month. At the end of this period, electrocardiogram (ECG); cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice.

Anti-inflammatory effects of zinc in PMA-treated human gingival fibroblast cells

PubMed Central

Kim, Sangwoo; Jeon, Sangmi; Hui, Zheng; Kim, Young; Im, Yeonggwan; Lim, Wonbong; Kim, Changsu; Choi, Hongran; Kim, Okjoon

2015-01-01

Objectives: Abnormal cellular immune response has been considered to be responsible for oral lesions in recurrent aphthous stomatitis. Zinc has been known to be an essential nutrient metal that is necessary for a broad range of biological activities including antioxidant, immune mediator, and anti-inflammatory drugs in oral mucosal disease. The objective of this study was to investigate the effects of zinc in a phorbol-12-myristate-13-acetate (PMA)-treated inflammatory model on human gingival fibroblast cells (hGFs). Study Design: Cells were pre-treated with zinc chloride, followed by PMA in hGFs. The effects were assessed on cell viability, cyclooxygenease-1,2(COX-1/2) protein expression, PGE2 release, ROS production and cytokine release, Results: The effects were assessed on cell viability, COX1/2 protein expression, PGE2 release, ROS production, cytokine release. The results showed that, in the presence of PMA, zinc treatment leads to reduce the production of ROS, which results in decrease of COX-2 expression and PGE2 release. Conclusions: Thus, we suggest that zinc treatment leads to the mitigation of oral inflammation and may prove to be an alternative treatment for recurrent aphthous stomatitis. Key words:Zinc, inflammatory response, cytokines, phorbol-12-myristate-13-acetate, gingival fibroblasts cells. PMID:25662537

The Effective Regulation of Pro- and Anti-inflammatory Cytokines Induced by Combination of PA-MSHA and BPIFB1 in Initiation of Innate Immune Responses.

PubMed

Zhou, Weiqiang; Duan, Zhiwen; Yang, Biao; Xiao, Chunling

2017-01-01

PA-MSHA and BPIFB1 play especially important roles in triggering innate immune responses by inducing production of pro- or anti-inflammatory cytokines in the oral cavity and upper airway. We found that PA-MSHA had a strong ability to activate pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α. However, BPIFB1 alone did not express a directly inductive effect. With incubation of PA-MSHA and BPIFB1, the combination can activate the CD14/TLR4/MyD88 complex and induce secretion of subsequent downstream cytokines. We used a proteome profiler antibody array to evaluate the phosphokinases status with PA-MSHA and BPIFB1 treatment. The results showed that the activation of MAPK, STAT, and PI-3K pathways is involved in PA-MSHA-BPIFB1 treatment, and that the related pathways control the secretion of targeting cytokines in the downstream. When we assessed the content changes of cytokines, we found that PA-MSHA-BPIFB1 treatment increased the production of pro-inflammatory cytokines in the early phase of treatment and induced the increase of IL-4 in the late phase. Our observations suggest that PA-MSHA-BPIFB1 stimulates the release of pro-inflammatory cytokines, and thereby initiates the innate immune system against inflammation. Meanwhile, the gradual release of anti-inflammatory cytokine IL-4 by PA-MSHA-BPIFB1 can also regulate the degree of inflammatory response; thus the host can effectively resist the environmental risks, but also manipulate inflammatory response in an appropriate and adjustable manner.

Inflammatory bowel disease imaging: Current practice and future directions

PubMed Central

Kilcoyne, Aoife; Kaplan, Jess L; Gee, Michael S

2016-01-01

The purpose of this paper is to evaluate the role of imaging in inflammatory bowel disease (IBD), including detection of extraluminal complications and extraintestinal manifestations of IBD, assessment of disease activity and treatment response, and discrimination of inflammatory from fibrotic strictures. IBD is a chronic idiopathic disease affecting the gastrointestinal tract that is comprised of two separate, but related intestinal disorders; Crohn’s disease and ulcerative colitis. The paper discusses, in detail the pros and cons of the different IBD imaging modalities that need to be considered in order to optimize the imaging and clinical evaluation of patients with IBD. Historically, IBD evaluation of the bowel has included imaging to assess the portions of the small bowel that are inaccessible to optical endoscopic visualization. This traditionally was performed using barium fluoroscopic techniques; however, cross-sectional imaging techniques (computed tomography and magnetic resonance imaging) are being increasingly utilized for IBD evaluation because they can simultaneously assess mural and extramural IBD manifestations. Recent advances in imaging technology, that continue to improve the ability of imaging to noninvasively follow disease activity and treatment response, are also discussed. This review article summarizes the current imaging approach in inflammatory bowel disease as well as the role of emerging imaging modalities. PMID:26811637

Ginger Extract Suppresses Inflammatory Response and Maintains Barrier Function in Human Colonic Epithelial Caco-2 Cells Exposed to Inflammatory Mediators.

PubMed

Kim, Yunyoung; Kim, Dong-Min; Kim, Ji Yeon

2017-05-01

The beneficial effects of ginger in the management of gastrointestinal disturbances have been reported. In this study, the anti-inflammatory potential of ginger extract was assessed in a cellular model of gut inflammation. In addition, the effects of ginger extract and its major active compounds on intestinal barrier function were evaluated. The response of Caco-2 cells following exposure to a mixture of inflammatory mediators [interleukin [IL]-1β, 25 ng/mL; lipopolysaccharides [LPS], 10 ng/mL; tumor necrosis factor [TNF]-α, 50 ng/mL; and interferon [INF]-γ, 50 ng/mL] were assessed by measuring the levels of secreted IL-6 and IL-8. In addition, the mRNA levels of cyclooxygenase-2 and inducible nitric oxide synthase were measured. Moreover, the degree of nuclear factor (NF)-κB inhibition was examined, and the intestinal barrier function was determined by measuring the transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran transfer. It was observed that ginger extract and its constituents improved inflammatory responses by decreasing the levels of nitrite, PGE2, IL-6, and IL-8 via NF-κB inhibition. The ginger extract also increased the TEER and decreased the transfer of FITC-dextran from the apical side of the epithelium to the basolateral side. Taken together, these results show that ginger extract may be developed as a functional food for the maintenance of gastrointestinal health. © 2017 Institute of Food Technologists®.

The contribution of inflammasome components on macrophage response to surface nanotopography and chemistry

NASA Astrophysics Data System (ADS)

Christo, Susan; Bachhuka, Akash; Diener, Kerrilyn R.; Vasilev, Krasimir; Hayball, John D.

2016-05-01

Implantable devices have become an established part of medical practice. However, often a negative inflammatory host response can impede the integration and functionality of the device. In this paper, we interrogate the role of surface nanotopography and chemistry on the potential molecular role of the inflammasome in controlling macrophage responses. To achieve this goal we engineered model substrata having precisely controlled nanotopography of predetermined height and tailored outermost surface chemistry. Bone marrow derived macrophages (BMDM) were harvested from genetically engineered mice deficient in the inflammasome components ASC, NLRP3 and AIM2. These cells were then cultured on these nanoengineered substrata and assessed for their capacity to attach and express pro-inflammatory cytokines. Our data provide evidence that the inflammasome components ASC, NLRP3 and AIM2 play a role in regulating macrophage adhesion and activation in response to surface nanotopography and chemistry. The findings of this paper are important for understanding the inflammatory consequences caused by biomaterials and pave the way to the rational design of future implantable devices having controlled and predictable inflammatory outcomes.

Inflammation and oxidative stress in vertebrate host–parasite systems

PubMed Central

Sorci, Gabriele; Faivre, Bruno

2008-01-01

Innate, inflammation-based immunity is the first line of vertebrate defence against micro-organisms. Inflammation relies on a number of cellular and molecular effectors that can strike invading pathogens very shortly after the encounter between inflammatory cells and the intruder, but in a non-specific way. Owing to this non-specific response, inflammation can generate substantial costs for the host if the inflammatory response, and the associated oxygen-based damage, get out of control. This imposes strong selection pressure that acts to optimize two key features of the inflammatory response: the timing of activation and resolution (the process of downregulation of the response). In this paper, we review the benefits and costs of inflammation-driven immunity. Our aim is to emphasize the importance of resolution of inflammation as a way of maintaining homeostasis against oxidative stress and to prevent the ‘horror autotoxicus’ of chronic inflammation. Nevertheless, host immune regulation also opens the way to pathogens to subvert host defences. Therefore, quantifying inflammatory costs requires assessing (i) short-term negative effects, (ii) delayed inflammation-driven diseases, and (iii) parasitic strategies to subvert inflammation. PMID:18930878

Abdominal adiposity is the main determinant of the C-reactive response to injury in subjects undergoing inguinal hernia repair

PubMed Central

2013-01-01

Background Obesity and serum C-reactive protein (CRP) (a sensitive marker of inflammatory activity) are associated with most chronic diseases. Abdominal adiposity along with age is the strongest determinant of baseline CRP levels in healthy subjects. The mechanism of the association of serum CRP with disease is uncertain. We hypothesized that baseline serum CRP is a marker of inflammatory responsiveness to injury and that abdominal adiposity is the main determinant of this responsiveness. We studied the effect of abdominal adiposity, age and other environmental risk factors for chronic disease on the CRP response to a standardised surgical insult, unilateral hernia repair to not only test this hypothesis but to inform the factors which must be taken into account when assessing systemic inflammatory responses to surgery. Methods 102 male subjects aged 24-94 underwent unilateral hernia repair by a single operator. CRP was measured at 0, 6, 24 and 48 hrs. Response was defined as the peak CRP adjusted for baseline CRP. Results Age and waist:hip ratio (WHR) were associated both with basal CRP and CRP response with similar effect sizes after adjustment for a wide-range of covariates. The adjusted proportional difference in CRP response per 10% increase in WHR was 1.50 (1.17-1.91) p = 0.0014 and 1.15(1.00-1.31) p = 0.05 per decade increase in age. There was no evidence of important effects of other environmental cardiovascular risk factors on CRP response. Conclusion Waist:hip ratio and age need to be considered when studying the inflammatory response to surgery. The finding that age and waist:hip ratio influence baseline and post-operative CRP levels to a similar extent suggests that baseline CRP is a measure of inflammatory responsiveness to casual stimuli and that higher age and obesity modulate the generic excitability of the inflammatory system leading to both higher baseline CRP and higher CRP response to surgery. The mechanism for the association of baseline CRP and waist:hip ratio to chronic disease outcomes could be through this increase in inflammatory system excitability. PMID:23391158

Exacerbated immune stress response during experimental magnesium deficiency results from abnormal cell calcium homeostasis.

PubMed

Malpuech-Brugère, C; Rock, E; Astier, C; Nowacki, W; Mazur, A; Rayssiguier, Y

1998-01-01

The aim of this study was to assess the potential mechanism underlying the enhanced inflammatory processes during magnesium deficit. In this study, exacerbated response to live bacteria and platelet activating factors was shown in rats fed a magnesium-deficient diet. Peritoneal cells from these animals also showed enhanced superoxide anion production and calcium mobilising potency following in vitro stimulation. The latter effect occurred very early in the course of magnesium deficiency. These studies first showed that an abnormal calcium handling induced by extracellular magnesium depression in vivo may be at the origin of exacerbated inflammatory response.

Bone marrow-derived macrophages from aged rats are more responsive to inflammatory stimuli.

PubMed

Barrett, James P; Costello, Derek A; O'Sullivan, Joan; Cowley, Thelma R; Lynch, Marina A

2015-04-09

Lipopolysaccharide (LPS) and interferon-γ (IFNγ) increase expression of tumour necrosis factor-α (TNFα) that characterizes the M1 activation state of macrophages. Whereas it is accepted that the immune system undergoes changes with age, there is inconsistency in the literature with respect to the impact of age on the response of macrophages to inflammatory stimuli. Here, we investigate the effect of age on the responsiveness of bone marrow-derived macrophages (BMDMs) to LPS and IFNγ. The context for addressing this question is that macrophages, which infiltrate the brain of aged animals, will encounter the neuroinflammatory environment that has been described with age. Brain tissue, prepared from young and aged rats, was assessed for expression of inflammatory markers by PCR and for evidence of infiltration of macrophages by flow cytometry. BMDMs were prepared from the long bones of young and aged rats, maintained in culture for 8 days and incubated in the presence or absence of LPS (100 ng/ml) or IFNγ (50 ng/ml). Cells were harvested and assessed for mRNA expression of markers of M1 activation including TNFα and NOS2, or for expression of IFNγR1 and TLR4 by western immunoblotting. To assess whether BMDMs induced glial activation, mixed glial cultures were incubated in the presence of conditioned media obtained from unstimulated BMDMs of young and aged rats and evaluated for expression of inflammatory markers. Markers associated with M1 activation were expressed to a greater extent in BMDMs from aged rats in response to LPS and IFNγ, compared with cells from young rats. The increased responsiveness was associated with increases in IFNγ receptor (IFNγR) and Toll-like receptor 4 (TLR4). The data show that conditioned media from BMDMs of aged rats increased the expression of pro-inflammatory mediators in glial cells. Significantly, there was an age-related increase in macrophage infiltration into the brain, and this was combined with increased expression of IFNγ and the Toll-like receptor 4 agonist, high-mobility group protein B1 (HMGB1). Exposure of infiltrating macrophages to the inflammatory microenvironment that develops in the brain with age is likely to contribute to a damaging cascade that negatively impacts neuronal function.

Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection

PubMed Central

2012-01-01

Background During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO) play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. Methods To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs), macrophages, CD4+ T and regulatory T cells (Treg) were assessed by FACS. Results Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Conclusions Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses. PMID:22873687

Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection.

PubMed

Feng, Yonghui; Zhu, Xiaotong; Wang, Qinghui; Jiang, Yongjun; Shang, Hong; Cui, Liwang; Cao, Yaming

2012-08-08

During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO) play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs), macrophages, CD4+ T and regulatory T cells (Treg) were assessed by FACS. Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses.

Association between social isolation and inflammatory markers in depressed and non-depressed individuals: results from the MONICA/KORA study.

PubMed

Häfner, S; Emeny, R T; Lacruz, M E; Baumert, J; Herder, C; Koenig, W; Thorand, B; Ladwig, K H

2011-11-01

Depressed individuals not only suffer from chronic low grade inflammation, but also exhibit an inflammatory hyper-responsiveness to acute stress. We investigate whether chronic stress also induces an exaggerated inflammatory response in individuals with increased depression features. As model for chronic stress, social isolation was chosen. Interleukin (IL)-6 and hs-CRP levels were assessed in 1547 subjects (847 men and 700 women), derived from the population-based MONICA/KORA study. Standardized questionnaires were used to assess depressed mood (depression and exhaustion subscale) and social isolation (social network index). The relationship between the two inflammatory markers, social isolation and depressed mood was examined taking into account interactions social isolation × depressed mood using multivariable linear regression models, adjusted for age, BMI, smoking, alcohol, and physical activity. Analyses were performed in men and women separately. We observed a significant interaction between depressed mood and social isolation regarding IL-6 and hs-CRP, respectively in men (p-value=0.02 for IL-6 and <0.01 for hs-CRP), evidencing a substantial synergistic effect of social isolation, and depressed mood on inflammatory responses. Furthermore, depressed and socially isolated men had highly significantly elevated IL-6 levels (geometric mean: 3.76 vs. 1.92 pg/ml, p-value <0.01) and heightened hs-CRP levels (geometric mean: 2.01 vs. 1.39 mg/l, p=0.08) in comparison with non-depressed and socially integrated men. In women, no significant associations were seen. The interaction of depressed mood and social isolation elicits a substantial synergistic impact on inflammatory markers in men, but not in depressed women. Copyright © 2011 Elsevier Inc. All rights reserved.

Inhaled corticosteroids do not influence the early inflammatory response and clinical presentation of hospitalized subjects with COPD exacerbation.

PubMed

Crisafulli, Ernesto; Guerrero, Mónica; Menéndez, Rosario; Huerta, Arturo; Martinez, Raquel; Gimeno, Alexandra; Soler, Néstor; Torres, Antoni

2014-10-01

Inhaled corticosteroids are anti-inflammatory medications that can down-regulate the immunologic response in patients with COPD; however, their role at onset of COPD exacerbation is still not understood. The aim of this study was to assess the early inflammatory response and clinical presentation of patients with COPD exacerbation mediated by inhaled corticosteroids. Prospective data were collected on 123 hospitalized subjects with COPD exacerbation over a 30-month period at 2 Spanish university hospitals. Based on domiciliary use, comparative analyses were performed between subjects who did not use inhaled corticosteroids (n = 58) and subjects who did (n = 65). Measurements of serum biomarkers were recorded on admission to the hospital (day 1) and on day 3; clinical, physiological, microbiological, and severity data and mortality/readmission rates were also recorded. At days 1 and 3, both groups showed a similar inflammatory response; fluticasone produced lower levels of interleukin-8 compared with budesonide (P < .01). All clinical features considered were similar in the 2 groups; multivariate analysis predicting clinical complications on hospitalization showed air-flow obstruction severity as the only predictive factor (odds ratio 3.13, 95% CI 1.13-8.63, P = .02). Our study demonstrates a lack of inhaled corticosteroid influence in the early systemic inflammatory response to and clinical presentation of COPD exacerbation. Copyright © 2014 by Daedalus Enterprises.

Analysis of G-Protein Coupled Receptor 30 (GPR30) on Endothelial Inflammation.

PubMed

Chakrabarti, Subhadeep; Davidge, Sandra T

2016-01-01

The female sex hormone estrogen (the most common form 17-β-estradiol or E2) is known to have both anti-inflammatory and pro-inflammatory effects. Given the diversity of estrogen responses mediated through its three distinct receptors, namely, estrogen receptor α (ERα), ERβ, and the G-protein coupled receptor 30 (GPR30), it is plausible that different receptors have specific modulatory effects on inflammation in different tissues. We have shown that activation of GPR30 exerted anti-inflammatory effects as demonstrated by significant attenuation of tumor necrosis factor (TNF)-mediated upregulation of adhesion molecules in isolated human umbilical vein endothelial cells. Interestingly, estrogen alone had no such effect and blockade of classical ERs restored the anti-inflammatory effect, suggesting that this effect was dependent on GPR30 and opposed to classical ERs. These findings were further validated by the negation of anti-inflammatory GPR30 effects by classical ER agonists. This chapter focuses on multiple pharmacological options to activate GPR30 and the use of TNF activated endothelial cells as a model system for inflammatory response as assessed by adhesion molecule detection through western blotting.

Stress-Induced Inflammatory Responses in Women: Effects of Race and Pregnancy

PubMed Central

Christian, Lisa M.; Glaser, Ronald; Porter, Kyle; Iams, Jay D.

2013-01-01

Objective African Americans experience preterm birth at nearly twice the rate of Whites. Chronic stress associated with minority status is implicated in this disparity. Inflammation is a key biological pathway by which stress may affect birth outcomes. This study examined effects of race and pregnancy on stress-induced inflammatory responses. Methods Thirty-nine women in the 2nd trimester of pregnancy (19 African American; 20 White) and 39 demographically similar nonpregnant women completed an acute stressor (Trier Social Stress Test). Psychosocial characteristics, health behaviors, and affective responses were assessed. Serum interleukin(IL)-6 was measured via high sensitivity ELISA at baseline, 45 minutes, and 120 minutes post-stressor. Results IL-6 responses at 120 minutes post-stressor were 46% higher in African Americans versus Whites (95%CI:8%-81%; t(72)=3.51, p=.001). This effect was present in pregnancy and nonpregnancy. IL-6 responses at 120 minutes post-stressor tended to be lower (15%) in pregnant versus nonpregnant women (95%CI:-5%-32%; p=0.14). Racial differences in inflammatory responses were not accounted for by demographics, psychological characteristics, health behaviors, or differences in salivary cortisol across the study session. Pregnant Whites showed lower negative affective responses than nonpregnant women of either race (ps≤.007). Conclusion This study provides novel evidence that stress-induced inflammatory responses are more robust among African American women versus Whites during pregnancy and nonpregnancy. The ultimate impact of stress on health is a function of stressor exposure and physiological responses. Individual differences in stress-induced inflammatory responses represent a clear target for continued research efforts in racial disparities in health during pregnancy and nonpregnancy. PMID:23873713

Inflammatory Cytokines as Preclinical Markers of Adverse Responses to Chemical Stressors

EPA Science Inventory

Abstract: The in vivo cytokine response to chemical stressors is a promising mainstream tool used to assess potential systemic inflammation and immune function changes. Notably, new instrumentation and statistical analysis provide the selectivity and sensitivity to rapidly diff...

Therapeutic effect of cortistatin on experimental arthritis by downregulating inflammatory and Th1 responses.

PubMed

Gonzalez-Rey, Elena; Chorny, Alejo; Del Moral, Raimundo G; Varela, Nieves; Delgado, Mario

2007-05-01

Rheumatoid arthritis is a chronic autoimmune disease of unknown aetiology characterised by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. To propose a new strategy for the treatment of arthritis based on the administration of cortistatin, a newly discovered neuropeptide with anti-inflammatory actions. DBA/1J mice with collagen-induced arthritis were treated with cortistatin after the onset of disease, and the clinical score and joint histopathology were evaluated. Inflammatory response was determined by measuring the levels of various inflammatory mediators (cytokines and chemokines) in joints and serum. T helper cell type 1 (Th1)-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with collagen and by assaying the content of serum autoantibodies. Cortistatin treatment significantly reduced the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of cortistatin was associated with a striking reduction in the two deleterious components of the disease-that is, the Th1-driven autoimmune and inflammatory responses. Cortistatin downregulated the production of various inflammatory cytokines and chemokines, decreased the antigen-specific Th1-cell expansion, and induced the production of regulatory cytokines, such as interleukin 10 and transforming growth factor beta1. Cortistatin exerted its effects on synovial cells through both somatostatin and ghrelin receptors, showing a higher effect than both peptides protecting against experimental arthritis. This work provides a powerful rationale for the assessment of the efficacy of cortistatin as a novel therapeutic approach to the treatment of rheumatoid arthritis.

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction.

PubMed

Nishikido, Toshiyuki; Oyama, Jun-ichi; Shiraki, Aya; Komoda, Hiroshi; Node, Koichi

2016-04-04

An excessive inflammatory response after myocardial infarction (MI) increases myocardial injury. The toll-like receptor (TLR)-4 is activated by the recognition of endogenous ligands and is proinflammatory when there is myocardial tissue injury. The apoptosis inhibitor of the macrophage (AIM) is known to provoke an efflux of saturated free fatty acids (FFA) due to lipolysis, which causes inflammation via the TLR-4 pathway. Therefore, this study investigated the hypothesis that AIM causes a proinflammatory response after MI. The left anterior descending coronary artery was ligated to induce MI in both AIM-knockout (AIM(-/-)) and wild-type (WT) mice. After 3 days, the inflammatory response from activation of the TLR-4/NFκB pathway was assessed, and infarct size was measured by staining with triphenyltetrazolium chloride. In addition, left ventricular remodeling was examined after 28 days. Although the area at risk was similar between AIM(-/-) and WT mice, the infarct size was significantly smaller in AIM(-/-) mice (P=0.02). The heart weight-to-body weight ratio and myocardial fibrosis were also decreased in the AIM(-/-) mice, and the 28-day survival rate was improved (P<0.01). With the reduction of plasma FFA in AIM(-/-) mice, myocardial IRAK4 and NFκB activity were decreased (all P<0.05). Moreover, there was a reduction in myeloperoxidase activity and inducible nitric oxide synthase as part of the inflammatory response (P<0.01, P=0.03, respectively). Furthermore, NFκB DNA-binding activation via TLR-4, neutrophil infiltration, and inflammatory mediators were decreased in AIM(-/-) mice. The deletion of AIM reduced the inflammatory response and infarct size and improved survival after myocardial infarction. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis.

PubMed

Gangell, Catherine; Gard, Samantha; Douglas, Tonia; Park, Judy; de Klerk, Nicholas; Keil, Tony; Brennan, Siobhain; Ranganathan, Sarath; Robins-Browne, Roy; Sly, Peter D

2011-09-01

We hypothesized that the inflammatory response in the lungs of children with cystic fibrosis (CF) would vary with the type of infecting organism, being greatest with Pseudomonas aeruginosa and Staphylococcus aureus. A microbiological surveillance program based on annual bronchoalveolar lavage (BAL) collected fluid for culture and assessment of inflammation was conducted. Primary analyses compared inflammation in samples that grew a single organism with uninfected samples in cross-sectional and longitudinal analyses. Results were available for 653 samples from 215 children with CF aged 24 days to 7 years. A single agent was associated with pulmonary infection (≥10(5) cfu/mL) in 67 BAL samples, with P. aeruginosa (n = 25), S. aureus (n = 17), and Aspergillus species (n = 19) being the most common. These microorganisms were associated with increased levels of inflammation, with P. aeruginosa being the most proinflammatory. Mixed oral flora (MOF) alone was isolated from 165 BAL samples from 112 patients, with 97 of these samples having a bacterial density ≥10(5) cfu/mL, and was associated with increased pulmonary inflammation (P < .001). For patients with current, but not past, infections there was an association with a greater inflammatory response, compared with those who were never infected (P < .05). However, previous infection with S. aureus was associated with a greater inflammatory response in subsequent BAL. Pulmonary infection with P. aeruginosa, S. aureus, or Aspergillus species and growth of MOF was associated with significant inflammatory responses in young children with CF. Our data support the use of specific surveillance and eradication programs for these organisms. The inflammatory response to MOF requires additional investigation.

Tobacco and e-cigarette products initiate Kupffer cell inflammatory responses.

PubMed

Rubenstein, David A; Hom, Sarah; Ghebrehiwet, Berhane; Yin, Wei

2015-10-01

Kupffer cells are liver resident macrophages that are responsible for screening and clearing blood of pathogens and foreign particles. It has recently been shown that Kupffer cells interact with platelets, through an adhesion based mechanism, to aid in pathogen clearance and then these platelets re-enter the general systemic circulation. Thus, a mechanism has been identified that relates liver inflammation to possible changes in the systemic circulation. However, the role that Kupffer cells play in cardiovascular disease initiation/progression has not been elucidated. Thus, our objective was to determine whether or not Kupffer cells are responsive to a classical cardiovascular risk factor and if these changes can be transmitted into the general systemic circulation. If Kupffer cells initiate inflammatory responses after exposure to classical cardiovascular risk factors, then this provides a potential alternative/synergistic pathway for cardiovascular disease initiation. We aimed to elucidate the prevalence of this potential pathway. We hypothesized that Kupffer cells would initiate a robust inflammatory response after exposure to tobacco cigarette or e-cigarette products and that the inflammatory response would have the potential to antagonize other salient cells for cardiovascular disease progression. To test this, Kupffer cells were incubated with tobacco smoke extracts, e-cigarette vapor extracts or pure nicotine. Complement deposition onto Kupffer cells, Kupffer cell complement receptor expression, oxidative stress production, cytokine release and viability and density were assessed after the exposure. We observed a robust inflammatory response, oxidative stress production and cytokine release after Kupffer cells were exposed to tobacco or e-cigarette extracts. We also observed a marginal decrease in cell viability coupled with a significant decrease in cell density. In general, this was not a function of the extract formulation (e.g. tobacco vs. e-cigarette products or the formulation of the cigarette product). These results indicate that Kupffer cells are responsive to classical cardiovascular risk factors and that an inflammatory response is initiated that may pass into the general systemic circulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of short-term weight loss on mental stress-induced cardiovascular and pro-inflammatory responses in women.

PubMed

Endrighi, Romano; Hamer, Mark; Hackett, Ruth A; Carvalho, Livia A; Jackson, Sarah E; Wardle, Jane; Steptoe, Andrew

2015-01-01

Epidemiologic evidence links psychosocial stress with obesity but experimental studies examining the mechanisms that mediates the effect of stress on adiposity are scarce. The aim of this study was to investigate whether changes in adiposity following minimal weight loss affect heightened stress responses in women, and examine the role of the adipokine leptin in driving inflammatory responses. Twenty-three overweight or obese, but otherwise healthy, women (M age = 30.41 ± 8.0 years; BMI = 31.9 ± 4.1 kg/m(2)) completed standardized acute mental stress before and after a 9-week calorie restriction program designed to modify adiposity levels. Cardiovascular (blood pressure and heart rate) and inflammatory cytokines (leptin and interleukin-6; IL-6) responses to mental stress were assessed several times between baseline and a 45-min post-stress recovery period. There were modest changes in adiposity measures while the adipokine leptin was markedly reduced (-27%) after the intervention. Blood pressure reactivity was attenuated (-3.38 ± 1.39 mmHg) and heart rate recovery was improved (2.07 ± 0.96 Bpm) after weight loss. Blood pressure responses were inversely associated with changes in waist to hip ratio post intervention. Decreased levels of circulating leptin following weight loss were inversely associated with the IL-6 inflammatory response to stress (r = -0.47). We offered preliminary evidence suggesting that modest changes in adiposity following a brief caloric restriction program may yield beneficial effect on cardiovascular stress responses. In addition, reductions in basal leptin activity might be important in blunting pro-inflammatory responses. Large randomized trials of the effect of adiposity on autonomic responses are thus warranted.

Violet/blue light activates Nrf2 signaling and modulates the inflammatory response of THP-1 monocytes.

PubMed

Trotter, L A; Patel, D; Dubin, S; Guerra, C; McCloud, V; Lockwood, P; Messer, R; Wataha, J C; Lewis, J B

2017-06-14

Several studies suggest that light in the UVA range (320-400 nm) activates signaling pathways that are anti-inflammatory and antioxidative. These effects have been attributed to Nrf2-mediated upregulation of "phase 2" genes such as heme oxygenase-1 (HO-1) that neutralize oxidative stress and metabolize electrophiles. Proteomics analysis previously had shown that small doses of blue light (400-500 nm) increased levels of peroxiredoxin phase 2 proteins in THP-1 monocytes, which led to our hypothesis that blue light activates Nrf2 signaling and thus may serve as an anti-inflammatory agent. THP-1 monocytes were treated with doses of blue light with and without lipopolysaccharide (LPS) inflammatory challenge. Cell lysates were tested for Nrf2 activation and HO-1 production. Treated cells were assessed for viability/mitochondrial activity via trypan blue exclusion and MTT assay, and secretion of two major pro-inflammatory cytokines, interleukin 8 (IL8) and tumor necrosis factor alpha (TNFα) was measured using ELISA. Blue light activated the phase 2 response in cultured THP-1 cells and was protective against LPS-induced cytotoxicity. Light pre-treatment also significantly reduced cytokine secretion in response to 0.1 μg ml -1 LPS, but had no anti-inflammatory effect at high LPS levels. This study is the first to report these effects using a light source that is approved for routine use on dental patients. Cellular responses to these light energies are worth further study and may provide therapeutic interventions for inflammation.

Role of S100A1 in hypoxia-induced inflammatory response in cardiomyocytes via TLR4/ROS/NF-κB pathway.

PubMed

Yu, Jiangkun; Lu, Yanyu; Li, Yapeng; Xiao, Lili; Xing, Yu; Li, Yanshen; Wu, Leiming

2015-09-01

S100A1 plays a crucial role in hypoxia-induced inflammatory response in cardiomyocytes. However, the role of S100A1 in hypoxia-induced inflammatory response in cardiomyocytes is still unknown. enzyme-linked immunosorbent assay (ELISA) was performed for the determination of inflammatory cytokines. Immunocytochemistry and immunofluorescence, Western blot analysis and Real-time polymerase chain reaction (RT-PCR) were conducted to assess protein or mRNA expressions. Fluorogenic probe dihydroethidium (DHE) was used to evaluate the generation of reactive oxygen species (ROS) while Hoechst 33342 staining for apoptosis. Small interfering RNA (siRNA) for S100A1 was used to evaluate the role of S100A1. The levels of ROS and inflammatory cytokine including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and IL-8 in H9c2 cells were increased remarkably by hypoxia. However, IL-37 protein or mRNA levels were decreased significantly. Both Toll-like receptor 4 (TLR4) inhibitor Ethyl (6R)-6-[N-(2-Chloro-4fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242) treatment or siRNA S100A1 downregulated TLR4 expression and inflammatory cytokine level and mRNA in H9c2 cells, as well as weakening ROS and phospho-p65 Nuclear factor (NF)-κB levels. Further, S100A1 treatment significantly reduced TNF-α protein or mRNA level whereas enhanced IL-37 protein or mRNA level, and could attenuate ROS and phospho-p65 NF-κB levels. Our results demonstrate that S100A1 can regulate the inflammatory response and oxidative stress in H9C2 cells via TLR4/ROS/NF-κB pathway. These findings provide an interesting strategy for protecting cardiomyocytes from hypoxia-induced inflammatory response. © 2015 Royal Pharmaceutical Society.

Bifidobacterium breve prevents necrotising enterocolitis by suppressing inflammatory responses in a preterm rat model.

PubMed

Satoh, T; Izumi, H; Iwabuchi, N; Odamaki, T; Namba, K; Abe, F; Xiao, J Z

2016-02-01

Necrotising enterocolitis (NEC) is associated with inflammatory responses and barrier dysfunction in the gut. In this study, we investigated the effect of Bifidobacterium breve M-16V on factors related to NEC development using an experimental rat model. Caesarean-sectioned rats were given formula milk with or without B. breve M-16V by oral gavage thrice daily, and experimental NEC was induced by exposing the rats to hypoxic conditions. Naturally delivered rats that were reared by their mother were used as healthy controls. The pathological score of NEC and the expression of molecules related to inflammatory responses and the barrier function were assessed in the ileum. B. breve M-16V reduced the pathological scores of NEC and resulted in some improvement in survivability. B. breve M-16V suppressed the increased expression of molecules related to inflammation and barrier function that resulted from NEC induction. B. breve M-16V normalised Toll-like receptor (TRL)4 expression and enhanced TLR2 expression. Our data suggest that B. breve M-16V prevents NEC development by modulating TLR expressions and suppressing inflammatory responses in a rat model.

Mononuclear cells in the corneal response to endotoxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Howes, E.L.; Cruse, V.K.; Kwok, M.T.

A severe keratitis can be produced after the direct injection of bacterial endotoxin, or lipopolysaccharide (LPS), in rabbits. Corneal inflammation can progress to scarring and vascularization within a 2 to 3 week period. Pretreatment with systemic adrenal corticosteroids (triamcinolone) prevents this response. Limbal cellular and vascular events were studied during the first 20 hr after injection of LPS in treated and nontreated rabbits. Perivascular limbal inflammatory cells were counted and limbal vascular permeability was assessed by extravasation of 131I-albumin and 125I-fibrinogen in the cornea. Corticosteroids decreased but did not prevent the early protein extravasation and profoundly altered the inflammatory cellmore » population around blood vessels at the limbus. Mononuclear cells, particularly mononuclear phagocytes, were sharply reduced. It is proposed that these cell types play an important role in the perpetuation and amplification of the inflammatory response in this reaction.« less

The Effects of Low Dose Irradiation on Inflammatory Response Proteins in a 3D Reconstituted Human Skin Tissue Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Varnum, Susan M.; Springer, David L.; Chaffee, Mary E.

Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis, and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low dose radiation (<10 cGy) is poorly understood. In order to address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDerm FT) and assessed changes in 23 cytokines twenty-four and forty eight hours following treatment of skin with either 3 or 10 cGy low-dose of radiation. Three cytokines, IFN-γ, IL-2, MIP-1α, weremore » significantly altered in response to low dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-γ, MIP-1α, TNF α, and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1α, IL-8, MIP-1α, MIP-1β, RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the non-radiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels following exposure to low dose radiation and this response is a sub-set of what is seen following a high dose in a human skin tissue model.« less

Anti-inflammatory, analgesic, and antipyretic activities of virgin coconut oil.

PubMed

Intahphuak, S; Khonsung, P; Panthong, A

2010-02-01

This study investigated some pharmacological properties of virgin coconut oil (VCO), the natural pure oil from coconut [Cocos nucifera Linn (Palmae)] milk, which was prepared without using chemical or high-heat treatment. The anti-inflammatory, analgesic, and antipyretic effects of VCO were assessed. In acute inflammatory models, VCO showed moderate anti-inflammatory effects on ethyl phenylpropiolate-induced ear edema in rats, and carrageenin- and arachidonic acid-induced paw edema. VCO exhibited an inhibitory effect on chronic inflammation by reducing the transudative weight, granuloma formation, and serum alkaline phosphatase activity. VCO also showed a moderate analgesic effect on the acetic acid-induced writhing response as well as an antipyretic effect in yeast-induced hyperthermia. The results obtained suggest anti-inflammatory, analgesic, and antipyretic properties of VCO.

BID Mediates Oxygen-Glucose Deprivation-Induced Neuronal Injury in Organotypic Hippocampal Slice Cultures and Modulates Tissue Inflammation in a Transient Focal Cerebral Ischemia Model without Changing Lesion Volume

PubMed Central

Martin, Nellie Anne; Bonner, Helena; Elkjær, Maria Louise; D’Orsi, Beatrice; Chen, Gang; König, Hans Georg; Svensson, Martina; Deierborg, Tomas; Pfeiffer, Shona; Prehn, Jochen H.; Lambertsen, Kate Lykke

2016-01-01

The BH3 interacting-domain death agonist (BID) is a pro-apoptotic protein involved in death receptor-induced and mitochondria-mediated apoptosis. Recently, it has also been suggested that BID is involved in the regulation of inflammatory responses in the central nervous system. We found that BID deficiency protected organotypic hippocampal slice cultures in vitro from neuronal injury induced by oxygen-glucose deprivation. In vivo, BID-knockout (KO) mice and wild type (WT) mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO) to induce focal cerebral ischemia, and allowed to recover for 24 h. Infarct volumes and functional outcome were assessed and the inflammatory response was evaluated using immunofluorescence, Western blotting, quantitative PCR (qPCR) and Mesoscale multiplex analysis. We observed no difference in the infarct volume or neurological outcome between BID-KO and WT mice. The inflammatory response was reduced by BID deficiency as indicated by a change in microglial/leukocyte response. In conclusion, our data suggest that BID deficiency is neuroprotective in an in vitro model and modulates the inflammatory response to focal cerebral ischemia in vivo. However, this is not translated into a robust neuroprotection in vivo. PMID:26869884

Wound repair in rat urinary bladder following electrocautery or holmium laser incision

NASA Astrophysics Data System (ADS)

Venzi, Giordano; Schmidlin, Franz R.; Gabbiani, Giulio; Delacretaz, Guy P.; Pittet, Brigitte; Leisinger, Hans-Juerg; Iselin, Christoph E.

1999-06-01

Woundhealing is a complex phenomenon which varies according the type of tissue but is also depending from the type of tissue injury. Electrocautery mainly induces coagulation necrosis while thermal damages induced by the Holmium laser primarily lead to tissue vaporization which may induce less tissue injury. The aim of this study was to evaluate the healing process of the Holmium laser induced lesions compared to electrocautery induced lesions in urothelial tissue by assessing the inflammatory response and myofibroblast behavior in sequential healing phases. A surgical wound was created in the urinary rat bladder of 32 rats either by electrocautery or by laser (N=16). The inflammatory response, the total lesion depth and the myofibroblast activity during woundhealing was then analyzed on a qualitative basis on days 0/2/4/8. The overall inflammatory response was comparable in both groups up to days two and four. However, at day eight less cellular inflammatory reaction and less myofibroblast activity was found in the specimen of lesions created by the Holmium laser. These results suggest that wound repair may be a less invasive process after Holmium laser than electrocautery.

Defining the neurotoxin derived illness chronic ciguatera using markers of chronic systemic inflammatory disturbances: a case/control study.

PubMed

Shoemaker, Ritchie C; House, Dennis; Ryan, James C

2010-01-01

Ciguatoxins are extremely potent neurotoxins, produced by tropical marine dinoflagellates, that persistently enter into our food web. Over 100,000 people annually experience acute ciguatera poisoning from consuming toxic fish. Roughly 5% of these victims will develop chronic ciguatera (CC), a widespread, multisymptom, multisystem, chronic illness that can last tens of years. CC is marked by disproportionate disability and non-specific refractory symptoms such as fatigue, cognitive deficits and pain, and is suggestive of other illnesses. Its unknown pathophysiology makes both diagnosis and treatment difficult. We wanted to compare objective parameters of visual contrast sensitivity testing, measures of innate immune response and genetic markers in cases to controls to assess the potential for the presence of persistent inflammatory parameters that are demonstrated in other biotoxin associated illnesses at a single specialty clinic. Using 59 CC cases and 59 controls we present in retrospective review, in all cases, abnormalities in immune responses paralleling the chronic systemic inflammatory response syndrome seen in several other chronic diseases. This study defines a preliminary case definition using medical history, total symptoms, visual contrast sensitivity, HLA DR genotype analysis, reduction of regulatory neuropeptides VIP and MSH, and multiple measures of inflammatory immune response, especially C4a and TGFβ1, thereby providing a basis for identification and targeted therapy. CC provides a model for chronic human illness associated with initiation of inflammatory responses by biologically produced neurotoxins. Copyright © 2010 Elsevier Inc. All rights reserved.

Effect of thoracic epidural block on infection-induced inflammatory response: A randomized controlled trial.

PubMed

Tyagi, Asha; Bansal, Anuradha; Das, Shukla; Sethi, Ashok Kumar; Kakkar, Aanchal

2017-04-01

Epidural block decreases inflammation and oxidative stress in experimental models of sepsis as well as after surgery. There is, however, no clinical evidence evaluating its effect on infection-induced inflammatory process. The present trial evaluated the effect of thoracic epidural block (TEB) on systemic inflammatory response in patients with small intestinal perforation peritonitis. Outcome measures included systemic levels of interleukin (IL)-6, IL-10, procalcitonin, and C-reactive protein and postoperative Sepsis-Related Organ Failure Assessment scores. Sixty adult patients undergoing emergency abdominal laparotomy without any contraindication to TEB were randomized to receive general anesthesia alone or in combination with the TEB, which was continued for 48 hours postoperatively (n = 30 each). Use of TEB was associated with a statistically insignificant trend of preservation of anti-inflammatory response depicted by higher levels of IL-10 and lack of alteration in proinflammatory IL-6, along with appreciably lower procalcitonin levels, decreased incidence of raised C-reactive protein levels, and better postoperative SOFA score (P > .05). It resulted in significantly better postoperative respiratory function and faster return of bowel motility (P < .05). Although the sample size is too small for conclusive statement, none of the patients developed epidural abscess. Thoracic epidural block showed a trend toward better preservation of anti-inflammatory response and clinical recovery that, however, failed to achieve statistical significance (P > .05). Copyright © 2016 Elsevier Inc. All rights reserved.

Fatigue and gene expression in human leukocytes: Increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue

PubMed Central

Bower, Julienne E.; Ganz, Patricia A.; Irwin, Michael R.; Arevalo, Jesusa M.G.; Cole, Steve W.

2013-01-01

Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n = 11) and non-fatigued controls (n = 10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p < .05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors. PMID:20854893

DOE Office of Scientific and Technical Information (OSTI.GOV)

Husain, Mainul, E-mail: mainul.husain@hc-sc.gc.ca; Kyjovska, Zdenka O., E-mail: zky@nrcwe.dk; Bourdon-Lacombe, Julie, E-mail: julie.bourdon-lacombe@hc-sc.gc.ca

Inhalation of carbon black nanoparticles (CBNPs) causes pulmonary inflammation; however, time course data to evaluate the detailed evolution of lung inflammatory responses are lacking. Here we establish a time-series of lung inflammatory response to CBNPs. Female C57BL/6 mice were intratracheally instilled with 162 μg CBNPs alongside vehicle controls. Lung tissues were examined 3 h, and 1, 2, 3, 4, 5, 14, and 42 days (d) post-exposure. Global gene expression and pulmonary inflammation were assessed. DNA damage was evaluated in bronchoalveolar lavage (BAL) cells and lung tissue using the comet assay. Increased neutrophil influx was observed at all time-points. DNA strandmore » breaks were increased in BAL cells 3 h post-exposure, and in lung tissues 2–5 d post-exposure. Approximately 2600 genes were differentially expressed (± 1.5 fold; p ≤ 0.05) across all time-points in the lungs of exposed mice. Altered transcript levels were associated with immune-inflammatory response and acute phase response pathways, consistent with the BAL profiles and expression changes found in common respiratory infectious diseases. Genes involved in DNA repair, apoptosis, cell cycle regulation, and muscle contraction were also differentially expressed. Gene expression changes associated with inflammatory response followed a biphasic pattern, with initial changes at 3 h post-exposure declining to base-levels by 3 d, increasing again at 14 d, and then persisting to 42 d post-exposure. Thus, this single CBNP exposure that was equivalent to nine 8-h working days at the current Danish occupational exposure limit induced biphasic inflammatory response in gene expression that lasted until 42 d post-exposure, raising concern over the chronic effects of CBNP exposure. - Highlights: • A single exposure to CBNPs induced expression changes in over 2600 genes in mouse lungs. • Altered genes were associated with immune-inflammatory and acute phase responses. • Several genes were involved in DNA repair, apoptosis, and muscle contraction. • Effects of a single exposure to CBNPs lasted until 42 d post-exposure. • A single exposure to CBNPs induced a biphasic inflammatory response in gene expression.« less

Epigallocatechin-3-gallate attenuates lipopolysaccharide-induced mastitis in rats via suppressing MAPK mediated inflammatory responses and oxidative stress.

PubMed

Chen, Jinglou; Xu, Jun; Li, Jingjing; Du, Lifen; Chen, Tao; Liu, Ping; Peng, Sisi; Wang, Mingwei; Song, Hongping

2015-05-01

Green tea (Camellia sinensis) is an extremely popular beverage worldwide. Epigallocatechin-3-gallate (EGCG) is one of the major catechins isolated from green tea and contributes to its beneficial therapeutic functions including antioxidant, anti-inflammatory and anti-cancer effects. However, the effect of EGCG on mastitis is not yet known. This study was to investigate the protective potential of EGCG against mastitis in rats. The rat mastitis model was induced by injecting lipopolysaccharide (LPS) into the duct of mammary gland. The mammary gland was collected after the experimental period. The levels of mammary oxidative stress and inflammatory responses were assessed by measuring the local activities of antioxidant enzymes and the levels of inflammatory cytokines. The mammary expressions of mitogen-activated protein kinases (MAPKs), nuclear factor κB-p65 (NFκB-p65) and hypoxia-inducible factor-1α (HIF-1α) were evaluated by western blot analysis. It was found that EGCG obviously normalized LPS-induced low activities of antioxidant enzymes as well as decreased the high levels of inflammatory cytokines. Additionally, EGCG inhibited the mammary over-expression of MAPKs, NFκB-p65 and HIF-1α. These results indicated that EGCG was able to attenuate LPS-induced mastitis in rats by suppressing MAPK related oxidative stress and inflammatory responses. Copyright © 2015 Elsevier B.V. All rights reserved.

Neuro-inflammatory response in rats chronically exposed to (137)Cesium.

PubMed

Lestaevel, Philippe; Grandcolas, Line; Paquet, François; Voisin, Philippe; Aigueperse, Jocelyne; Gourmelon, Patrick

2008-03-01

After the Chernobyl nuclear accident, behavioural disorders and central nervous system diseases were frequently observed in populations living in the areas contaminated by (137)Cs. Until now, these neurological disturbances were not elucidated, but the presence of a neuro-inflammatory response could be one explanation. Rats were exposed for 3 months to drinking water contaminated with (137)Cs at a dose of 400Bqkg(-1), which is similar to that ingested by the population living in contaminated areas in the former USSR countries. Pro-inflammatory and anti-inflammatory cytokine genes were assessed by real-time PCR in the frontal cortex and the hippocampus. At this level of exposure, gene expression of TNF-alpha and IL-6 increased in the hippocampus and gene expression of IL-10 increased in the frontal cortex. Concentration of TNF-alpha, measured by ELISA assays, was also increased in the hippocampus. The central NO-ergic pathway was also studied: iNOS gene expression and cNOS activity were significantly increased in the hippocampus. In conclusion, this study showed for the first time that sub-chronic exposure with post-accidental doses of (137)Cs leads to molecular modifications of pro- and anti-inflammatory cytokines and NO-ergic pathway in the brain. This neuro-inflammatory response could contribute to the electrophysiological and biochemical alterations observed after chronic exposure to (137)Cs.

Nonesterified fatty acids modify inflammatory response and eicosanoid biosynthesis in bovine endothelial cells.

PubMed

Contreras, G A; Raphael, W; Mattmiller, S A; Gandy, J; Sordillo, L M

2012-09-01

Intense lipid mobilization during the transition period in dairy cows is associated with increased disease susceptibility. The potential impact of altered plasma nonesterified fatty acids (NEFA) concentrations and composition on host inflammatory responses that may contribute to disease incidence and severity are not known. The objective of this study was to evaluate if increased NEFA concentrations could modify vascular inflammatory responses in vitro by changing the expression of important inflammatory mediators that are important in the pathogenesis of infectious diseases of transition cows such as mastitis and metritis. Bovine aortic endothelial cells (BAEC) were cultured with different concentrations of a NEFA mixture that reflected the plasma NEFA composition during different stages of lactation. The expression of cytokines, adhesion molecules, and eicosanoids were measured to assess changes in BAEC inflammatory phenotype. Addition of NEFA mixtures altered the fatty acid profile of BAEC by increasing the concentration of stearic acid (C18:0) and decreasing the content of arachidonic acid (C20:4n6c) and other long-chain polyunsaturated fatty acids in the phospholipid fraction. A significant increase also occurred in mRNA expression of cytokine and adhesion molecules that are associated with increased inflammatory responses during the transition period. Expression of cyclooxygenase 2, an important enzyme associated with eicosanoid biosynthesis, was increased in a NEFA concentration-dependent manner. The production of linoleic acid-derived eicosanoids 9- and 13-hydroxyoctadecadienoic acids also was increased significantly after treatment with NEFA mixtures. This research described for the first time specific changes in vascular inflammatory response during in vitro exposure to NEFA mixtures that mimic the composition and concentration found in cows during the transition period. These findings could explain, in part, alterations in inflammatory responses observed during intense lipid mobilization stages such as in the transition period of dairy cows. Future studies should analyze specific mechanisms by which high NEFA concentrations induce a vascular proinflammatory phenotype including the effect of 9 and 13-hydroxyoctadecadienoic acids and other lipid mediators. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression.

PubMed

Li, Yong; Pan, Yiyuan; Gao, Lin; Lu, Guotao; Zhang, Jingzhu; Xie, Xiaochun; Tong, Zhihui; Li, Baiqiang; Li, Gang; Li, Weiqin

2018-01-22

Previous studies have shown that acute inflammation is associated with increased sympathetic activity, which in turn increases the inflammatory response and leads to organ damage. The present study aimed to investigate whether dexmedetomidine administration during acute pancreatitis (AP) lessens pancreatic pathological and functional injury and the inflammatory response, and to explore the underlying mechanisms. Mild pancreatitis was induced in mice with caerulein, and severe pancreatitis was induced with caerulein plus lipopolysaccharide (LPS). After pancreatitis induction, dexmedetomidine at 10 or 20 μg/kg was injected via the tail vein. Pancreatic pathological and functional injury was assessed by histology and serum levels of amylase and lipase, respectively. The inflammatory response was evaluated by determining serum levels of inflammatory factors. The expression of myeloperoxidase (MPO) was examined by immunohistochemistry. The expression of norepinephrine transporter (NET), NLRP3, pro-IL-1β, and interleukin (IL)-1β in pancreatic tissue was detected by Western blot and real-time PCR. Dexmedetomidine at 20 μg/kg significantly attenuated pancreatic pathological injury, reduced serum levels of amylase, lipase, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, and decreased the expression of MPO in pancreatic tissue in both mouse models of pancreatitis. In addition, dexmedetomidine at 20 μg/kg significantly down-regulated the expression of NLRP3, pro-IL-1β, and IL-1β in pancreatic tissue, but up-regulated the expression of NET in both mouse models. Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis possibly by reducing NLRP3 activation and up-regulating NET expression. Copyright © 2018 Elsevier Inc. All rights reserved.

Particulate matter triggers depressive-like response associated with modulation of inflammatory cytokine homeostasis and brain-derived neurotrophic factor signaling pathway in mice.

PubMed

Liu, Xuemei; Qian, Xin; Xing, Jing; Wang, Jinhua; Sun, Yixuan; Wang, Qin'geng; Li, Huiming

2018-04-23

Particulate matter (PM) exposure may contribute to depressive-like response in mice. However, few studies have evaluated the adaptive impacts of long-term PM exposure on depressive-like response associated with systemic inflammation and brain-derived neurotrophic factor (BDNF) signaling pathway. We studied the association among depressive-like behaviors, mRNA levels of pro- and anti-inflammatory cytokines, and the expression of BDNF signaling pathway in mice by long-term PM exposure. C57BL/6 male mice were exposed to ambient air alongside control mice breathing air filtered through a high-efficiency air PM (HEPA) filter. Depressive-like behaviors were assessed together with pro-inflammatory, anti-inflammatory cytokine mRNA levels and the modulation of BDNF pathway in hippocampus and olfactory-bulb of mice exposed to PM for 4, 8, and 12 weeks. Exposure to HEPA filtered air for 4 weeks may exert antidepressant like effects in mice. Pro-inflammatory cytokines were up-regulated while the expression of BDNF, its high-affinity receptor tropomyosin-related kinase B (TrkB), and the transcription factor cAMP-response-element binding protein (CREB) were down-regulated in ambient air mice. However, after 8 weeks, there was no significant difference in the rate of depressive-like behaviors between the two groups. After 12 weeks, mice exposed to ambient air again had a higher rate of depressive-like behaviors, significant up-regulation of pro-inflammatory cytokines, down-regulation of interleukin-10 (IL-10), BDNF, TrkB, and CREB than HEPA mice. Ultrafine PM in brain tissues of mice exposed to ambient air was observed. Our results suggest continuous high-level PM exposure alters the depressive-like response in mice and induces a damage-repair-imbalance reaction.

In vivo modulation of foreign body response on polyurethane by surface entrapment technique.

PubMed

Khandwekar, Anand P; Patil, Deepak P; Hardikar, Anand A; Shouche, Yogesh S; Doble, Mukesh

2010-11-01

Implanted polymeric materials, such as medical devices, provoke the body to initiate an inflammatory reaction, known as the foreign body response (FBR), which causes several complications. In this study, polyurethane (Tecoflex®, PU) surface modified with the nonionic surfactant Tween80® (PU/T80) and the cell adhesive PLL-RGD peptide (PU/PLL-RGD) by a previously described entrapment technique were implanted in the peritoneal cavity of Wistar rats for 30 days. Implants were retrieved and examined for tissue reactivity and cellular adherence by various microscopic and analytical techniques. Surface-induced inflammatory response was assessed by real-time PCR based quantification of proinflammatory cytokine transcripts, namely, TNF-α and IL-1β, normalized to housekeeping gene GAPDH. Cellular adherence and their distribution profile were assessed by microscopic examination of H&E stained implant sections. It was observed that PU/PLL-RGD followed by the bare PU surface exhibited severe inflammatory and fibrotic response with an average mean thickness of 19 and 12 μm, respectively, in 30 days. In contrast, PU/T80 surface showed only a cellular monolayer of 2-3 μm in thickness, with a mild inflammatory response and no fibrotic encapsulation. The PU/PLL-RGD peptide-modified substrate promoted an enhanced rate of macrophage cell fusion to form foreign body giant cell (FBGCs), whereas FBGCs were rarely observed on Tween80®-modified substrate. The expression levels of proinflammatory cytokines (TNF-α and IL-1β) were upregulated on PU/PLL-RGD surface followed by bare PU, whereas the cytokine expressions were significantly suppressed on PU/T80 surface. Thus, our study highlights modulation of foreign body response on polyurethane surfaces through surface entrapment technique in the form of differential responses observed on PLL-RGD and Tween80® modified surfaces with the former effective in triggering tissue cell adhesion thereby fibrous encapsulation, while the later being mostly resistant to this phenomenon.

Uncaria tomentosa (cat's claw) improves quality of life in patients with advanced solid tumors.

PubMed

de Paula, Larissa Carvalho Lopes; Fonseca, Fernando; Perazzo, Fabio; Cruz, Felipe Melo; Cubero, Daniel; Trufelli, Damila Cristina; Martins, Suelen Patrícia Dos Santos; Santi, Patrícia Xavier; da Silva, Eliana Araújo; Del Giglio, Auro

2015-01-01

Cat's claw (Uncaria tomentosa) is a native Amazon plant that exhibits anti-inflammatory and antitumor properties. We wanted to assess its activity for symptom management of terminal cancer patients. This prospective phase II study assessed the effects of a 100-mg dose of a dry extract of U. tomentosa three times per day in patients with advanced solid tumors who had no further therapeutic options and a life expectancy of at least 2 months. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) and Functional Assessment of Chronic Illness Therapy - Fatigue questionnaires were used to assess the participants' quality of life, the Hospital Anxiety and Depression Scale questionnaire was used to assess anxiety and depression, and the Pittsburgh Sleep Quality Index was used to assess sleep quality. In addition, several biochemical and inflammatory parameters were analyzed. Fifty-one volunteers were recruited. Their median age was 64 (range, 33-85) years, and 47% of patients were female. More than 65% of patients had scores on the Karnofsky Performance Scale of 80% or less. Treatment improved the patients' overall quality of life (p=0.0411) and social functioning (p=0.0341), as assessed by the EORTC QLQ C-30, and reduced fatigue (p=0.0496) according to the Chalder Fatigue Questionnaire. None of the biochemical or inflammatory parameters assessed (interleukin-1 and -6, C-reactive protein, tumor necrosis factor-α, erythrocyte sedimentation rate, and α-1-acid glycoprotein) changed significantly. No tumor response was detected according to the Response Evaluation Criteria In Solid Tumors; however, the disease stabilized for more than 8 months in four participants. The medication was well tolerated by most patients. Use of cat's claw might be beneficial in patients with advanced cancer by improving their quality of life and reducing fatigue. The mechanism of action does not seem to be related to the anti-inflammatory properties of this plant.

Acute exercise boosts cell proliferation and the heat shock response in lymphocytes: correlation with cytokine production and extracellular-to-intracellular HSP70 ratio.

PubMed

Heck, Thiago Gomes; Scomazzon, Sofia Pizzato; Nunes, Patrícia Renck; Schöler, Cinthia Maria; da Silva, Gustavo Stumpf; Bittencourt, Aline; Faccioni-Heuser, Maria Cristina; Krause, Mauricio; Bazotte, Roberto Barbosa; Curi, Rui; Homem de Bittencourt, Paulo Ivo

2017-03-01

Exercise stimulates immune responses, but the appropriate "doses" for such achievements are unsettled. Conversely, in metabolic tissues, exercise improves the heat shock (HS) response, a universal cytoprotective response to proteostasis challenges that are centred on the expression of the 70-kDa family of intracellular heat shock proteins (iHSP70), which are anti-inflammatory. Concurrently, exercise triggers the export of HSP70 towards the extracellular milieu (eHSP70), where they work as pro-inflammatory cytokines. As the HS response is severely compromised in chronic degenerative diseases of inflammatory nature, we wondered whether acute exercise bouts of different intensities could alter the HS response of lymphocytes from secondary lymphoid organs and whether this would be related to immunoinflammatory responses. Adult male Wistar rats swam for 20 min at low, moderate, high or strenuous intensities as per an overload in tail base. Controls remained at rest under the same conditions. Afterwards, mesenteric lymph node lymphocytes were assessed for the potency of the HS response (42 °C for 2 h), NF-κB binding activity, mitogen-stimulated proliferation and cytokine production. Exercise stimulated cell proliferation in an "inverted-U" fashion peaking at moderate load, which was paralleled by suppression of NF-κB activation and nuclear location, and followed by enhanced HS response in relation to non-exercised animals. Comparative levels of eHSP70 to iHSP70 (H-index) matched IL-2/IL-10 ratios. We conclude that exercise, in a workload-dependent way, stimulates immunoinflammatory performance of lymphocytes of tissues far from the circulation and this is associated with H-index of stress response, which is useful to assess training status and immunosurveillance balance.

Bovine Intestinal Alkaline Phosphatase Reduces Inflammation After Induction of Acute Myocardial Infarction in Mice.

PubMed

Fiechter, Danielle; Kats, Suzanne; Brands, Ruud; van Middelaar, Ben; Pasterkamp, Gerard; de Kleijn, Dominique; Seinen, Willem

2011-10-01

There has been increasing evidence suggesting that lipopolysaccharide or endotoxin may be an important activator of the innate immune system after acute myocardial infarction. Bovine intestinal alkaline phosphatase reduces inflammation in several endotoxin mediated diseases by dephosphorylation of the lipid A moiety of lipopolysaccharide. The aim of this study was to investigate the effect of bovine intestinal alkaline phosphatase on reducing inflammation after acute myocardial infarction. Just before permanent ligation of the left anterior descending coronary (LAD) artery to induce acute myocardial infarction in Balb/c mice, bovine intestinal alkaline phosphatase (bIAP) was administrated intravenously. After 4 hours, mice were sacrificed and the inflammatory response was assessed. Acute myocardial infarction induced the production of different cytokines, which were measured in blood. Treatment with bovine intestinal alkaline phosphatase resulted in a significant reduction of the pro-inflammatory cytokines IL-6, IL-1β and the chymase mouse mast cell protease-1. No difference in the production of the anti-inflammatory cytokine IL-10 was observed between the control group and the bovine intestinal alkaline phosphatase treated group. In a mouse model of permanent LAD coronary artery ligation, bIAP diminishes the pro-inflammatory responses but does not have an effect on the anti-inflammatory response in the acute phase after acute myocardial infarction.

Pseudolaric acid B attenuates atherosclerosis progression and inflammation by suppressing PPARγ-mediated NF-κB activation.

PubMed

Li, Tan; Wang, Wei; Li, Yu-Xiu; Li, Xiao; Ji, Wen-Jie; Ma, Yong-Qiang; Chen, Hong; Zhao, Ji-Hong; Zhou, Xin

2018-06-01

Atherosclerosis is a progressive disease of large arteries characterized with chronic inflammation and aberrant immune response. Pseudolaric acid B (PB) has been found to exert multiple effects by inhibiting inflammatory response. However, there is no comprehensive assessment of the effects of PB on atherosclerosis using relevant in vivo and in vitro models. Male ApoE -/- mice were treated with PB orally with a high fat diet (HFD) to clarify its anti-atherosclerotic activities. RAW264.7 macrophage line, a well-accepted cell model of atherosclerosis, was used to investigate anti-inflammatory effects and molecular mechanisms of PB. PB significantly attenuated atherosclerotic lesions by modulating plasma lipid profiles as well as inhibiting inflammatory responses in macrophages of atherosclerotic mice. Meanwhile, PB markedly suppressed the expression of pro-inflammatory cytokines, and regulated cholesterol efflux related genes in oxidative low density lipoprotein (ox-LDL)-loaded macrophages. The cellular uptake of Dil-labeled ox-LDL was significantly inhibited by PB either. Moreover, the ability of PB to suppress nuclear factor kappa B (NF-κB) and activate peroxisome proliferator-activated receptor gamma (PPARγ) was confirmed using luciferase reporter assays. Conversely, the selective PPARγ antagonist GW9662 reversed the influence of PB in macrophages. Together, these findings indicate that PB exerts its protective effects on atherosclerosis by inhibiting macrophage-mediated inflammatory response and cellular ox-LDL uptake, and promoting cholesterol efflux by suppressing NF-κB activation PPARγ-dependently. Therefore, PB may be a promising agent for inflammatory and atherosclerotic diseases. Copyright © 2018. Published by Elsevier B.V.

Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis

PubMed Central

2014-01-01

Introduction Post-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture. The pro-inflammatory cytokines, interleukin 1(IL-1) and tumor necrosis factor alpha (TNF-α), are acutely elevated following joint injury and remain elevated for prolonged periods post-injury. To investigate the role of local and systemic inflammation in the development of post-traumatic arthritis, we targeted both the initial acute local inflammatory response and a prolonged 4 week systemic inflammatory response by inhibiting IL-1 or TNF-α following articular fracture in the mouse knee. Methods Anti-cytokine agents, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor II (sTNFRII), were administered either locally via an acute intra-articular injection or systemically for a prolonged 4 week period following articular fracture of the knee in C57BL/6 mice. The severity of arthritis was then assessed at 8 weeks post-injury in joint tissues via histology and micro computed tomography, and systemic and local biomarkers were assessed in serum and synovial fluid. Results Intra-articular inhibition of IL-1 significantly reduced cartilage degeneration, synovial inflammation, and did not alter bone morphology following articular fracture. However, systemic inhibition of IL-1, and local or systemic inhibition of TNF provided no benefit or conversely led to increased arthritic changes in the joint tissues. Conclusion These results show that intra-articular IL-1, rather than TNF-α, plays a critical role in the acute inflammatory phase of joint injury and can be inhibited locally to reduce post-traumatic arthritis following a closed articular fracture. Targeted local inhibition of IL-1 following joint injury may represent a novel treatment option for PTA. PMID:24964765

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease.

PubMed

Giles, E M; Sanders, T J; McCarthy, N E; Lung, J; Pathak, M; MacDonald, T T; Lindsay, J O; Stagg, A J

2017-01-01

Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNβ in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non-inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNβ selectively reduced T-cell production of the pro-regulatory cytokine interleukin-10 (IL-10) and increased IFNγ synthesis. In contrast, neutralization of IFNβ in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease.

Histological quantification of brain tissue inflammatory cell infiltration after focal cerebral infarction: a systematic review.

PubMed

Russek, Natanya S; Jensen, Matthew B

2014-03-01

Ischemic stroke is a leading cause of death and disability, and current treatments to limit tissue injury and improve recovery are limited. Cerebral infarction is accompanied by intense brain tissue inflammation involving many inflammatory cell types that may cause both negative and positive effects on outcomes. Many potential neuroprotective and neurorestorative treatments may affect, and be affected by, this inflammatory cell infiltration, so that accurate quantification of this tissue response is needed. We performed a systematic review of histological methods to quantify brain tissue inflammatory cell infiltration after cerebral infarction. We found reports of multiple techniques to quantify different inflammatory cell types. We found no direct comparison studies and conclude that more research is needed to optimize the assessment of this important stroke outcome.

Peficitinib, an Oral Janus Kinase Inhibitor, in Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2 Study.

PubMed

Sands, Bruce E; Sandborn, William J; Feagan, Brian G; Lichtenstein, Gary R; Zhang, Hongyan; Strauss, Richard; Szapary, Philippe; Johanns, Jewel; Panes, Julian; Vermeire, Severine; O'Brien, Christopher D; Yang, Zijiang; Bertelsen, Kirk; Marano, Colleen

2018-06-15

Janus kinase (JAK) inhibitors have shown efficacy in ulcerative colitis (UC). We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC. In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25mg once daily (qd), 75mg qd, 150mg qd, and 75mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8 with response assessed using Mayo score change from baseline. Secondary endpoints were clinical response, clinical remission, mucosal healing, change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ), and normalization of inflammatory biomarkers at Week 8; other secondary endpoints were treatment response through Week 16 and through Week 32 for patients in clinical response at Week 8. Safety was assessed through Week 36 or 4 weeks after the last dose. A statistically significant peficitinib dose-response was not demonstrated at Week 8, although a numerically greater proportion of patients receiving peficitinib ≥75mg qd achieved clinical response, remission, and mucosal healing at Week 8, supported by IBDQ improvement and inflammatory biomarker normalization. Treatment-emergent adverse event (TEAE) rates reported through Week 8 and the final safety visit were higher in the combined peficitinib group than placebo; patients receiving doses of ≥75mg qd peficitinib reported TEAEs more frequently. While no dose-response in patients with moderate-to-severe UC was demonstrated with peficitinib, evidence of efficacy was suggested at doses ≥75mg qd. The safety profile of peficitinib was consistent with current information. ClinicalTrials.gov NCT01959282.

The Role of Regulatory T Cell in Nontypeable Haemophilus influenzae-Induced Acute Exacerbation of Chronic Obstructive Pulmonary Disease

PubMed Central

Guan, Xuewa; Lu, Yanjiao; Wang, Guoqiang; Fang, Keyong; Wang, Ziyan; Pang, Zhiqiang; Guo, Yingqiao; Lu, Junying; Yuan, Yuze; Ran, Nan

2018-01-01

Chronic obstructive pulmonary disease (COPD) is associated with irreversible persistent airflow limitation and enhanced inflammation. The episodes of acute exacerbation (AECOPD) largely depend on the colonized pathogens such as nontypeable Haemophilus influenzae (NTHi), one of the most commonly isolated bacteria. Regulatory T cells (Tregs) are critical in controlling inflammatory immune responses and maintaining tolerance; however, their role in AECOPD is poorly understood. In this study, we hypothesized a regulatory role of Tregs, as NTHi participated in the progress of COPD. Immunological pathogenesis was investigated in a murine COPD model induced by cigarette smoke (CS). NTHi was administrated through intratracheal instillation for an acute exacerbation. Weight loss and lung function decline were observed in smoke-exposed mice. Mice in experimental groups exhibited serious inflammatory responses via histological and cytokine assessment. Expression levels of Tregs and Th17 cells with specific cytokines TGF-β1 and IL-17 were detected to assess the balance of pro-/anti-inflammatory influence partially. Our findings suggested an anti-inflammatory activity of Tregs in CS-induced model. But this activity was suppressed after NTHi administration. Collectively, these data suggested that NTHi might play a necessary role in downregulating Foxp3 to impair the function of Tregs, helping development into AECOPD. PMID:29725272

21 CFR 862.3080 - Breath nitric oxide test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... fractional nitric oxide concentration in expired breath aids in evaluating an asthma patient's response to anti-inflammatory therapy, as an adjunct to established clinical and laboratory assessments of asthma...

Hepatocyte growth factor modulates interleukin-6 production in bone marrow derived macrophages: implications for inflammatory mediated diseases.

PubMed

Coudriet, Gina M; He, Jing; Trucco, Massimo; Mars, Wendy M; Piganelli, Jon D

2010-11-02

The generation of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β fuel the acute phase response (APR). To maintain body homeostasis, the increase of inflammatory proteins is resolved by acute phase proteins via presently unknown mechanisms. Hepatocyte growth factor (HGF) is transcribed in response to IL-6. Since IL-6 production promotes the generation of HGF and induces the APR, we posited that accumulating HGF might be a likely candidate for quelling excess inflammation under non-pathological conditions. We sought to assess the role of HGF and how it influences the regulation of inflammation utilizing a well-defined model of inflammatory activation, lipopolysaccharide (LPS)-stimulation of bone marrow derived macrophages (BMM). BMM were isolated from C57BL6 mice and were stimulated with LPS in the presence or absence of HGF. When HGF was present, there was a decrease in production of the pro-inflammatory cytokine IL-6, along with an increase in the anti-inflammatory cytokine IL-10. Altered cytokine production correlated with an increase in phosphorylated GSK3β, increased retention of the phosphorylated NFκB p65 subunit in the cytoplasm, and an enhanced interaction between CBP and phospho-CREB. These changes were a direct result of signaling through the HGF receptor, MET, as effects were reversed in the presence of a selective inhibitor of MET (SU11274) or when using BMM from macrophage-specific conditional MET knockout mice. Combined, these data provide compelling evidence that under normal circumstances, HGF acts to suppress the inflammatory response.

Predictive Validity of Sepsis-3 Definitions and Sepsis Outcomes in Critically Ill Patients: A Cohort Study in 49 ICUs in Argentina.

PubMed

Estenssoro, Elisa; Kanoore Edul, Vanina S; Loudet, Cecilia I; Osatnik, Javier; Ríos, Fernando G; Vázquez, Daniela N; Pozo, Mario O; Lattanzio, Bernardo; Pálizas, Fernando; Klein, Francisco; Piezny, Damián; Rubatto Birri, Paolo N; Tuhay, Graciela; Díaz, Anatilde; Santamaría, Analía; Zakalik, Graciela; Dubin, Arnaldo

2018-05-08

The new Sepsis-3 definitions have been scarcely assessed in low- and middle-income countries; besides, regional information of sepsis outcomes is sparse. Our objective was to evaluate Sepsis-3 definition performance in Argentina. Cohort study of 3-month duration beginning on July 1, 2016. Forty-nine ICUs. Consecutive patients admitted to the ICU with suspected infection that triggered blood cultures and antibiotic administration. None. Patients were classified as having infection, sepsis (infection + change in Sequential Organ Failure Assessment ≥ 2 points), and septic shock (vasopressors + lactate > 2 mmol/L). Patients on vasopressors and lactate less than or equal to 2 mmol/L (cardiovascular dysfunction) were analyzed separately, as those on vasopressors without serum lactate measurement. Systemic inflammatory response syndrome was also recorded. Main outcome was hospital mortality. Of 809 patients, 6% had infection, 29% sepsis, 20% cardiovascular dysfunction, 40% septic shock, and 3% received vasopressors with lactate unmeasured. Hospital mortality was 13%, 20%, 39%, 51%, and 41%, respectively (p = 0.000). Independent predictors of outcome were lactate, Sequential Organ Failure Assessment score, comorbidities, prior duration of symptoms (hr), mechanical ventilation requirement, and infection by highly resistant microorganisms. Area under the receiver operating characteristic curves for mortality for systemic inflammatory response syndrome and Sequential Organ Failure Assessment were 0.53 (0.48-0.55) and 0.74 (0.69-0.77), respectively (p = 0.000). Increasing severity of Sepsis-3 categories adequately tracks mortality; cardiovascular dysfunction subgroup, not included in Sepsis-3, has distinct characteristics. Sequential Organ Failure Assessment score shows adequate prognosis accuracy-contrary to systemic inflammatory response syndrome. This study supports the predictive validity of Sepsis-3 definitions.

Assessing NLRP3 Inflammasome Activation by Nanoparticles.

PubMed

Sharma, Bhawna; McLeland, Christopher B; Potter, Timothy M; Stern, Stephan T; Adiseshaiah, Pavan P

2018-01-01

NLRP3 inflammasome activation is one of the initial steps in an inflammatory cascade against pathogen/danger-associated molecular patterns (PAMPs/DAMPs), such as those arising from environmental toxins or nanoparticles, and is essential for innate immune response. NLRP3 inflammasome activation in cells can lead to the release of IL-1β cytokine via caspase-1, which is required for inflammatory-induced programmed cell death (pyroptosis). Nanoparticles are commonly used as vaccine adjuvants and drug delivery vehicles to improve the efficacy and reduce the toxicity of chemotherapeutic agents. Several studies indicate that different nanoparticles (e.g., liposomes, polymer-based nanoparticles) can induce NLRP3 inflammasome activation. Generation of a pro-inflammatory response is beneficial for vaccine delivery to provide adaptive immunity, a necessary step for successful vaccination. However, similar immune responses for intravenously injected, drug-containing nanoparticles can result in immunotoxicity (e.g., silica nanoparticles). Evaluation of NLRP3-mediated inflammasome activation by nanoparticles may predict pro-inflammatory responses in order to determine if these effects may be mitigated for drug delivery or optimized for vaccine development. In this protocol, we outline steps to monitor the release of IL-1β using PMA-primed THP-1 cells, a human monocytic leukemia cell line, as a model system. IL-1β release is used as a marker of NLRP3 inflammasome activation.

Effect of the systemic inflammatory response, as provoked by elective orthopaedic surgery, on HbA1c.

PubMed

Chadburn, Andrew J; Garman, Elizabeth; Abbas, Raad; Modupe, Anu; Ford, Clare; Thomas, Osmond L; Chugh, Sanjiv; Deshpande, Shreeram; Gama, Rousseau

2017-07-01

Background In acutely ill patients with new onset hyperglycaemia, plasma glucose cannot reliably distinguish between stress hyperglycaemia and undiagnosed diabetes mellitus. We, therefore, investigated the diagnostic reliability of glycated haemoglobin (HbA1c) in acute illness by prospectively evaluating the effect of the systemic inflammatory response, as provoked by elective orthopaedic surgery, on HbA 1c . Methods HbA 1c and serum C-reactive protein concentrations were compared before and two days after elective knee or hip surgery in 30 patients without diabetes. C-reactive protein was used to assess the systemic inflammatory response. Results The mean (standard deviation) serum C-reactive protein increased following surgery (4.8 [7.5] vs. 179.7 [61.9] mg/L; P<0.0001). HbA 1c was similar before and after surgery (39.2 [5.4] vs. 38.1 [5.1] mmol/moL, respectively; P = 0.4363). Conclusions HbA 1c is unaffected within two days of a systemic inflammatory response as provoked by elective orthopaedic surgery. This suggests that HbA 1c may be able to differentiate newly presenting type 2 diabetes mellitus from stress hyperglycaemia in acutely ill patients with new onset hyperglycaemia.

Scaling of titanium implants entrains inflammation-induced osteolysis

PubMed Central

Eger, Michal; Sterer, Nir; Liron, Tamar; Kohavi, David; Gabet, Yankel

2017-01-01

With millions of new dental and orthopedic implants inserted annually, periprosthetic osteolysis becomes a major concern. In dentistry, peri-implantitis management includes cleaning using ultrasonic scaling. We examined whether ultrasonic scaling releases titanium particles and induces inflammation and osteolysis. Titanium discs with machined, sandblasted/acid-etched and sandblasted surfaces were subjected to ultrasonic scaling and we physically and chemically characterized the released particles. These particles induced a severe inflammatory response in macrophages and stimulated osteoclastogenesis. The number of released particles and their chemical composition and nanotopography had a significant effect on the inflammatory response. Sandblasted surfaces released the highest number of particles with the greatest nanoroughness properties. Particles from sandblasted/acid-etched discs induced a milder inflammatory response than those from sandblasted discs but a stronger inflammatory response than those from machined discs. Titanium particles were then embedded in fibrin membranes placed on mouse calvariae for 5 weeks. Using micro-CT, we observed that particles from sandblasted discs induced more osteolysis than those from sandblasted/acid-etched discs. In summary, ultrasonic scaling of titanium implants releases particles in a surface type-dependent manner and may aggravate peri-implantitis. Future studies should assess whether surface roughening affects the extent of released wear particles and aseptic loosening of orthopedic implants. PMID:28059080

Affective and inflammatory responses among orchestra musicians in performance situation.

PubMed

Pilger, Alexander; Haslacher, Helmuth; Ponocny-Seliger, Elisabeth; Perkmann, Thomas; Böhm, Karl; Budinsky, Alexandra; Girard, Angelika; Klien, Katharina; Jordakieva, Galateja; Pezawas, Lukas; Wagner, Oswald; Godnic-Cvar, Jasminka; Winker, Robert

2014-03-01

A number of studies have shown that mental challenge under controlled experimental conditions is associated with elevations in inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). However, relatively little work has been done on the effects of 'naturalistic' stressors on acute changes in inflammatory markers. The present study examined whether perceived arousal, valence and dominance in musicians are associated with pro-inflammatory and oxidative responses to a concert situation. Blood and salivary samples obtained from 48 members of a symphony orchestra on the day of rehearsal (i.e., control situation) and on the following day of premiere concert (i.e., test situation) were used to determine changes in salivary cortisol, pro-inflammatory markers (plasma myeloperoxidase, serum CRP, plasma IL-6), oxidative stress markers (paraoxonase1 activity and malondialdehyde), and homocysteine, a risk factor for vascular disease. Results of regression analyses showed a significant trend to increased myeloperoxidase (MPO) response in individuals with low valence score. Both affective states, valence and arousal, were identified as significant predictors of cortisol response during concert. In addition, control levels of plasma malondialdehyde were positively correlated with differences in IL-6 levels between premiere and rehearsal (r=.38, p=.012), pointing to higher oxidative stress in individuals with pronounced IL-6 response. Our results indicate that stress of public performance leads to increased concentrations of plasma MPO (20%), IL-6 (27%) and salivary cortisol (44%) in musicians. The decreasing effect of pleasantness on the MPO response was highly pronounced in non-smokers (r=-.60, p<.001), suggesting a significant role of emotional valence in stress-induced secretion of MPO. Additional studies are needed to assess the generalizability of these findings to other 'naturalistic' stress situations. Copyright © 2013 Elsevier Inc. All rights reserved.

Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue.

PubMed

Bower, Julienne E; Ganz, Patricia A; Irwin, Michael R; Arevalo, Jesusa M G; Cole, Steve W

2011-01-01

Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n=11) and non-fatigued controls (n=10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p<.05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors. Copyright © 2010 Elsevier Inc. All rights reserved.

Long-term inflammatory response to liquid injectable silicone, cartilage, and silicone sheet.

PubMed

Hizal, Evren; Buyuklu, Fuat; Ozdemir, B Handan; Erbek, Selim S

2014-11-01

To show and compare the long-term inflammatory responses to subdermal microdroplet injections of 1,000 centistoke (cS) and 5,000 cS liquid injectable silicone (LIS), and to assess the applicability of insulin pen as an alternative LIS delivery device in an animal model. Animal study. Eighteen healthy adult Sprague-Dawley rats were used. Two graft recipient sites and four injection sites were prepared on each rat's back for: 1) autogenous auricular cartilage graft; 2) silicone sheet; 3) 1,000 cS LIS injection with insulin syringe; 4) 1,000 cS LIS injection with insulin pen; 5) 5,000 cS LIS injection with insulin syringe; and 6) 5,000 cS LIS injection with insulin pen. The animals were followed up for 6 months, and skin biopsies were examined for the evaluation of LIS microdroplets in situ and the degree of inflammatory tissue response. Immunohistochemistry was used for the examination of macrophages and the density of microvessels. Biopsies from 17 animals were assessed. There was no statistically significant difference among the groups in terms of the number of lymphocytes (P = 0.081), macrophages (P = 0.857), and neutrophils (P = 0.995), the degree of vascular proliferation (P = 0.698), and the mean LIS microdroplet diameter (P = 0.540). Grossly, there was no sign of granuloma formation in any of the specimens. There is a low-grade, well-tolerated long-term inflammatory response to microdroplet injections of 1,000 cS and 5,000 cS LIS that is comparable to autogenous cartilage graft in rats. Standard dose delivery devices such as insulin pens can be used for controlled LIS injections. N/A. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

Faecal calprotectin assay after induction with anti-Tumour Necrosis Factor α agents in inflammatory bowel disease: Prediction of clinical response and mucosal healing at one year.

PubMed

Guidi, Luisa; Marzo, Manuela; Andrisani, Gianluca; Felice, Carla; Pugliese, Daniela; Mocci, Giammarco; Nardone, Olga; De Vitis, Italo; Papa, Alfredo; Rapaccini, Gianlodovico; Forni, Franca; Armuzzi, Alessandro

2014-11-01

Faecal calprotectin levels correlate with inflammation in inflammatory bowel disease. We evaluated the role of faecal calprotectin after anti-Tumour Necrosis Factor α induction in inflammatory bowel disease patients to predict therapeutic effect at one year. Faecal calprotectin levels were measured in stools of 63 patients before and after induction of anti-Tumour Necrosis Factor α therapy. Clinical activity, measured by clinical indices, was assessed before and after biologic treatment. Clinical responders after induction were included in the study and colonoscopy was performed before and after one year of treatment to assess mucosal healing. 63 patients (44 Crohn's disease, 19 ulcerative colitis) were prospectively included (41.2% males, mean age at diagnosis 33 years). A sustained clinical response during the first year was observed in 57% of patients; median faecal calprotectin was 106 μg/g after induction versus 308 μg/g pre-induction (p<0.0001). Post-induction faecal calprotectin was significantly lower in responders versus non-responders (p=0.0002). Post-induction faecal calprotectin had 83% sensitivity and 74% specificity (cut-off ≤ 168 μg/g) for predicting a sustained clinical response at one year (p=0.0001); also, sensitivity was 79% and specificity 57% (cut-off ≤ 121 μg/g) for predicting mucosal healing (p=0.0001). In inflammatory bowel disease faecal calprotectin assay after anti-Tumour Necrosis Factor α induction can be used as a marker to predict sustained clinical response and mucosal healing at one year. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Inflammation Caused by Praziquantel Treatment Depends on the Location of the Taenia solium Cysticercus in Porcine Neurocysticercosis

PubMed Central

Cangalaya, Carla; Zimic, Mirko; Marzal, Miguel; González, Armando E.; Guerra-Giraldez, Cristina; Mahanty, Siddhartha; Nash, Theodore E.; García, Hector H.

2015-01-01

Background Neurocysticercosis (NCC), infection of the central nervous system by Taenia solium cysticerci, is a pleomorphic disease. Inflammation around cysticerci is the major cause of disease but is variably present. One factor modulating the inflammatory responses may be the location and characteristics of the brain tissue adjacent to cysticerci. We analyzed and compared the inflammatory responses to cysticerci located in the parenchyma to those in the meninges or cysticerci partially in contact with both the parenchyma and the meninges (corticomeningeal). Methodology/Principal Findings Histological specimens of brain cysticerci (n = 196) from 11 pigs naturally infected with Taenia solium cysticerci were used. Four pigs were sacrificed after 2 days and four after 5 days of a single dose of praziquantel; 3 pigs did not receive treatment. All pigs were intravenously injected with Evans Blue to assess disruption of the blood-brain barrier. The degree of inflammation was estimated by use of a histological score (ISC) based on the extent of the inflammation in the pericystic areas as assessed in an image composed of several photomicrographs taken at 40X amplification. Parenchymal cysticerci provoked a significantly greater level of pericystic inflammation (higher ISC) after antiparasitic treatment compared to meningeal and corticomeningeal cysticerci. ISC of meningeal cysticerci was not significantly affected by treatment. In corticomeningeal cysticerci, the increase in ISC score was correlated to the extent of the cysticercus adjacent to the brain parenchyma. Disruption of the blood-brain barrier was associated with treatment only in parenchymal tissue. Significance Inflammatory response to cysticerci located in the meninges was significantly decreased compared to parenchymal cysticerci. The suboptimal inflammatory response to cysticidal drugs may be the reason subarachnoid NCC is generally refractory to treatment compared to parenchymal NCC. PMID:26658257

Inflammatory and Oxidative Responses Induced by Exposure to Commonly Used e-Cigarette Flavoring Chemicals and Flavored e-Liquids without Nicotine.

PubMed

Muthumalage, Thivanka; Prinz, Melanie; Ansah, Kwadwo O; Gerloff, Janice; Sundar, Isaac K; Rahman, Irfan

2017-01-01

Background: The respiratory health effects of inhalation exposure to e-cigarette flavoring chemicals are not well understood. We focused our study on the immuno-toxicological and the oxidative stress effects by these e-cigarette flavoring chemicals on two types of human monocytic cell lines, Mono Mac 6 (MM6) and U937. The potential to cause oxidative stress by these flavoring chemicals was assessed by measuring the production of reactive oxygen species (ROS). We hypothesized that the flavoring chemicals used in e-juices/e-liquids induce an inflammatory response, cellular toxicity, and ROS production. Methods: Two monocytic cell types, MM6 and U937 were exposed to commonly used e-cigarette flavoring chemicals; diacetyl, cinnamaldehyde, acetoin, pentanedione, o-vanillin, maltol and coumarin at different doses between 10 and 1,000 μM. Cell viability and the concentrations of the secreted inflammatory cytokine interleukin 8 (IL-8) were measured in the conditioned media. Cell-free ROS produced by these commonly used flavoring chemicals were also measured using a 2',7'dichlorofluorescein diacetate probe. These DCF fluorescence data were expressed as hydrogen peroxide (H 2 O 2 ) equivalents. Cytotoxicity due to the exposure to selected e-liquids was assessed by cell viability and the IL-8 inflammatory cytokine response in the conditioned media. Results: Treatment of the cells with flavoring chemicals and flavored e-liquid without nicotine caused cytotoxicity dose-dependently. The exposed monocytic cells secreted interleukin 8 (IL-8) chemokine in a dose-dependent manner compared to the unexposed cell groups depicting a biologically significant inflammatory response. The measurement of cell-free ROS by the flavoring chemicals and e-liquids showed significantly increased levels of H 2 O 2 equivalents in a dose-dependent manner compared to the control reagents. Mixing a variety of flavors resulted in greater cytotoxicity and cell-free ROS levels compared to the treatments with individual flavors, suggesting that mixing of multiple flavors of e-liquids are more harmful to the users. Conclusions: Our data suggest that the flavorings used in e-juices can trigger an inflammatory response in monocytes, mediated by ROS production, providing insights into potential pulmonary toxicity and tissue damage in e-cigarette users.

Inflammatory and Oxidative Responses Induced by Exposure to Commonly Used e-Cigarette Flavoring Chemicals and Flavored e-Liquids without Nicotine

PubMed Central

Muthumalage, Thivanka; Prinz, Melanie; Ansah, Kwadwo O.; Gerloff, Janice; Sundar, Isaac K.; Rahman, Irfan

2018-01-01

Background: The respiratory health effects of inhalation exposure to e-cigarette flavoring chemicals are not well understood. We focused our study on the immuno-toxicological and the oxidative stress effects by these e-cigarette flavoring chemicals on two types of human monocytic cell lines, Mono Mac 6 (MM6) and U937. The potential to cause oxidative stress by these flavoring chemicals was assessed by measuring the production of reactive oxygen species (ROS). We hypothesized that the flavoring chemicals used in e-juices/e-liquids induce an inflammatory response, cellular toxicity, and ROS production. Methods: Two monocytic cell types, MM6 and U937 were exposed to commonly used e-cigarette flavoring chemicals; diacetyl, cinnamaldehyde, acetoin, pentanedione, o-vanillin, maltol and coumarin at different doses between 10 and 1,000 μM. Cell viability and the concentrations of the secreted inflammatory cytokine interleukin 8 (IL-8) were measured in the conditioned media. Cell-free ROS produced by these commonly used flavoring chemicals were also measured using a 2′,7′dichlorofluorescein diacetate probe. These DCF fluorescence data were expressed as hydrogen peroxide (H2O2) equivalents. Cytotoxicity due to the exposure to selected e-liquids was assessed by cell viability and the IL-8 inflammatory cytokine response in the conditioned media. Results: Treatment of the cells with flavoring chemicals and flavored e-liquid without nicotine caused cytotoxicity dose-dependently. The exposed monocytic cells secreted interleukin 8 (IL-8) chemokine in a dose-dependent manner compared to the unexposed cell groups depicting a biologically significant inflammatory response. The measurement of cell-free ROS by the flavoring chemicals and e-liquids showed significantly increased levels of H2O2 equivalents in a dose-dependent manner compared to the control reagents. Mixing a variety of flavors resulted in greater cytotoxicity and cell-free ROS levels compared to the treatments with individual flavors, suggesting that mixing of multiple flavors of e-liquids are more harmful to the users. Conclusions: Our data suggest that the flavorings used in e-juices can trigger an inflammatory response in monocytes, mediated by ROS production, providing insights into potential pulmonary toxicity and tissue damage in e-cigarette users. PMID:29375399

The effect of manual acupuncture on blood neutrophil counts in moderate intensity exercise

NASA Astrophysics Data System (ADS)

Ciang, C. Y.; Simadibrata, C.; Tobing, A.; Srilestari, A.

2017-08-01

Exercise, even though it has a beneficial effect, can cause muscle damage and trigger inflammatory responses, as evidenced by increased neutrophils in the blood. Acupuncture is a therapeutic modality that is expected to reduce acute inflammatory responses due to exercise. Thirty untrained men were divided randomly into two groups. The manual acupuncture group (n = 15) received stimulation at acupoints ST36 and SP6 bilateral by needle insertion, while the placebo group (n = 15) received insertion of needles on plaster without penetrating the skin. Therapy was done once for 30 minutes immediately after the subjects completed the exercise. Blood neutrophil counts were assessed before exercise and one hour after exercise ended. The results show there is a statistically significant difference in the number of neutrophils before and after exercise between the manual acupuncture group and the placebo group (0.08±0.91 and 0.97±0.70 p = 0.006). Acupuncture therapy effectively mitigates the acute inflammatory response triggered by exercise.

Toxicity of boehmite nanoparticles: impact of the ultrafine fraction and of the agglomerates size on cytotoxicity and pro-inflammatory response.

PubMed

Forest, Valérie; Pailleux, Mélanie; Pourchez, Jérémie; Boudard, Delphine; Tomatis, Maura; Fubini, Bice; Sennour, Mohamed; Hochepied, Jean-François; Grosseau, Philippe; Cottier, Michèle

2014-08-01

Boehmite (γ-AlOOH) nanoparticles (NPs) are used in a wide range of industrial applications. However, little is known about their potential toxicity. This study aimed at a better understanding of the relationship between the physico-chemical properties of these NPs and their in vitro biological activity. After an extensive physico-chemical characterization, the cytotoxicity, pro-inflammatory response and oxidative stress induced by a bulk industrial powder and its ultrafine fraction were assessed using RAW264.7 macrophages. Although the bulk powder did not trigger a significant biological activity, pro-inflammatory response was highly enhanced with the ultrafine fraction. This observation was confirmed with boehmite NPs synthesized at the laboratory scale, with well-defined and tightly controlled physico-chemical features: toxicity was increased when NPs were dispersed. In conclusion, the agglomerates size of boehmite NPs has a major impact on their toxicity, highlighting the need to study not only raw industrial powders containing NPs but also the ultrafine fractions representative of respirable particles.

Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism.

PubMed

Kaseda, Ryohei; Tsuchida, Yohei; Yang, Hai-Chun; Yancey, Patricia G; Zhong, Jianyong; Tao, Huan; Bian, Aihua; Fogo, Agnes B; Linton, Mac Rae F; Fazio, Sergio; Ikizler, Talat Alp; Kon, Valentina

2018-01-27

Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDL CKD and HDL Cont , respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1β), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist. There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HD CKD was significantly less effective than HDL Cont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1-23.7] vs control (26.5% [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDL CKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1β, and NF-κB) versus HDL Cont . The heightened cytokine response to HDL CKD was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2. Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDL CKD . Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDL CKD . However, LXR agonism actually increases the pro-inflammatory effects of HDL CKD through activation of TLRs and ERK1/2 pathways.

Inflammatory and nutritional statuses of patients submitted to resection of gastrointestinal tumors.

PubMed

Fruchtenicht, Ana Valéria Gonçalves; Poziomyck, Aline Kirjner; Reis, Audrey Machado Dos; Galia, Carlos Roberto; Kabke, Georgia Brum; Moreira, Luis Fernando

2018-01-01

to evaluate the association between the nutritional and the inflammatory statuses of patients with cancer of the gastrointestinal tract undergoing surgical resection and to identify predictors of mortality in these patients. we conducted a prospective study of 41 patients with gastrointestinal tract cancer submitted to surgery between October 2012 and December 2014. We evaluated the nutritional status by subjective and objective methods. We assessed the inflammatory response and prognosis using the modified Glasgow Prognostic Score (mGPS), Neutrophil/Lymphocyte Ratio (NLR), Onodera Prognostic Nutritional Index (mPNI), Inflammatory-Nutritional Index (INI) and C-Reactive Protein/Albumin ratio (mPINI). half of the patients were malnourished and 27% were at nutritional risk. There was a positive association between the percentage of weight loss (%WL) and the markers NLR (p=0.047), mPINI (p=0.014) and INI (p=0.015). Serum albumin levels (p=0.015), INI (p=0.026) and mPINI (p=0.026) were significantly associated with the PG-SGA categories. On multivariate analysis, albumin was the only inflammatory marker independently related to death (p=0.004). inflammatory markers were significantly associated with malnutrition, demonstrating that the higher the inflammatory response, the worse the PG-SGA (B and C) scores and the higher the %WL in these patients. However, further studies aimed at improving surgical outcomes and determining the role of these markers as predictors of mortality are required.

Scavenger Receptor-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer's disease pathophysiology.

PubMed

Cornejo, Francisca; Vruwink, Marianne; Metz, Claudia; Muñoz, Paola; Salgado, Nicole; Poblete, Joaquín; Andrés, María Estela; Eugenín, Jaime; von Bernhardi, Rommy

2018-03-01

Late onset Alzheimer disease's (LOAD) main risk factor is aging. Although it is not well known which age-related factors are involved in its development, evidence points out to the involvement of an impaired amyloid-β (Aβ) clearance in the aged brain among possible causes. Glial cells are the main scavengers of the brain, where Scavenger Receptor class A (SR-A) emerges as a relevant player in AD because of its participation in Aβ uptake and in the modulation of glial cell inflammatory response. Here, we show that SR-A expression is reduced in the hippocampus of aged animals and APP/PS1 mice. Given that Aβ deposition increases in the aging brain, we generated a triple transgenic mouse, which accumulates Aβ and is knockout for SR-A (APP/PS1/SR-A -/- ) to evaluate Aβ accumulation and the inflammatory outcome of SR-A depletion in the aged brain. The lifespan of APP/PS1/SR-A -/- mice was greatly reduced, accompanied by a 3-fold increase in plasmatic pro-inflammatory cytokines, and reduced performance in a working memory behavioral assessment. Microglia and astrocytes lacking SR-A displayed impaired oxidative response and nitric oxide production, produced up to 7-fold more pro-inflammatory cytokines and showed a 12-fold reduction in anti-inflammatory cytokines release, with conspicuous changes in lipopolysaccharide-induced glial activation. Isolated microglia from young and adult mice lacking SR-A showed a 50% reduction in phagocytic activity. Our results indicate that reduced expression of SR-A can deregulate glial inflammatory response and potentiate Aβ accumulation, two mechanisms that could contribute to AD progression. Copyright © 2017 Elsevier Inc. All rights reserved.

Naringin attenuates diabetic retinopathy by inhibiting inflammation, oxidative stress and NF-κB activation in vivo and in vitro

PubMed Central

Liu, Lihua; Zuo, Zhongfu; Lu, Sijing; Liu, Aihua; Liu, Xuezheng

2017-01-01

Objective(s): Naringin, an essential flavonoid, inhibits inflammatory response and oxidative stress in diabetes. However, whether naringin has beneficial effects on diabetic retinopathy (DR) remains unknown. Materials and Methods: Streptozotocin (STZ, 65 mg/kg) was intraperitoneally injected into male rats (8 weeks old weighting 200-250 g) to establish diabetic model, then naringin (20, 40 or 80 mg/kg/day) was intraperitoneally injected into the diabetic rats for twelve weeks. Glial fibrillary acidic protein (GFAP) level, thickness of ganglion cell layer (GCL) and ganglion cell counts were assessed in diabetic retina in vivo. Naringin (50 μM) that significantly inhibited high glucose (HG, 25 mM)-induced cell proliferation was used to treat rat Muller cell line (rMC1) in vitro. Inflammatory response, oxidative stress and activation of nuclear factor kappa B (NF-κB) p65 were evaluated in retina in vivo and in rMC1 cells in vitro. Results: Naringin alleviated DR symptoms as evidenced by the increased retinal ganglion cells and decreased GFAP level in rat retina. Naringin exhibited anti-inflammatory and antioxidative effects as confirmed by the down-regulated pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and the up-regulated antioxidants, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in DR rats. Moreover, we found that naringin inhibited HG-induced proliferation, abnormal inflammatory response and oxidative stress in rMC1 cells. In addition, the enhanced nuclear translocation of NF-κB p65 in diabetic rat retina and HG-induced rMC1 cells was suppressed by naringin. Conclusion: Naringin attenuates inflammatory response, oxidative stress and NF-κB activation in experimental models of DR. PMID:28852447

Naringin attenuates diabetic retinopathy by inhibiting inflammation, oxidative stress and NF-κB activation in vivo and in vitro.

PubMed

Liu, Lihua; Zuo, Zhongfu; Lu, Sijing; Liu, Aihua; Liu, Xuezheng

2017-07-01

Naringin, an essential flavonoid, inhibits inflammatory response and oxidative stress in diabetes. However, whether naringin has beneficial effects on diabetic retinopathy (DR) remains unknown. Streptozotocin (STZ, 65 mg/kg) was intraperitoneally injected into male rats (8 weeks old weighting 200-250 g) to establish diabetic model, then naringin (20, 40 or 80 mg/kg/day) was intraperitoneally injected into the diabetic rats for twelve weeks. Glial fibrillary acidic protein (GFAP) level, thickness of ganglion cell layer (GCL) and ganglion cell counts were assessed in diabetic retina in vivo . Naringin (50 μM) that significantly inhibited high glucose (HG, 25 mM)-induced cell proliferation was used to treat rat Muller cell line (rMC1) in vitro . Inflammatory response, oxidative stress and activation of nuclear factor kappa B (NF-κB) p65 were evaluated in retina in vivo and in rMC1 cells in vitro . Naringin alleviated DR symptoms as evidenced by the increased retinal ganglion cells and decreased GFAP level in rat retina. Naringin exhibited anti-inflammatory and antioxidative effects as confirmed by the down-regulated pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and the up-regulated antioxidants, glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in DR rats. Moreover, we found that naringin inhibited HG-induced proliferation, abnormal inflammatory response and oxidative stress in rMC1 cells. In addition, the enhanced nuclear translocation of NF-κB p65 in diabetic rat retina and HG-induced rMC1 cells was suppressed by naringin. Naringin attenuates inflammatory response, oxidative stress and NF-κB activation in experimental models of DR.

Effects of simulated inflammation on the corrosion of 316L stainless steel.

PubMed

Brooks, Emily K; Brooks, Richard P; Ehrensberger, Mark T

2017-02-01

Stainless steel alloys, including 316L, find use in orthopaedics, commonly as fracture fixation devices. Invasive procedures involved in the placement of these devices will provoke a local inflammatory response that produces hydrogen peroxide (H 2 O 2 ) and an acidic environment surrounding the implant. This study assessed the influence of a simulated inflammatory response on the corrosion of 316L stainless steel. Samples were immersed in an electrolyte representing either normal or inflammatory physiological conditions. After 24h of exposure, electrochemical impedance spectroscopy (EIS) and inductively coupled plasma mass spectroscopy (ICPMS) were used to evaluate differences in corrosion behavior and ion release induced by the inflammatory conditions. Scanning electron microscopy (SEM) and energy-dispersive x-ray spectroscopy (EDX) were used to evaluate surface morphology and corrosion products formed on the sample surface. Inflammatory conditions, involving the presence of H 2 O 2 and an acidic pH, significantly alter the corrosion processes of 316L stainless steel, promoting aggressive and localized corrosion. It is demonstrated that particular consideration should be given to 316L stainless steel implants with crevice susceptible areas (ex. screw-head/plate interface), as those areas may have an increased probability of rapid and aggressive corrosion when exposed to inflammatory conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Bovine Intestinal Alkaline Phosphatase Reduces Inflammation After Induction of Acute Myocardial Infarction in Mice

PubMed Central

Fiechter, Danielle; Kats, Suzanne; Brands, Ruud; van Middelaar, Ben; Pasterkamp, Gerard; de Kleijn, Dominique; Seinen, Willem

2011-01-01

Background There has been increasing evidence suggesting that lipopolysaccharide or endotoxin may be an important activator of the innate immune system after acute myocardial infarction. Bovine intestinal alkaline phosphatase reduces inflammation in several endotoxin mediated diseases by dephosphorylation of the lipid A moiety of lipopolysaccharide. The aim of this study was to investigate the effect of bovine intestinal alkaline phosphatase on reducing inflammation after acute myocardial infarction. Methods Just before permanent ligation of the left anterior descending coronary (LAD) artery to induce acute myocardial infarction in Balb/c mice, bovine intestinal alkaline phosphatase (bIAP) was administrated intravenously. After 4 hours, mice were sacrificed and the inflammatory response was assessed. Acute myocardial infarction induced the production of different cytokines, which were measured in blood. Results Treatment with bovine intestinal alkaline phosphatase resulted in a significant reduction of the pro-inflammatory cytokines IL-6, IL-1β and the chymase mouse mast cell protease-1. No difference in the production of the anti-inflammatory cytokine IL-10 was observed between the control group and the bovine intestinal alkaline phosphatase treated group. Conclusion In a mouse model of permanent LAD coronary artery ligation, bIAP diminishes the pro-inflammatory responses but does not have an effect on the anti-inflammatory response in the acute phase after acute myocardial infarction. PMID:28357012

Bakery flour dust exposure causes non-allergic inflammation and enhances allergic airway inflammation in mice

PubMed Central

Marraccini, Paolo; Brass, David M.; Hollingsworth, John W.; Maruoka, Shuichiro; Garantziotis, Stavros; Schwartz, David A.

2014-01-01

Background Baker’s asthma is one of the most commonly reported occupational lung diseases in countries where fresh bread is baked daily in large quantities, and is characterized by rhinitis, bronchial hyperresponsiveness, and reversible airflow obstruction. Epidemiological studies have identified pre-existing atopy as an important risk factor for developing baker’s asthma, yet the etiology and pathogenesis of baker’s asthma remain poorly understood. Objective We sought to develop a mouse model of baker’s asthma that could be used to characterize the development and progression of baker’s asthma. Methods We were unable to sensitize mice to bakery flour dust or flour dust extract. We assessed total inflammatory cells, cellular differential, total serum IgE and the pro-inflammatory cytokine response to oropharyngeally instilled bakery flour dust or flour dust extract by itself or in the context of OVA sensitization and challenge. Results Both bakery flour dust and flour dust extract consistently elicited a neutrophilic inflammation in a tlr4-independent manner; suggesting that endotoxin is not playing a role in the inflammatory response to flour dust. Moreover, bakery flour dust and dust extract significantly enhance the inflammatory response in OVA sensitized and challenged mice. Conclusions Bakery flour dust and flour dust extract are strongly pro-inflammatory and can cause non-allergic airway inflammation and can enhance allergen-mediated airway inflammation. PMID:18564331

Characterization of the anti-inflammatory properties of NCX 429, a dual-acting compound releasing nitric oxide and naproxen.

PubMed

Amoruso, Angela; Fresu, Luigia Grazia; Dalli, Jesmond; Miglietta, Daniela; Bardelli, Claudio; Federici Canova, Donata; Perretti, Mauro; Brunelleschi, Sandra

2015-04-01

Cyclooxygenase (COX)-inhibiting nitric oxide donors (CINODs) are a new class of drugs that structurally combine a COX inhibitor with a nitric oxide (NO) donating moiety. This combination reduces potential toxicity of the non-steroidal anti-inflammatory drugs (NSAIDs) whilst maintaining the analgesic and anti-inflammatory effects. The present study was undertaken to investigate the anti-inflammatory effects of NCX 429, a naproxen-based CINOD, and to assess the additional properties of NO donation beyond those related to naproxen. We evaluated the in vitro effects of NCX 429 on oxy-radical production, phagocytosis, cytokine release, MMP-9, PPARγ expression and NF-κB activation in human monocytes/MDM and compared to naproxen. Moreover, we compared the in vivo efficacy of NCX 429 and naproxen in a murine model of peritonitis. In all the experiments performed in vitro, NCX 429 reduced the inflammatory responses with equal or higher efficacy compared to naproxen. Moreover, in in vivo experiments, NCX 429, at the lowest dose tested, was able to significantly inhibit cell influx in response to IL-1β administration although naproxen was found to be more potent than NCX 429 at reducing PGE2 in inflammatory exudates. These results demonstrate that both in vitro and in vivo--in a murine model of peritonitis--NCX 429 elicits significant anti-inflammatory activity, beyond the simple COX inhibition or pure NO release. Therefore, NO donation along with COX inhibition may represent a strategy for investigating inflammatory diseases in which pain and function are not fully resolved by analgesics/anti-inflammatory drugs. © 2015.

Vamorolone, a dissociative steroidal compound, reduces pro-inflammatory cytokine expression in glioma cells and increases activity and survival in a murine model of cortical tumor.

PubMed

Wells, Elizabeth; Kambhampati, Madhuri; Damsker, Jesse M; Gordish-Dressman, Heather; Yadavilli, Sridevi; Becher, Oren J; Gittens, Jamila; Stampar, Mojca; Packer, Roger J; Nazarian, Javad

2017-02-07

Corticosteroids, such as dexamethasone, are routinely used as palliative care in neuro-oncology for their anti-inflammatory benefits, however many patients experience dose limiting side effects caused by glucocorticoid response element (GRE)-mediated transcription. The purpose of this study was to use a murine model to investigate a new steroid alternative, vamorolone, which promises to reduce side effects through dissociating GRE-mediated transcription and NF-κB -mediated anti-inflammatory actions. To compare vamorolone to dexamethasone in reducing pro-inflammatory signals in vitro, murine glioma cells were treated with dexamethasone, vamorolone or vehicle control. Changes in mRNA expression were assessed using the nanostring inflammatory platform. Furthermore, drug efficacy, post-treatment behavioral activity and side effects were assessed by treating two cohorts of brain tumor bearing mice with dexamethasone, vamorolone, or vehicle control. Our investigation showed that treatment with vamorolone resulted in a reduction of pro-inflammatory signals in tumor cells in vitro similar to treatment with dexamethasone. Treatment with vamorolone resulted in a better safety profile in comparison to dexamethasone treatment. Vamorolone- treated mice showed similar or better activity and survival when compared to dexamethasone-treated mice. Our data indicate vamorolone is a potential steroid-sparing alternative for treating patients with brain tumors.

Rifaximin decreases virulence of Crohn's disease-associated Escherichia coli and epithelial inflammatory responses.

PubMed

Dogan, Belgin; Fu, Jing; Zhang, Shiying; Scherl, Ellen J; Simpson, Kenneth W

2018-05-01

Escherichia coli with an adherent and invasive pathotype (AIEC) is implicated in the pathogenesis of Crohn's disease (CD). Rifaximin improves symptoms in mild-to-moderate CD. It is unclear if this outcome is due to its effects on bacteria or intestinal epithelial inflammatory responses. We examined the effects of rifaximin on the growth and virulence of CD-associated E. coli and intestinal epithelial inflammatory responses. Seven well-characterized CD-associated E. coli strains (six AIEC, one non-AIEC; four rifaximin-resistant, three sensitive) were evaluated. We assessed the effects of rifaximin on CD-associated E. coli growth, adhesion to, and invasion of epithelial cells, virulence gene expression, motility, and survival in macrophages. Additionally, we determined the effects of rifaximin on intestinal epithelial inflammatory responses. In vitro rifaximin exerted a dose-dependent effect on the growth of sensitive strains but did not affect the growth of resistant strains. Rifaximin reduced adhesion, invasion, virulence gene expression and motility of CD-associated E. coli in a manner that was independent of its antimicrobial effect. Furthermore, rifaximin reduced IL-8 secretion from pregnane X receptor-expressing T84 colonic epithelial cells. The effect of rifaximin on adhesion was largely attributable to its action on bacteria, whereas decreases in invasion and cytokine secretion were due to its effect on the epithelium. In conclusion, our results show that rifaximin interferes with multiple steps implicated in host-AIEC interactions related to CD, including adhesion to, and invasion of epithelial cells, virulence gene expression, motility, and pro-inflammatory cytokine secretion. Further study is required to determine the relationship of these effects to clinical responses in CD patients.

In vitro and in vivo protective effect of arginine against lipopolysaccharide induced inflammatory response in the intestine of juvenile Jian carp (Cyprinus carpio var. Jian).

PubMed

Jiang, Jun; Shi, Dan; Zhou, Xiao-Qiu; Hu, Yi; Feng, Lin; Liu, Yang; Jiang, Wei-Dan; Zhao, Ye

2015-02-01

The present study was designed to assess the possible protective effects of arginine (Arg) against lipopolysaccharide (LPS) induced inflammatory response in juvenile Jian carp (Cyprinus carpio var. Jian) in vivo and in enterocytes in vitro. Firstly, inflammatory response was established by exposing enterocytes to different concentrations of LPS for 24 h. Secondly, the protective effects of Arg against subsequent LPS exposure were studied in enterocytes. Finally, we investigated whether dietary Arg supplementation could attenuate immune challenge induced by LPS in vivo. The result indicated that 10 mg/L LPS could induced inflammatory response in enterocytes. Cells exposed to LPS (10-30 mg/L) alone for 24 h resulted in a significant increase in lactate dehydrogenase release (LDH) (P < 0.05). The cell viability, protein content, alkaline phosphatase activity were decreased by LPS (P < 0.05). Moreover, LPS exposure significantly increased TNF-α, IL-1β, and IL-6 mRNA expression in vitro (P < 0.05). However, pre-treatment with Arg remarkably prevented the increase of TNF-α, IL-1β, and IL-6 by inhibiting the excessive activation of TLR4-Myd88 signaling pathway through down-regulating TLR4, Myd88, NFκB p65, and MAPK p38 mRNA expression (P < 0.05). Interestingly, the experiment in vivo showed that Arg pre-supplementation could attenuate immune challenge induced by LPS via TLR4-Myd88 signaling pathway, and thus protect fish against LPS-induced inflammatory response. In conclusion, all of these results indicated pre-supplementation with Arg decreased LPS induced immune damage and regulated TLR4-Myd88 signaling pathway in juvenile Jian carp in vivo and in enterocytes in vitro. Copyright © 2014 Elsevier Ltd. All rights reserved.

Two-dimensional grayscale ultrasound and spectral Doppler waveform evaluation of dogs with chronic enteropathies.

PubMed

Gaschen, Lorrie; Kircher, Patrick

2007-08-01

Sonography is an important diagnostic tool to examine the gastrointestinal tract of dogs with chronic diarrhea. Two-dimensional grayscale ultrasound parameters to assess for various enteropathies primarily focus on wall thickness and layering. Mild, generalized thickening of the intestinal wall with maintenance of the wall layering is common in inflammatory bowel disease. Quantitative and semi-quantitative spectral Doppler arterial waveform analysis can be utilized for various enteropathies, including inflammatory bowel disease and food allergies. Dogs with inflammatory bowel disease have inadequate hemodynamic responses during digestion of food. Dogs with food allergies have prolonged vasodilation and lower resistive and pulsatility indices after eating allergen-inducing foods.

Response to intramuscular methyl prednisolone in inflammatory hand pain: evidence for a targeted clinical, ultrasonographic and therapeutic approach

PubMed Central

Karim, Zunaid; Quinn, Mark A; Wakefield, Richard J; Brown, Andrew K; Green, Michael J; Hensor, Elizabeth M A; Conaghan, Philip G; Emery, Paul

2007-01-01

Background Hand pain with stiffness is a common clinical presentation to early arthritis clinics, with outcome varying from resolution to the development of rheumatoid arthritis. Objective To assess the response and predictors of response to intramuscular methylprednisolone (MP) and hydroxychloroquine (HCQ) using a standardised treatment protocol. Methods Patients with inflammatory hand pain (IHP), defined as predominantly hand pain and morning stiffness of at least 30 min duration, received a standardised assessment prior to receiving intramuscular MP. Response (primary outcome) at 4 weeks was a 50% improvement in symptoms as perceived by the patient; responders who relapsed received repeat intramuscular MP and HCQ. Results 102 patients were recruited, of which 21% were rheumatoid factor (RF) positive, 23% had clinical synovitis, 25% had raised C‐reactive protein level and 55% had ultrasound‐detected synovitis. 73% responded, with associated significant reductions in morning stiffness, Health Assessment Questionnaire, painful and tender joint counts, and visual analogue scores (p⩽0.006 for all). Ultrasound‐detected synovitis (p<0.001) and RF (p = 0.04), but not clinical synovitis (p = 0.74), were significantly associated with response to intramuscular MP. 86% who remained on HCQ long term reported a benefit. Conclusions Patients with IHP have significant improvement in symptoms and function following intramuscular MP. Further placebo‐controlled trials are required to assess the role of intramuscular MP and ultrasonography in managing this patient group. PMID:17127687

Panax Notoginseng Saponin Controls IL-17 Expression in Helper T Cells

PubMed Central

Wei, Jia-Ru; Wen, Xiaofeng; Bible, Paul W.; Li, Zhiyu; Nussenblatt, Robert B.

2017-01-01

Abstract Purpose: Panax Notoginseng, a traditional Chinese medicine, is known as an anti-inflammatory herb. However, the molecular mechanism by which it controls helper T cell mediated immune responses is largely unknown. Methods: Naive CD4+ T cells isolated from healthy donors, patients with Behcet's disease, and C57BL/6 mice were polarized into Th1, Th17, and Treg cells. Proliferation and cytokine expression were measured in these cells with the presence or absence of Panax Notoginseng saponins (PNS). Genomewide expression profiles of Th1, Th17, and Treg cells were assessed using Affymetrix microarray analysis. Results: We found that PNS control the proliferation and differentiation of Th17 cells by globally downregulating the expression of inflammatory cytokines and cell cycle genes. Conclusions: These findings demonstrated that PNS function as an anti-inflammatory agent through directly targeting Th17 cell mediated immune response. PMID:28051353

Brief report: development of the inflammatory bowel disease family responsibility questionnaire.

PubMed

Greenley, Rachel Neff; Doughty, Alyssa; Stephens, Mike; Kugathasan, Subra

2010-03-01

To present psychometric data on youth and parent versions of the Inflammatory Bowel Disease-Family Responsibility Questionnaire (IBD-FRQ), a measure of family involvement in IBD management. Fifty-eight adolescents with inflammatory bowel disease (IBD), along with 55 mothers and 26 fathers completed the IBD-FRQ, a demographics questionnaire, and a measure of family involvement in decision making in non-IBD domains. Medical information was obtained via chart review. Support for the internal consistency of the IBD-FRQ was obtained. Evidence of validity was documented via moderate to high intercorrelations among reporters. Youth involvement increased with youth age, while maternal and paternal involvement decreased with youth age. Across all reporters, maternal involvement was higher than paternal involvement. Preliminary analyses offer support for the measure's reliability and validity. The measure shows promise as a means of assessing family involvement in IBD condition management; however, further validation studies are needed.

Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury.

PubMed

Chen, Xiangrong; Chen, Chunnuan; Fan, Sining; Wu, Shukai; Yang, Fuxing; Fang, Zhongning; Fu, Huangde; Li, Yasong

2018-04-20

Microglial polarization and the subsequent neuroinflammatory response are contributing factors for traumatic brain injury (TBI)-induced secondary injury. High mobile group box 1 (HMGB1) mediates the activation of the NF-κB pathway, and it is considered to be pivotal in the late neuroinflammatory response. Activation of the HMGB1/NF-κB pathway is closely related to HMGB1 acetylation, which is regulated by the sirtuin (SIRT) family of proteins. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that ω-3 PUFA inhibited TBI-induced microglial activation and the subsequent neuroinflammatory response by regulating the HMGB1/NF-κB signaling pathway. However, no studies have elucidated if ω-3 PUFA affects the HMGB1/NF-κB pathway in a HMGB1 deacetylation of dependent SIRT1 manner, thus regulating microglial polarization and the subsequent neuroinflammatory response. The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and HMGB1, were used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1/NF-κB signaling pathway activation to evaluate the effects of ω-3 PUFA supplementation. The impact of SIRT1 deacetylase activity on HMGB1 acetylation and the interaction between HMGB1 and SIRT1 were assessed to evaluate anti-inflammation effects of ω-3 PUFAs, and also, whether these effects were dependent on a SIRT1-HMGB1/NF-κB axis to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. The results of our study showed that ω-3 PUFA supplementation promoted a shift from the M1 microglial phenotype to the M2 microglial phenotype and inhibited microglial activation, thus reducing TBI-induced inflammatory factors. In addition, ω-3 PUFA-mediated downregulation of HMGB1 acetylation and its extracellular secretion was found to be likely due to increased SIRT1 activity. We also found that treatment with ω-3 PUFA inhibited HMGB1 acetylation and induced direct interactions between SIRT1 and HMGB1 by elevating SIRT1 activity following TBI. These events lead to inhibition of HMGB1 nucleocytoplasmic translocation/extracellular secretion and alleviated HMGB1-mediated activation of the NF-κB pathway following TBI-induced microglial activation, thus inhibiting the subsequent inflammatory response. The results of this study suggest that ω-3 PUFA supplementation attenuates the inflammatory response by modulating microglial polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway, leading to neuroprotective effects following experimental traumatic brain injury.

The importance of intestinal ultrasound and elastographic techniques in inflammatory bowel diseases.

PubMed

Marin, Andreea; Tribus, Laura; Fierbinteanu-Braticevici, Carmen

2018-05-02

Inflammatory bowel diseases have an important impact upon the economic and social status due to their increasing incidence and prevalence, often affecting young people. At the moment, the therapeutic goal goes beyond the improvement of symptoms and laboratory parameters, being represented by endoscopic mucosal healing, changing the disease's natural history. Even though endoscopy is the gold standard for the assessment of mucosal healing, it is an invasive maneuver and it lacks good repeatability. These patients require frequent evaluation; therefore, interest for noninvasive techniques has risen.As a consequence, the importance of intestinal ultrasound has increased lately and recent studies support its use to assess the degree of inflammation, to differentiate between remission and relapse, to monitor therapy response and guide treatment, to evaluate prognosis, and to diagnose complications. Another promising noninvasive imagistic technique is elastography which has gained interest because of its capacity to discriminate between inflammatory and fibrotic tissue, taking into account the different therapeutic options for the fibrotic strictures compared to inflammatory processes. This review summarizes the actual recommendations regarding the use of intestinal ultrasound and elastographic techniques for the diagnosis and monitoring of inflammatory bowel diseases.

Chronic Interpersonal Stress Predicts Activation of Pro- and Anti- Inflammatory Signaling Pathways Six Months Later

PubMed Central

Miller, Gregory; Rohleder, Nicolas; Cole, Steve W.

2009-01-01

OBJECTIVE Chronic interpersonal difficulties have a detrimental influence on mental and physical health, but little is known about the mechanisms underlying this phenomenon. METHODS 103 healthy young women (mean age = 17) were administered a structured interview to assess the degree of chronic interpersonal stress in their lives. At the same time blood was drawn to measure systemic inflammation, the expression of signaling molecules that regulate immune activation, and leukocyte production of the cytokine interleukin-6 following ex vivo stimulation with lipopolysaccharide. All of the immunologic assessments were repeated six months later. RESULTS To the extent subjects were high in chronic interpersonal stress at baseline, their leukocytes displayed greater increases in mRNA for the pro-inflammatory transcription factor nuclear factor-kappa B (NF-κB) over the next six months. They also showed larger increases in mRNA for inhibitor of kappaB, a molecule that sequesters NF-κB in the cytoplasm and minimizes its pro-inflammatory activities. Chronic interpersonal stress at baseline was unrelated to changes in biomarkers of systemic inflammation, but was associated with increasingly pronounced interleukin-6 responses to lipopolysaccharide. These associations were independent of demographics, lifestyle variables, and depressive symptoms. CONCLUSIONS These findings suggest that chronic interpersonal difficulties accentuate expression of pro- and anti-inflammatory signaling molecules. While this process does not result in systemic inflammation under quiescent conditions, it does accentuate leukocytes’ inflammatory response to microbial challenge. These dynamics may underlie the excess morbidity associated with social stress, particularly in inflammation-sensitive diseases like depression and atherosclerosis. PMID:19073750

Vitamin D ameliorates impaired wound healing in streptozotocin-induced diabetic mice by suppressing NF-κB-mediated inflammatory genes.

PubMed

Yuan, YiFeng; Das, Sushant K; Li, MaoQuan

2018-04-27

Diabetic wounds are characterized by delayed wound healing due to persistent inflammation and excessive production of reactive oxygen species. Vitamin D, which is well acknowledged to enhance intestinal calcium absorption and increase in plasma calcium level, has recently been shown to display beneficial effects in various vascular diseases by promoting angiogenesis and inhibiting inflammatory responses. However, the role of Vitamin D in diabetic wound healing is still unclear. In the present study, we investigated the role of Vitamin D in cutaneous wound healing in streptozotocin (STZ)-induced diabetic mice. Four weeks after injection of STZ, a full thickness excisional wound was created with a 6-mm diameter sterile biopsy punch on the dorsum of the mice. Vitamin D was given consecutively for 14 days by intraperitoneal injection. Vitamin D supplementation significantly accelerated wound healing in diabetic mice and improved the healing quality as assessed by measuring the wound closure rate and histomorphometric analyses. By monitoring the level of pro-inflammatory cytokines tumor necrosis factor-α ( TNF-α ), interleukin (IL) 6 ( IL-6 ), IL-1β ) in the wounds, reduced inflammatory response was found in VD treatment group. Furthermore, nuclear factor κB (NF-κB) pathway was found to be involved in the process of diabetic wound healing by assessing the relative proteins in diabetic wounds. Vitamin D supplementation obviously suppressed NF-κB pathway activation. These results demonstrated that Vitamin D improves impaired wound healing in STZ-induced diabetic mice through suppressing NF-κB-mediated inflammatory gene expression. © 2018 The Author(s).

Diagnostic value of inflammatory cell infiltrates, tumor stroma percentage and disease-free survival in patients with colorectal cancer

PubMed Central

Jakubowska, Katarzyna; Kisielewski, Wojciech; Kańczuga-Koda, Luiza; Koda, Mariusz; Famulski, Waldemar

2017-01-01

The anticancer immune defense mechanism involves humoral and cellular responses. The main effector mechanisms of antitumor responses involve the following: the activity of cytotoxic T cells; the activation of macrophages and neutrophils; the activity of cytokines secreted by T cells; and natural killer cell activity. Selected cell populations are responsible for the stimulation or suppression of the immune system against tumor cells. Therefore, the aim of the present study was to evaluate the location, extent and composition of the cellular inflammatory infiltration of tumors in patients with colorectal cancer (CRC). In addition, the correlation between cellular inflammatory infiltration, and anatomoclinical and histopathological features of patients was evaluated. The study involved 160 patients diagnosed with primary operable CRC. The local inflammatory infiltrate was assessed in the invasive front and center of the tumor using light microscopy with hematoxylin and eosin (H&E) staining, according to the Klintrup-Makinen criteria, tumor stroma percentage, and Glasgow microenvironment score. The inflammatory infiltrate in the invasive front of the tumor was correlated with gender (P=0.018), the invasion of blood vessels (P=0.020) and lymph vessels (P=0.038), the presence of tumor-infiltrating lymphocytes in the invasive front (P=0.033) and center (P<0.001) of the tumor, fibrosis (P<0.001), and the degree of desmoplasmic stroma (P=0.004). In contrast, inflammatory infiltration in the center of the tumor was associated with the tumor node metastasis stage (P=0.012), Dukes' stage (P=0.009), primary tumor stage (P=0.036), lymph node status (P=0.005), number of lymph nodes (P=0.006), invasion of lymph node pouches (P=0.021), size of lymph node metastasis (P=0.025) and the degree of desmoplasmic stroma (P=0.002). The low-group, who demonstrated an absent or weak inflammatory cell infiltrate in the invasive front of the tumor, had a statistically significant shorter disease-free survival (DFS) time (P=0.004). Inflammatory cell infiltrate in the invasive front was identified as an independent predictive factor in CRC (P=0.041). In conclusion, the degree of inflammatory cell infiltration in the invasive front of the primary tumor significantly affects various variables that determine disease progression and DFS rates of patients with CRC. Furthermore, the routine histopathological assessment of this parameter in tissue stained with H&E may have potential prognostic value. PMID:28927159

Donor brain death predisposes human kidney grafts to a proinflammatory reaction after transplantation.

PubMed

de Vries, D K; Lindeman, J H N; Ringers, J; Reinders, M E J; Rabelink, T J; Schaapherder, A F M

2011-05-01

Donor brain death has profound effects on post-transplantation graft function and survival. We hypothesized that changes initiated in the donor influence the graft's response to ischemia and reperfusion. In this study, human brain dead donor kidney grafts were compared to living and cardiac dead donor kidney grafts. Pretransplant biopsies of brain dead donor kidneys contained notably more infiltrating T lymphocytes and macrophages. To assess whether the different donor conditions result in a different response to reperfusion, local cytokine release from the reperfused kidney was studied by measurement of paired arterial and renal venous blood samples. Reperfusion of kidneys from brain dead donors was associated with the instantaneous release of inflammatory cytokines, such as G-CSF, IL-6, IL-9, IL-16 and MCP-1. In contrast, kidneys from living and cardiac dead donors showed a more modest cytokine response with release of IL-6 and small amounts of MCP-1. In conclusion, this study shows that donor brain death initiates an inflammatory state of the graft with T lymphocyte and macrophage infiltration and massive inflammatory cytokine release upon reperfusion. These observations suggest that brain dead donors require a novel approach for donor pretreatment aimed at preventing this inflammatory response to increase graft survival. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

Sleep Loss and the Inflammatory Response in Mice Under Chronic Environmental Circadian Disruption

PubMed Central

Castanon-Cervantes, Oscar; Natarajan, Divya; Delisser, Patrick; Davidson, Alec J.; Paul, Ketema N.

2013-01-01

Shift work and trans-time zone travel lead to insufficient sleep and numerous pathologies. Here, we examined sleep/wake dynamics during chronic exposure to environmental circadian disruption (ECD), and if chronic partial sleep loss associated with ECD influences the induction of shift-related inflammatory disorder. Sleep and wakefulness were telemetrically recorded across three months of ECD, in which the dark-phase of a light-dark cycle was advanced weekly by 6 h. A three month regimen of ECD caused a temporary reorganization of sleep (NREM and REM) and wake processes across each week, resulting in an approximately 10% net loss of sleep each week relative to baseline levels. A separate group of mice were subjected to ECD or a regimen of imposed wakefulness (IW) aimed to mimic sleep amounts under ECD for one month. Fos-immunoreactivity (IR) was quantified in sleep-wake regulatory areas: the nucleus accumbens (NAc), basal forebrain (BF), and medial preoptic area (MnPO). To assess the inflammatory response, trunk blood was treated with lipopolysaccharide (LPS) and subsequent release of IL-6 was measured. Fos-IR was greatest in the NAc, BF, and MnPO of mice subjected to IW. The inflammatory response to LPS was elevated in mice subjected to ECD, but not mice subjected to IW. Thus, the net sleep loss that occurs under ECD is not associated with a pathological immune response. PMID:23696854

A double blind placebo controlled randomized trial of the effect of acute uric acid changes on inflammatory markers in humans: A pilot study

PubMed Central

Milaneschi, Yuri; Zhang, Yongqing; Becker, Kevin G.; Zukley, Linda; Ferrucci, Luigi

2017-01-01

Uric acid has been linked with increased risk of chronic disease such as cardiovascular disease and this association has been attributed to a pro-inflammatory effect. Indeed, observational studies have shown that high uric acid is associated with high level of pro-inflammatory cytokines in the blood. However, whether high uric acid directly affects inflammation or rather represents a parallel defensive antioxidant mechanism in response to pathology that causes inflammation is unknown. To determine whether acute increase or decrease uric acid levels affects inflammation in healthy individuals, a randomized, placebo-controlled, double blind clinical study of uric acid or rasburicase with 20 healthy volunteers in each treatment-placebo group was conducted at the National Institute on Aging (NIA) Clinical Research Unit (CRU) at Harbor Hospital in Baltimore, MD. Change in inflammatory response was assessed by administering an oral lipid tolerance before and after the treatment of uric acid, rasburicase and placebo. Following uric acid administration, there was an accentuated increase in IL-6 during the oral lipid tolerance test (P<0.001). No significant differences were observed after lowering of uric acid with rasburicase. No side effects were reported throughout the trial. In health individuals, acute increase in uric acid results in an increased IL-6 response when challenged with lipid load. Such effect of amplification of inflammatory response may explain the higher risk of chronic diseases observed in subclinical hyperuricemia in observational studies. Trial Registration: ClinicalTrials.gov NCT01323335 PMID:28786993

Orally administered Taenia solium Calreticulin prevents experimental intestinal inflammation and is associated with a type 2 immune response

PubMed Central

Cruz-Rivera, Mayra; Diaz-Gandarilla, Jose Alfredo; Flores-Torres, Marco Antonio; Avila, Guillermina; Perfiliev, Maria; Salazar, Ana Maria; Arriaga-Pizano, Lourdes; Ostrosky-Wegman, Patricia; Flisser, Ana

2017-01-01

Intestinal helminth antigens are inducers of type 2 responses and can elicit regulatory immune responses, resulting in dampened inflammation. Several platyhelminth proteins with anti-inflammatory activity have been reported. We have identified, cloned and expressed the Taenia solium calreticulin (rTsCRT) and shown that it predominantly induces a type 2 response characterized by IgG1, IL-4 and IL-5 production in mice. Here, we report the rTsCRT anti-inflammatory activity in a well-known experimental colitis murine model. Mice were orally immunized with purified rTsCRT and colitis was induced with trinitrobenzene sulfonic acid (TNBS). Clinical signs of disease, macroscopic and microscopic tissue inflammation, cytokine production and micronuclei formation, as a marker of genotoxicity, were measured in order to assess the effect of rTsCRT immunization on experimentally induced colitis. rTsCRT administration prior to TNBS instillation significantly reduced the inflammatory parameters, including the acute phase cytokines TNF-α, IL-1β and IL-6. Dampened inflammation was associated with increased local expression of IL-13 and systemic IL-10 and TGF-β production. Genotoxic damage produced by the inflammatory response was also precluded. Our results show that oral treatment with rTsCRT prevents excessive TNBS-induced inflammation in mice and suggest that rTsCRT has immunomodulatory properties associated with the expression of type 2 and regulatory cytokines commonly observed in other helminths. PMID:29036211

Obesity-related chronic kidney disease is associated with spleen-derived IL-10.

PubMed

Gotoh, Koro; Inoue, Megumi; Masaki, Takayuki; Chiba, Seiichi; Shiraishi, Kentaro; Shimasaki, Takanobu; Matsuoka, Kazue; Ando, Hisae; Fujiwara, Kansuke; Fukunaga, Naoya; Aoki, Kohei; Nawata, Tomoko; Katsuragi, Isao; Kakuma, Tetsuya; Seike, Masataka; Yoshimatsu, Hironobu

2013-05-01

Obesity is associated with systemic low-grade inflammation and is a risk factor for chronic kidney disease (CKD), but the molecular mechanism remains uncertain. We noticed spleen-derived interleukin (IL)-10 because it is observed that obesity reduces several cytokines in the spleen. We examined whether spleen-derived IL-10 regulates CKD caused by a high-fat diet (HF)-induced obesity as follows: (i) male mice were fed with HF (60% fat) during 8 weeks and IL-10 induction from the spleen was examined, (ii) glomerular hypertrophy, fibrosis, inflammatory responses in the kidney and systolic blood pressure (SBP) were evaluated in splenectomy (SPX)-treated mice fed HF, (iii) exogenous IL-10 was systemically administered to HF-induced obese mice and the alteration of obesity-induced pathogenesis caused by IL-10 treatment was assessed. (iv) IL-10 knockout (IL-10KO) mice were treated with SPX and glomerular hypertrophy, fibrosis and the inflammatory condition in the kidney and SBP were also investigated. Obesity decreased serum levels of only IL-10, an anti-inflammatory cytokine even though pro- and anti-inflammatory cytokine expression in the spleen was significantly lower in the obese group. SPX aggravated HF-induced inflammatory responses in the kidney and hypertension. These HF-induced alterations were inhibited by systemically administered IL-10. Moreover, SPX had little effect on inflammatory responses and SBP in the kidney of IL-10KO mice. We suggest that obesity reduces IL-10 induction from the spleen, and spleen-derived IL-10 may protect against the development of CKD induced by obesity.

The systemic inflammatory response syndrome.

PubMed

Robertson, Charles M; Coopersmith, Craig M

2006-04-01

The systemic inflammatory response syndrome (SIRS) is the body's response to an infectious or noninfectious insult. Although the definition of SIRS refers to it as an "inflammatory" response, it actually has pro- and anti-inflammatory components. This review outlines the pathophysiology of SIRS and highlights potential targets for future therapeutic intervention in patients with this complex entity.

Involvement of Nitric Oxide in a Rat Model of Carrageenin-Induced Pleurisy

PubMed Central

Iwata, Masahiro; Suzuki, Shigeyuki; Asai, Yuji; Inoue, Takayuki; Takagi, Kenji

2010-01-01

Some evidence indicates that nitric oxide (NO) contributes to inflammation, while other evidence supports the opposite conclusion. To clarify the role of NO in inflammation, we studied carrageenin-induced pleurisy in rats treated with an NO donor (NOC-18), a substrate for NO formation (L-arginine), and/or an NO synthase inhibitor (S-(2-aminoethyl) isothiourea or NG-nitro-L-arginine). We assessed inflammatory cell migration, nitrite/nitrate values, lipid peroxidation and pro-inflammatory mediators. NOC-18 and L-arginine reduced the migration of inflammatory cells and edema, lowered oxidative stress, and normalized antioxidant enzyme activities. NO synthase inhibitors increased the exudate formation and inflammatory cell number, contributed to oxidative stress, induced an oxidant/antioxidant imbalance by maintaining high O2 −, and enhanced the production of pro-inflammatory mediators. L-arginine and NOC-18 reversed the proinflammatory effects of NO synthase inhibitors, perhaps by reducing the expression of adhesion molecules on endothelial cells. Thus, our results indicate that NO is involved in blunting—not enhancing—the inflammatory response. PMID:20592757

Relievable effect of dietary Allium hookeri on LPS-induced intestinal inflammation response in young broiler chickens

USDA-ARS?s Scientific Manuscript database

A study using 150 one-day- old broilers was conducted to assess the effects of Allium hookeri (AH) root and fermented root on inflammatory responses and intestinal barrier integrity of LPS challenged broiler chickens. Birds were randomly assigned to six groups (n = 25 birds/treatment) and fed standa...

Temporal pattern and effect of sex on lipopolysaccharide-induced stress hormone and cytokine response in pigs

USDA-ARS?s Scientific Manuscript database

The temporal pattern and gender effect of immune and stress hormone responses to a lipopolysaccharide (LPS) challenge were assessed using a pig model. Secretion of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 increased in a time-dependent manner f...

Residential proximity to abandoned uranium mines and serum inflammatory potential in chronically exposed Navajo communities.

PubMed

Harmon, Molly E; Lewis, Johnnye; Miller, Curtis; Hoover, Joseph; Ali, Abdul-Mehdi S; Shuey, Chris; Cajero, Miranda; Lucas, Selita; Zychowski, Katherine; Pacheco, Bernadette; Erdei, Esther; Ramone, Sandy; Nez, Teddy; Gonzales, Melissa; Campen, Matthew J

2017-07-01

Members of the Navajo Nation, who possess a high prevalence of cardiometabolic disease, reside near hundreds of local abandoned uranium mines (AUM), which contribute uranium, arsenic and other metals to the soil, water and air. We recently reported that hypertension is associated with mine waste exposures in this population. Inflammation is a major player in the development of numerous vascular ailments. Our previous work establishing that specific transcriptional responses of cultured endothelial cells treated with human serum can reveal relative circulating inflammatory potential in a manner responsive to pollutant exposures, providing a model to assess responses associated with exposure to these waste materials in this population. To investigate a potential link between exposures to AUM and serum inflammatory potential in affected communities, primary human coronary artery endothelial cells were treated for 4 h with serum provided by Navajo study participants (n=145). Endothelial transcriptional responses of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and chemokine ligand 2 (CCL2) were measured. These transcriptional responses were then linked to AUM exposure metrics, including surface area-weighted AUM proximity and estimated oral intake of metals. AUM proximity strongly predicted endothelial transcriptional responses to serum including CCL2, VCAM-1 and ICAM-1 (P<0.0001 for each), whereas annual water intakes of arsenic and uranium did not, even after controlling for all major effect modifiers. Inflammatory potential associated with proximity to AUMs, but not oral intake of specific metals, additionally suggests a role for inhalation exposure as a contributor to cardiovascular disease.

Effects of low-dose hydrocortisone therapy on immune function in neonatal horses

PubMed Central

Hart, Kelsey A.; Barton, Michelle H.; Vandenplas, Michel L.; Hurley, David J.

2011-01-01

Low-dose hydrocortisone therapy modulates inflammatory responses in adults and improves outcomes in some septic adults and neonates, but its immunologic effects have not been evaluated in neonates. The objective of this study was to evaluate effects of low-dose hydrocortisone (LDHC) therapy on ex vivo immune function in neonatal horses (foals). We hypothesized that LDHC treatment would dampen pro-inflammatory responses without impairing neutrophil function. Hydrocortisone (1.3 mg/kg/day i.v.) was administered to foals in a tapering 3.5 day course. Peripheral blood leukocytes were collected from foals before, during and after hydrocortisone treatment. A separate group of age-matched untreated foals served as controls. Endotoxin-induced peripheral blood mononuclear cell gene expression of inflammatory cytokines was measured by real time quantitative RT-PCR. Neutrophils were incubated with labeled, killed S. aureus or E. coli for assessment of phagocytosis, and with phorbol myristate acetate, zymosan, or endotoxin for measurement of reactive oxygen species (ROS) production. Neutrophil phagocytosis and ROS production were similar in both groups. Foals receiving hydrocortisone had significantly decreased endotoxin-induced expression of TNF-α, IL-6, IL-8, and IL-1β. These data suggest that this LDHC treatment regimen ameliorates endotoxin-induced pro-inflammatory cytokine expression in neonatal foals without impairing innate immune responses needed to combat bacterial infection. PMID:21430601

HETEROGENEITY OF SYSTEMIC INFLAMMATORY RESPONSES TO PERIODONTAL THERAPY

PubMed Central

Behle, Jan H.; Sedaghatfar, Michael H.; Demmer, Ryan T.; Wolf, Dana L.; Celenti, Romanita; Kebschull, Moritz; Belusko, Paul B.; Herrera-Abreu, Miriam; Lalla, Evanthia; Papapanou, Panos N.

2009-01-01

Aims We investigated the effect of comprehensive periodontal therapy on the levels of multiple systemic inflammatory biomarkers. Methods Thirty patients with severe periodontitis received comprehensive periodontal therapy within a 6-week period. Blood samples were obtained at: one week pre- therapy (T1), therapy initiation (T2), treatment completion (T3), and 4 weeks thereafter (T4). We assessed plasma concentrations of 19 biomarkers using multiplex assays, and serum IgG antibodies to periodontal bacteria using checkerboard immunoblotting. At T2 and T4, dental plaque samples were analyzed using checkerboard hybridizations. Results At T3, PAI-1, sE-selectin, sVCAM-1, MMP-9, myeloperoxidase, and a composite Summary Inflammatory Score (SIS) were significantly reduced. However, only sE-selectin, sICAM, and serum amyloid P sustained a reduction at T4. Responses were highly variable: analyses of SIS slopes between baseline and T4 showed that approximately 1/3 and 1/4 of the patients experienced marked reduction and pronounced increase in systemic inflammation, respectively, while the remainder were seemingly unchanged. Changes in inflammatory markers correlated poorly with clinical, microbiological and serological markers of periodontitis. Conclusions Periodontal therapy resulted in an overall reduction of systemic inflammation, but the responses were inconsistent across subjects and largely not sustainable. The determinants of this substantial heterogeneity need to be explored further. PMID:19426174

Role of histamine in the inhibitory effects of phycocyanin in experimental models of allergic inflammatory response.

PubMed Central

Remirez, D; Ledón, N; González, R

2002-01-01

It has recently been reported that phycocyanin, a biliprotein found in the blue-green microalgae Spirulina, exerts anti-inflammatory effects in some animal models of inflammation. Taking into account these findings, we decided to elucidate whether phycocyanin might exert also inhibitory effects in the induced allergic inflammatory response and on histamine release from isolated rat mast cells. In in vivo experiments, phycocyanin (100, 200 and 300mg/kg post-orally (p.o.)) was administered 1 h before the challenge with 1 microg of ovalbumin (OA) in the ear of mice previously sensitized with OA. One hour later, myeloperoxidase activity and ear edema were assessed. Phycocyanin significantly reduced both parameters. In separate experiments, phycocyanin (100 and 200 mg/kg p.o.) also reduced the blue spot area induced by intradermal injections of histamine, and the histamine releaser compound 48/80 in rat skin. In concordance with the former results, phycocyanin also significantly reduced histamine release induced by compound 48/80 from isolated peritoneal rat mast cells. The inhibitory effects of phycocyanin were dose dependent. Taken together, our results suggest that inhibition of allergic inflammatory response by phycocyanin is mediated, at least in part, by inhibition of histamine release from mast cells. PMID:12061428

Oxidative potential and inflammatory impacts of source apportioned ambient air pollution in Beijing.

PubMed

Liu, Qingyang; Baumgartner, Jill; Zhang, Yuanxun; Liu, Yanju; Sun, Yongjun; Zhang, Meigen

2014-11-04

Air pollution exposure is associated with a range of adverse health impacts. Knowledge of the chemical components and sources of air pollution most responsible for these health effects could lead to an improved understanding of the mechanisms of such effects and more targeted risk reduction strategies. We measured daily ambient fine particulate matter (<2.5 μm in aerodynamic diameter; PM2.5) for 2 months in peri-urban and central Beijing, and assessed the contribution of its chemical components to the oxidative potential of ambient air pollution using the dithiothreitol (DTT) assay. The composition data were applied to a multivariate source apportionment model to determine the PM contributions of six sources or factors: a zinc factor, an aluminum factor, a lead point factor, a secondary source (e.g., SO4(2-), NO3(2-)), an iron source, and a soil dust source. Finally, we assessed the relationship between reactive oxygen species (ROS) activity-related PM sources and inflammatory responses in human bronchial epithelial cells. In peri-urban Beijing, the soil dust source accounted for the largest fraction (47%) of measured ROS variability. In central Beijing, a secondary source explained the greatest fraction (29%) of measured ROS variability. The ROS activities of PM collected in central Beijing were exponentially associated with in vivo inflammatory responses in epithelial cells (R2=0.65-0.89). We also observed a high correlation between three ROS-related PM sources (a lead point factor, a zinc factor, and a secondary source) and expression of an inflammatory marker (r=0.45-0.80). Our results suggest large differences in the contribution of different PM sources to ROS variability at the central versus peri-urban study sites in Beijing and that secondary sources may play an important role in PM2.5-related oxidative potential and inflammatory health impacts.

Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS)

PubMed Central

2011-01-01

Introduction Cryopyrin-associated periodic syndrome (CAPS) represents a spectrum of three auto-inflammatory syndromes, familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome (NOMID/CINCA) with etiology linked to mutations in the NLRP3 gene resulting in elevated interleukin-1β (IL-1β) release. CAPS is a rare hereditary auto-inflammatory disease, which may start early in childhood and requires a life-long treatment. Canakinumab, a fully human anti-IL-1β antibody, produces sustained selective inhibition of IL-1β. This study was conducted to assess the efficacy, safety, and pharmacokinetics of canakinumab in the treatment of pediatric CAPS patients. Methods Seven pediatric patients (five children and two adolescents) with CAPS were enrolled in a phase II, open-label study of canakinumab in patients with CAPS. Canakinumab was administered at a dose of 2 mg/kg subcutaneously (s.c.) (for patients with body weight ≤ 40 kg) or 150 mg s.c. (for patients with body weight > 40 kg) with re-dosing upon each relapse. The primary efficacy variable was time to relapse following achievement of a complete response (defined as a global assessment of no or minimal disease activity and no or minimal rash and values for serum C-reactive protein (CRP) and/or serum amyloid A (SAA) within the normal range, < 10 mg/L). Results All patients achieved a complete response within seven days after the first dose of canakinumab and responses were reinduced on retreatment following relapse. Improvements in symptoms were evident within 24 hours after the first dose, according to physician assessments. The estimated median time to relapse was 49 days (95% CI 29 to 68) in children who received a dose of 2 mg/kg. Canakinumab was well tolerated. One serious adverse event, vertigo, was reported, but resolved during treatment. Conclusions Canakinumab, 2 mg/kg or 150 mg s.c., induced rapid and sustained clinical and biochemical responses in pediatric patients with CAPS. Trial registration number ClinicalTrials.gov: NCT00487708 PMID:21356079

Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS).

PubMed

Kuemmerle-Deschner, Jasmin B; Ramos, Eduardo; Blank, Norbert; Roesler, Joachim; Felix, Sandra D; Jung, Thomas; Stricker, Kirstin; Chakraborty, Abhijit; Tannenbaum, Stacey; Wright, Andrew M; Rordorf, Christiane

2011-02-28

Cryopyrin-associated periodic syndrome (CAPS) represents a spectrum of three auto-inflammatory syndromes, familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome (NOMID/CINCA) with etiology linked to mutations in the NLRP3 gene resulting in elevated interleukin-1β (IL-1β) release. CAPS is a rare hereditary auto-inflammatory disease, which may start early in childhood and requires a life-long treatment. Canakinumab, a fully human anti-IL-1β antibody, produces sustained selective inhibition of IL-1β. This study was conducted to assess the efficacy, safety, and pharmacokinetics of canakinumab in the treatment of pediatric CAPS patients. Seven pediatric patients (five children and two adolescents) with CAPS were enrolled in a phase II, open-label study of canakinumab in patients with CAPS. Canakinumab was administered at a dose of 2 mg/kg subcutaneously (s.c.) (for patients with body weight ≤ 40 kg) or 150 mg s.c. (for patients with body weight > 40 kg) with re-dosing upon each relapse. The primary efficacy variable was time to relapse following achievement of a complete response (defined as a global assessment of no or minimal disease activity and no or minimal rash and values for serum C-reactive protein (CRP) and/or serum amyloid A (SAA) within the normal range, < 10 mg/L). All patients achieved a complete response within seven days after the first dose of canakinumab and responses were reinduced on retreatment following relapse. Improvements in symptoms were evident within 24 hours after the first dose, according to physician assessments. The estimated median time to relapse was 49 days (95% CI 29 to 68) in children who received a dose of 2 mg/kg. Canakinumab was well tolerated. One serious adverse event, vertigo, was reported, but resolved during treatment. Canakinumab, 2 mg/kg or 150 mg s.c., induced rapid and sustained clinical and biochemical responses in pediatric patients with CAPS. ClinicalTrials.gov: NCT00487708.

A trial assessing N-3 as treatment for injury-induced cachexia (ATLANTIC trial): does a moderate dose fish oil intervention improve outcomes in older adults recovering from hip fracture?

PubMed

Miller, Michelle D; Yaxley, Alison; Villani, Anthony; Cobiac, Lynne; Fraser, Robert; Cleland, Leslie; James, Michael; Crotty, Maria

2010-10-22

Proximal femoral fractures are associated with increased morbidity and mortality. Pre-existing malnutrition and weight loss amongst this patient group is of primary concern, with conventional nutrition support being largely ineffective. The inflammatory response post proximal femoral fracture surgery and the subsequent risk of cachexia may explain the inability of conventional high energy high protein management to produce an anabolic response amongst these patients. Omega-3 fatty acids derived from fish oils have been extensively studied for their anti-inflammatory benefits. Due to their anti-inflammatory properties, the benefit of fish oil combined with individualized nutrition support amongst proximal femoral fracture patients post surgery is an attractive potential therapeutic strategy. The aim of the ATLANTIC trial is to assess the potential benefits of an anti-inflammatory dose of fish oil within the context of a 12 week individualised nutrition program, commencing seven days post proximal femoral fracture surgery. This randomized controlled, double blinded trial, will recruit 150 community dwelling elderly patients aged ≥65 years, within seven days of surgery for proximal femoral fracture. Participants will be randomly allocated to receive either a 12 week individualized nutrition support program complemented with 20 ml/day anti-inflammatory dose fish oil (~3.6 g eicosapentaenoic acid, ~2.4 g docosahexanoic acid; intervention), or, a 12 week individualized nutrition support program complemented with 20 ml/day low dose fish oil (~0.36 g eicosapentaenoic acid, ~0.24 g docosahexanoic acid; control). The ATLANTIC trial is the first of its kind to provide fish oil combined with individualized nutrition therapy as an intervention to address the inflammatory response experienced post proximal femoral fracture surgery amongst elderly patients. The final outcomes of this trial will assist clinicians in the development of effective and alternative treatment methods post proximal femoral fracture surgery which may ultimately result in a reduction in systemic inflammation, loss of weight and lean muscle and improvements in nutritional status, mobility, independence and quality of life among elderly patients. ACTRN12609000241235.

A trial assessing N-3 as treatment for injury-induced cachexia (ATLANTIC trial): does a moderate dose fish oil intervention improve outcomes in older adults recovering from hip fracture?

PubMed Central

2010-01-01

Background Proximal femoral fractures are associated with increased morbidity and mortality. Pre-existing malnutrition and weight loss amongst this patient group is of primary concern, with conventional nutrition support being largely ineffective. The inflammatory response post proximal femoral fracture surgery and the subsequent risk of cachexia may explain the inability of conventional high energy high protein management to produce an anabolic response amongst these patients. Omega-3 fatty acids derived from fish oils have been extensively studied for their anti-inflammatory benefits. Due to their anti-inflammatory properties, the benefit of fish oil combined with individualized nutrition support amongst proximal femoral fracture patients post surgery is an attractive potential therapeutic strategy. The aim of the ATLANTIC trial is to assess the potential benefits of an anti-inflammatory dose of fish oil within the context of a 12 week individualised nutrition program, commencing seven days post proximal femoral fracture surgery. Methods/Design This randomized controlled, double blinded trial, will recruit 150 community dwelling elderly patients aged ≥65 years, within seven days of surgery for proximal femoral fracture. Participants will be randomly allocated to receive either a 12 week individualized nutrition support program complemented with 20 ml/day anti-inflammatory dose fish oil (~3.6 g eicosapentaenoic acid, ~2.4 g docosahexanoic acid; intervention), or, a 12 week individualized nutrition support program complemented with 20 ml/day low dose fish oil (~0.36 g eicosapentaenoic acid, ~0.24 g docosahexanoic acid; control). Discussion The ATLANTIC trial is the first of its kind to provide fish oil combined with individualized nutrition therapy as an intervention to address the inflammatory response experienced post proximal femoral fracture surgery amongst elderly patients. The final outcomes of this trial will assist clinicians in the development of effective and alternative treatment methods post proximal femoral fracture surgery which may ultimately result in a reduction in systemic inflammation, loss of weight and lean muscle and improvements in nutritional status, mobility, independence and quality of life among elderly patients. Trial Registration ACTRN12609000241235 PMID:20964865

IGF-I, IGFBPs, and inflammatory cytokine responses during gender-integrated Israeli Army basic combat training.

PubMed

Nindl, Bradley C; Scofield, Dennis E; Strohbach, Cassandra A; Centi, Amanda J; Evans, Rachel K; Yanovich, Ran; Moran, Daniel S

2012-07-01

Insulin-like growth factor 1 (IGF-I) is a robust metabolic and anabolic biomarker that has been demonstrated to be reflective of military training-induced body composition changes and influenced by initial aerobic fitness level. Greater mechanistic insight into the IGF-I response to physical training can potentially be gleaned by also examining other regulatory factors that influence IGF-I biological activity (i.e., insulin-like growth factor-binding proteins [IGFBPs] and inflammatory cytokine responses). The purpose of this study was to assess the influence of sex and initial fitness level on the IGF-I and inflammatory cytokine response to gender-integrated Israeli Defense Forces (IDF) basic combat training (BCT). Recruits (29 men, 19.1 ± 1.3 years; 93 women, 18.8 ± 0.6 years) were recruited from a 4-month gender-integrated BCT of the IDF. Blood was drawn and assayed for total IGF-I, free IGF-I, IGFBPs 1-6, tumor necrosis factor alpha (TNF-α), interleukin 6, and interleukin 1 beta. Body composition was determined via a 4-site skinfold (biceps, triceps, suprailiac, and subscapular) equation. Physical performance was assessed via a maximum volume of oxygen consumption (V[Combining Dot Above]O₂max) test using a treadmill protocol. All measures were obtained pre- and posttraining. A 2-way (sex × time) analysis of variance was used to test for statistical differences (p ≤ 0.05). Additionally, subjects were further partitioned (men and women separately) by tertiles of initial V[Combining Dot Above]O₂max to assess the influence of initial fitness level on the IGF-I system and inflammatory cytokine responses to physical training. Pearson product moment correlational analysis was also used to examine relationships between percent changes in blood measures and physical performance and body composition changes. All data are presented as mean ± SE. Time effects were observed only for total IGF-I, IGFBP-2, TNF-α, V[Combining Dot Above]O₂max, fat-free mass, and fat mass. The only significant (p ≤ 0.05) correlations observed for percent changes were in men between total IGF-I and V[Combining Dot Above]O₂max (r = 0.49) and body mass (r = -0.42) During gender-integrated Israeli Army BCT, men and women generally respond in a similar fashion with regard to blood measures (IGF-I system and inflammatory cytokines) and V[Combining Dot Above]O₂max. Initial fitness level only influenced the IGF-I response to training in women. Although the training-induced changes in total IGF-I (increase), IGFBP-2 (decrease), and TNF-α (decrease) are all indicative of an enhanced circulating anabolic milieu, only total IGF-I for the men was correlated with body composition and fitness improvements.

Sirtuin inhibition attenuates the production of inflammatory cytokines in lipopolysaccharide-stimulated macrophages

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fernandes, Claudia A.; Fievez, Laurence; Neyrinck, Audrey M.

Highlights: Black-Right-Pointing-Pointer Lipopolysaccharide-stimulated macrophages were treated with cambinol and sirtinol. Black-Right-Pointing-Pointer Cambinol and sirtinol decreased lipopolysaccharide-induced cytokines. Black-Right-Pointing-Pointer Cambinol decreased NF-{kappa}B activity but had no impact on p38 MAPK activation. Black-Right-Pointing-Pointer Sirtuins are an interesting target for the treatment of inflammatory diseases. -- Abstract: In several inflammatory conditions such as rheumatoid arthritis or sepsis, the regulatory mechanisms of inflammation are inefficient and the excessive inflammatory response leads to damage to the host. Sirtuins are class III histone deacetylases that modulate the activity of several transcription factors that are implicated in immune responses. In this study, we evaluated the impact ofmore » sirtuin inhibition on the activation of lipopolysaccharide (LPS)-stimulated J774 macrophages by assessing the production of inflammatory cytokines. The pharmacologic inhibition of sirtuins decreased the production of tumour necrosis factor-alpha (TNF-{alpha}) interleukin 6 (IL-6) and Rantes. The reduction of cytokine production was associated with decreased nuclear factor kappa B (NF-{kappa}B) activity and inhibitor kappa B alpha (I{kappa}B{alpha}) phosphorylation while no impact was observed on the phosphorylation status of p38 mitogen-activated kinase (p38 MAPK). This work shows that sirtuin pharmacologic inhibitors are a promising tool for the treatment of inflammatory conditions.« less

Size- and structure-dependent toxicity of silica particulates

NASA Astrophysics Data System (ADS)

Hanada, Sanshiro; Miyaoi, Kenichi; Hoshino, Akiyoshi; Inasawa, Susumu; Yamaguchi, Yukio; Yamamoto, Kenji

2011-03-01

Nano- and micro-particulates firmly attach with the surface of various biological systems. In some chronic pulmonary disease such as asbestosis and silicosis, causative particulates will induce chronic inflammatory disorder, followed by poor prognosis diseases. However, nano- and micro-scale specific toxicity of silica particulates is not well examined enough to recognize the risk of nano- and micro-particulates from the clinical aspect. To clarify the effect of the size and structure of silica particulates on the cellular damage and the biological response, we assessed the cytotoxicity of the various kinds of silica particles including amorphous and crystalline silica, in mouse alveolar macrophage culture, focusing on the fibrotic and inflammatory response. Our study showed that the cytotoxicity, which depends on the particle size and surface area, is correlated with their inflammatory response. By contrast, production of TGF-β, which is one of the fibrotic agents in lung, by addition of crystal silica was much higher than that of amorphous silica. We conclude that fibrosis and inflammation are induced at different phases and that the size- and structure-differences of silica particulates affect the both biological responses, caused by surface activity, radical species, and so on.

Suppression of pro-inflammatory T-cell responses by human mesothelial cells.

PubMed

Lin, Chan-Yu; Kift-Morgan, Ann; Moser, Bernhard; Topley, Nicholas; Eberl, Matthias

2013-07-01

Human γδ T cells reactive to the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) contribute to acute inflammatory responses. We have previously shown that peritoneal dialysis (PD)-associated infections with HMB-PP producing bacteria are characterized by locally elevated γδ T-cell frequencies and poorer clinical outcome compared with HMB-PP negative infections, implying that γδ T cells may be of diagnostic, prognostic and therapeutic value in acute disease. The regulation by local tissue cells of these potentially detrimental γδ T-cell responses remains to be investigated. Freshly isolated γδ or αβ T cells were cultured with primary mesothelial cells derived from omental tissue, or with mesothelial cell-conditioned medium. Stimulation of cytokine production and proliferation by peripheral T cells in response to HMB-PP or CD3/CD28 beads was assessed by flow cytometry. Resting mesothelial cells were potent suppressors of pro-inflammatory γδ T cells as well as CD4+ and CD8+ αβ T cells. The suppression of γδ T-cell responses was mediated through soluble factors released by primary mesothelial cells and could be counteracted by SB-431542, a selective inhibitor of TGF-β and activin signalling. Recombinant TGF-β1 but not activin-A mimicked the mesothelial cell-mediated suppression of γδ T-cell responses to HMB-PP. The present findings indicate an important regulatory function of mesothelial cells in the peritoneal cavity by dampening pro-inflammatory T-cell responses, which may help preserve the tissue integrity of the peritoneal membrane in the steady state and possibly during the resolution of acute inflammation.

Protection of donor lung inflation in the setting of cold ischemia against ischemia-reperfusion injury with carbon monoxide, hydrogen, or both in rats.

PubMed

Meng, Chao; Ma, Liangjuan; Niu, Li; Cui, Xiaoguang; Liu, Jinfeng; Kang, Jiyu; Liu, Rongfang; Xing, Jingchun; Jiang, Changlin; Zhou, Huacheng

2016-04-15

Lung ischemia-reperfusion injury (IRI) may be attenuated through carbon monoxide (CO)'s anti-inflammatory effect or hydrogen (H2)'s anti-oxidant effect. In this study, the effects of lung inflation with CO, H2, or both during the cold ischemia phase on graft function were observed. Rat donor lungs, inflated with 40% oxygen (control group), 500ppm CO (CO group), 3% H2 (H2 group) or 500ppm CO+3% H2 (COH group), were kept at 4°C for 180min. After transplantation, the recipients' artery blood gas and pressure-volume (P-V) curves were analyzed. The inflammatory response, oxidative stress and apoptosis in the recipients were assessed at 180min after reperfusion. Oxygenation in the CO and H2 groups were improved compared with the control group. The CO and H2 groups also exhibited significantly improved P-V curves, reduced lung injury, and decreased inflammatory response, malonaldehyde content, and cell apoptosis in the grafts. Furthermore, the COH group experienced enhanced improvements in oxygenation, P-V curves, inflammatory response, lipid peroxidation, and graft apoptosis compared to the CO and H2 groups. Lung inflation with CO or H2 protected against IRI via anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms in a model of lung transplantation in rats, which was enhanced by combined treatment with CO and H2. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of indigenous microbiota on experimental toxoplasmosis in conventional and germ-free mice.

PubMed

Nascimento, Bruna B; Cartelle, Christiane T; Noviello, Maria de L; Pinheiro, Breno V; de Almeida Vitor, Ricardo W; Souza, Danielle da G; de Vasconcelos Generoso, Simone; Cardoso, Valbert N; Martins, Flaviano Dos S; Nicoli, Jacques R; Arantes, Rosa M E

2017-08-01

Toxoplasmosis represents one of the most common zoonoses worldwide. Its agent, Toxoplasma gondii, causes a severe innate pro-inflammatory response. The indigenous intestinal microbiota promotes host animal homoeostasis and may protect the host against pathogens. Germ-free (GF) animals provide an important tool for the study of interactions between host and microbiota. In this study, we assessed the role of indigenous microorganisms in disease development utilizing a murine toxoplasmosis model, which includes conventional (CV) and GF NIH Swiss mice. CV and GF mice orally inoculated with T. gondii had similar survival curves. However, disease developed differently in the two animal groups. In CV mice, intestinal permeability increased and levels of intestinal pro-inflammatory cytokines were altered. In GF animals, there were discrete epithelial degenerative changes and mucosal oedema, but the liver and lungs displayed significant lesions. We conclude that, despite similar survival curves, CV animals succumb to an exaggerated inflammatory response, whereas GF mice fail to produce an adequate systemic response. © 2017 The Authors. International Journal of Experimental Pathology © 2017 International Journal of Experimental Pathology.

High serum soluble tumor necrosis factor receptor 1 predicts poor treatment response in acute-stage schizophrenia.

PubMed

Nishimon, Shohei; Ohnuma, Tohru; Takebayashi, Yuto; Katsuta, Narimasa; Takeda, Mayu; Nakamura, Toru; Sannohe, Takahiro; Higashiyama, Ryoko; Kimoto, Ayako; Shibata, Nobuto; Gohda, Tomohito; Suzuki, Yusuke; Yamagishi, Sho-Ichi; Tomino, Yasuhiko; Arai, Heii

2017-06-02

Inflammation may be involved in the pathophysiology of schizophrenia. However, few cross-sectional or longitudinal studies have examined changes in biomarker expression to evaluate diagnostic and prognostic efficacy in acute-stage schizophrenia. We compared serum inflammatory biomarker concentrations in 87 patients with acute-stage schizophrenia on admission to 105 age-, sex-, and body mass index (BMI)-matched healthy controls. The measured biomarkers were soluble tumor necrosis factor receptor 1 (sTNFR1) and adiponectin, which are associated with inflammatory responses, and pigment epithelium-derived factor (PEDF), which has anti-inflammatory properties. We then investigated biomarker concentrations and associations with clinical factors in 213 patients (including 42 medication-free patients) and 110 unmatched healthy controls to model conditions typical of clinical practice. Clinical symptoms were assessed using the Brief Psychiatric Rating Scale and Global Assessment of Function. In 121 patients, biomarker levels and clinical status were evaluated at both admission and discharge. Serum sTNFR1 was significantly higher in patients with acute-stage schizophrenia compared to matched controls while no significant group differences were observed for the other markers. Serum sTNFR1 was also significantly higher in the 213 patients compared to unmatched controls. The 42 unmedicated patients had significantly lower PEDF levels compared to controls. Between admission and discharge, sTNFR1 levels decreased significantly; however, biomarker changes did not correlate with clinical symptoms. The discriminant accuracy of sTNFR1 was 93.2% between controls and patients, showing no symptom improvement during care. Inflammation and a low-level anti-inflammatory state may be involved in both schizophrenia pathogenesis and acute-stage onset. High serum sTNFR1 in the acute stage could be a useful prognostic biomarker for treatment response in clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

Specific Inhibition of the Redox Activity of Ape1/Ref-1 by E3330 Blocks Tnf-Α-Induced Activation of Il-8 Production in Liver Cancer Cell Lines

PubMed Central

Vascotto, Carlo; Leonardi, Antonio; Kelley, Mark R.; Tiribelli, Claudio; Tell, Gianluca

2013-01-01

APE1/Ref-1 is a main regulator of cellular response to oxidative stress via DNA-repair function and co-activating activity on the NF-κB transcription factor. APE1 is central in controlling the oxidative stress-based inflammatory processes through modulation of cytokines expression and its overexpression is responsible for the onset of chemoresistance in different tumors including hepatic cancer. We examined the functional role of APE1 overexpression during hepatic cell damage related to fatty acid accumulation and the role of the redox function of APE1 in the inflammatory process. HepG2 cells were stably transfected with functional and non-functional APE1 encoding plasmids and the protective effect of APE1 overexpression toward genotoxic compounds or FAs accumulation, was tested. JHH6 cells were stimulated with TNF-α in the presence or absence of E3330, an APE1 redox inhibitor. IL-8 promoter activity was assessed by a luciferase reporter assay, gene expression by Real-Time PCR and cytokines (IL-6, IL-8, IL-12) levels measured by ELISA. APE1 over-expression did not prevent cytotoxicity induced by lipid accumulation. E3330 treatment prevented the functional activation of NF-κB via the alteration of APE1 subcellular trafficking and reduced IL-6 and IL-8 expression induced by TNF-α and FAs accumulation through blockage of the redox-mediated activation of NF-κB. APE1 overexpression observed in hepatic cancer cells may reflect an adaptive response to cell damage and may be responsible for further cell resistance to chemotherapy and for the onset of inflammatory response. The efficacy of the inhibition of APE1 redox activity in blocking TNF-α and FAs induced inflammatory response opens new perspectives for treatment of inflammatory-based liver diseases. PMID:23967134

Effect of Wild-Type Shigella Species and Attenuated Shigella Vaccine Candidates on Small Intestinal Barrier Function, Antigen Trafficking, and Cytokine Release

PubMed Central

Fiorentino, Maria; Levine, Myron M.

2014-01-01

Bacterial dysentery due to Shigella species is a major cause of morbidity and mortality worldwide. The pathogenesis of Shigella is based on the bacteria's ability to invade and replicate within the colonic epithelium, resulting in severe intestinal inflammatory response and epithelial destruction. Although the mechanisms of pathogenesis of Shigella in the colon have been extensively studied, little is known on the effect of wild-type Shigella on the small intestine and the role of the host response in the development of the disease. Moreover, to the best of our knowledge no studies have described the effects of apically administered Shigella flexneri 2a and S. dysenteriae 1 vaccine strains on human small intestinal enterocytes. The aim of this study was to assess the coordinated functional and immunological human epithelial responses evoked by strains of Shigella and candidate vaccines on small intestinal enterocytes. To model the interactions of Shigella with the intestinal mucosa, we apically exposed monolayers of human intestinal Caco2 cells to increasing bacterial inocula. We monitored changes in paracellular permeability, examined the organization of tight-junctions and the pro-inflammatory response of epithelial cells. Shigella infection of Caco2 monolayers caused severe mucosal damage, apparent as a drastic increase in paracellular permeability and disruption of tight junctions at the cell-cell boundary. Secretion of pro-inflammatory IL-8 was independent of epithelial barrier dysfunction. Shigella vaccine strains elicited a pro-inflammatory response without affecting the intestinal barrier integrity. Our data show that wild-type Shigella infection causes a severe alteration of the barrier function of a small intestinal cell monolayer (a proxy for mucosa) and might contribute (along with enterotoxins) to the induction of watery diarrhea. Diarrhea may be a mechanism by which the host attempts to eliminate harmful bacteria and transport them from the small to the large intestine where they invade colonocytes inducing a strong inflammatory response. PMID:24416363

Inflammatory potential of diet, weight gain, and incidence of overweight/obesity: The SUN cohort.

PubMed

Ramallal, Raúl; Toledo, Estefanía; Martínez, J Alfredo; Shivappa, Nitin; Hébert, James R; Martínez-González, Miguel A; Ruiz-Canela, Miguel

2017-06-01

This study prospectively assessed the association of the inflammatory potential of a diet using the dietary inflammatory index (DII) with average yearly weight changes and incident overweight/obesity. Seven thousand and twenty-seven university graduates with body mass index <25 from the Seguimiento Universidad de Navarra (SUN) cohort were followed up during a median of 8.1 years. The DII, a validated tool based on scientific evidence to appraise the relationship between dietary parameters and inflammatory biomarkers, was used. A validated food-frequency questionnaire was used to assess intake of total energy, food, and nutrients, from which DII scores were calculated at baseline and after 10 years of follow-up. After a median follow-up of 8.1 years, 1,433 incident cases of overweight or obesity were observed. Hazard ratios for overweight/obesity were calculated, including multivariable time-dependent Cox regression models with repeated measures of diet. The hazard ratio for subjects in the highest quartile (most pro-inflammatory diet) was 1.32 (95% confidence interval 1.08-1.60) compared with participants in the lowest quartile (most anti-inflammatory diet), with a significant linear dose-response relationship (P = 0.004). Consistently, increases in average yearly weight gains were significantly associated with proinflammatory diets. A proinflammatory diet was significantly associated with a higher annual weight gain and higher risk of developing new-onset overweight or obesity. © 2017 The Obesity Society.

Persistent inflammatory state after photoreceptor loss in an animal model of retinal degeneration

PubMed Central

Noailles, Agustina; Maneu, Victoria; Campello, Laura; Gómez-Vicente, Violeta; Lax, Pedro; Cuenca, Nicolás

2016-01-01

Microglia act as the resident immune cells of the central nervous system, including the retina. In response to damaging stimuli microglia adopt an activated state, which can progress into a phagocytic phenotype and play a potentially harmful role by eliciting the expression and release of pro-inflammatory cytokines. The aim of the present study was to assess longitudinal changes in microglia during retinal degeneration in the homozygous P23H rat, a model of dominant retinitis pigmentosa. Microglial phenotypes, morphology and density were analyzed by immunohistochemistry, flow cytometry, and cytokine antibody array. In addition, we performed electroretinograms to evaluate the retinal response. In the P23H retina, sclera, choroid and ciliary body, inflammatory cells increased in number compared with the control at all ages analyzed. As the rats became older, a higher number of amoeboid MHC-II+ cells were observed in the P23H retina, which correlated with an increase in the expression of pro-inflammatory cytokines. These findings suggest that, in the P23H model, retinal neuroinflammation persists throughout the rat’s life span even after photoreceptor depletion. Therefore, the inclusion of anti-inflammatory drugs at advanced stages of the neurodegenerative process may provide better retinal fitness so the remaining cells could still be used as targets of cellular or gene therapies. PMID:27624537

Magnetic resonance measurement of muscle T2, fat-corrected T2 and fat fraction in the assessment of idiopathic inflammatory myopathies

PubMed Central

Yao, Lawrence; Yip, Adrienne L.; Shrader, Joseph A.; Mesdaghinia, Sepehr; Volochayev, Rita; Jansen, Anna V.; Miller, Frederick W.

2016-01-01

Objective. This study examines the utility of MRI, including T2 maps and T2 maps corrected for muscle fat content, in evaluating patients with idiopathic inflammatory myopathy. Methods. A total of 44 patients with idiopathic inflammatory myopathy, 18 of whom were evaluated after treatment with rituximab, underwent MRI of the thighs and detailed clinical assessment. T2, fat fraction (FF) and fat corrected T2 (fc-T2) maps were generated from standardized MRI scans, and compared with semi-quantitative scoring of short tau inversion recovery (STIR) and T1-weighted sequences, as well as various myositis disease metrics, including the Physician Global Activity, the modified Childhood Myositis Assessment Scale and the muscle domain of the Myositis Disease Activity Assessment Tool-muscle (MDAAT-muscle). Results. Mean T2 and mean fc-T2 correlated similarly with STIR scores (Spearman rs = 0.64 and 0.64, P < 0.01), while mean FF correlated with T1 damage scores (rs = 0.69, P < 0.001). Baseline T2, fc-T2 and STIR scores correlated significantly with the Physician Global Activity, modified Childhood Myositis Assessment Scale and MDAAT-muscle (rs range = 0.41–0.74, P < 0.01). The response of MRI measures to rituximab was variable, and did not significantly agree with a standardized clinical definition of improvement. Standardized response means for the MRI measures were similar. Conclusion. Muscle T2, fc-T2 and FF measurements exhibit content validity with reference to semi-quantitative scoring of STIR and T1 MRI, and also exhibit construct validity with reference to several myositis activity and damage measures. T2 was as responsive as fc-T2 and STIR scoring, although progression of muscle damage was negligible during the study. PMID:26412808

Trauma-induced systemic inflammatory response versus exercise-induced immunomodulatory effects.

PubMed

Fehrenbach, Elvira; Schneider, Marion E

2006-01-01

Accidental trauma and heavy endurance exercise, both induce a kind of systemic inflammatory response, also called systemic inflammatory response syndrome (SIRS). Exercise-related SIRS is conditioned by hyperthermia and concomitant heat shock responses, whereas trauma-induced SIRS manifests concomitantly with tissue necrosis and immune activation, secondarily followed by fever. Inflammatory cytokines are common denominators in both trauma and exercise, although there are marked quantitative differences. Different anti-inflammatory cytokines may be involved in the control of inflammation in trauma- and exercise-induced stress. Exercise leads to a balanced equilibrium between inflammatory and anti-inflammatory responses. Intermittent states of rest, as well as anti-oxidant capacity, are lacking or minor in trauma but are high in exercising individuals. Regular training may enhance immune competence, whereas trauma-induced SIRS often paves the way for infectious complications, such as sepsis.

NSAID-activated gene 1 and its implications for mucosal integrity and intervention beyond NSAIDs.

PubMed

Moon, Yuseok

2017-07-01

In spite of the beneficial actions of non-steroid anti-inflammatory drugs (NSAIDs) in epithelial inflammation and cancers, their use is limited because of their cyclooxygenase-dependent or independent gastrointestinal toxicity. As an eicosanoid-independent mediator, NSAID-activated gene 1 (NAG-1) has been assessed for its involvement in cellular integrity and pathogenesis in mucosal inflammation and carcinogenesis. At the cellular levels, NAG-1 is involved in the cell growth regulation (cell death, cell cycle arrest, or proliferation) in epithelial and mesenchymal tissues. Moreover, NAG-1 can modulate inflammatory responses in either direct or indirect manner, which ultimately affects fibrogenic and tumorigenic processes in various disease states. Finally, NAG-1 has been assessed for its contribution to cellular behavior, such as the mobility of epithelial and malignant cells in response to the external insults or oncogenic stimulation in the mucosa. This review on the "Yin-Yang" nature of NAG-1-mediated responses provides comprehensive insights into therapeutic and diagnostic interventions for mucosal health and integrity in the human body. Copyright © 2017 Elsevier Ltd. All rights reserved.

Histamine release and fibrinogen adsorption mediate acute inflammatory responses to biomaterial implants in humans

PubMed Central

Zdolsek, Johann; Eaton, John W; Tang, Liping

2007-01-01

Background Medical implants often fail as a result of so-called foreign body reactions during which inflammatory cells are recruited to implant surfaces. Despite the clinical importance of this phenomenon, the mechanisms involved in these reactions to biomedical implants in humans are not well understood. The results from animal studies suggest that both fibrinogen adsorption to the implant surface and histamine release by local mast cells are involved in biomaterial-mediated acute inflammatory responses. The purpose of this study was to test this hypothesis in humans. Methods Thirteen male medical student volunteers (Caucasian, 21–30 years of age) were employed for this study. To assess the importance of fibrinogen adsorption, six volunteers were implanted with polyethylene teraphthalate disks pre-coated with their own (fibrinogen-containing) plasma or (fibrinogen-free) serum. To evaluate the importance of histamine, seven volunteers were implanted with uncoated disks with or without prior oral administration of histamine receptor antagonists. The acute inflammatory response was estimated 24 hours later by measuring the activities of implant-associated phagocyte-specific enzymes. Results Plasma coated implants accumulated significantly more phagocytes than did serum coated implants and the recruited cells were predominantly macrophage/monocytes. Administration of both H1 and H2 histamine receptor antagonists greatly reduced the recruitment of macrophages/monocytes and neutrophils on implant surfaces. Conclusion In humans – as in rodents – biomaterial-mediated inflammatory responses involve at least two crucial events: histamine-mediated phagocyte recruitment and phagocyte accumulation on implant surfaces engendered by spontaneously adsorbed host fibrinogen. Based on these results, we conclude that reducing fibrinogen:surface interactions should enhance biocompatibility and that administration of histamine receptor antagonists prior to, and shortly after, medical device implantation should improve the functionality and longevity of medical implants. PMID:17603911

Systemic Chemical Desensitization of Peptidergic Sensory Neurons with Resiniferatoxin Inhibits Experimental Periodontitis

PubMed Central

Breivik, Torbjørn; Gundersen, Yngvar; Gjermo, Per; Fristad, Inge; Opstad, Per Kristian

2011-01-01

Background and objective: The immune system is an important player in the pathophysiology of periodontitis. The brain controls immune responses via neural and hormonal pathways, and brain-neuro-endocrine dysregulation may be a central determinant for pathogenesis. Our current knowledge also emphasizes the central role of sensory nerves. In line with this, we wanted to investigate how desensitization of peptidergic sensory neurons influences the progression of ligature-induced periodontitis, and, furthermore, how selected cytokine and stress hormone responses to Gram-negative bacterial lipopolysaccharide (LPS) stimulation are affected. Material and methods: Resiniferatoxin (RTX; 50 μg/kg) or vehicle was injected subcutaneously on days 1, 2, and 3 in stress high responding and periodontitis-susceptible Fischer 344 rats. Periodontitis was induced 2 days thereafter. Progression of the disease was assessed after the ligatures had been in place for 20 days. Two h before decapitation all rats received LPS (150 μg/kg i.p.) to induce a robust immune and stress response. Results: Desensitization with RTX significantly reduced bone loss as measured by digital X-rays. LPS provoked a significantly higher increase in serum levels of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α, but lower serum levels of the anti-inflammatory cytokine interleukin (IL)-10 and the stress hormone corticosterone. Conclusions: In this model RTX-induced chemical desensitization of sensory peptidergic neurons attenuated ligature-induced periodontitis and promoted a shift towards stronger pro-inflammatory cytokine and weaker stress hormone responses to LPS. The results may partly be explained by the attenuated transmission of immuno-inflammatory signals to the brain. In turn, this may weaken the anti-inflammatory brain-derived pathways. PMID:21339860

Sex Differences in Depressive and Socioemotional Responses to an Inflammatory Challenge: Implications for Sex Differences in Depression

PubMed Central

Moieni, Mona; Irwin, Michael R; Jevtic, Ivana; Olmstead, Richard; Breen, Elizabeth C; Eisenberger, Naomi I

2015-01-01

Substantial evidence demonstrates that inflammatory processes may underlie depression for a subset of patients, including work showing that healthy subjects exposed to an inflammatory challenge show increases in depressed mood and feelings of social disconnection. However, despite the fact that depression is two times as likely to occur in females than males, the vast majority of this work has been carried out in males. Thus, the objective of this study was to determine whether females (vs males) would show greater increases in proinflammatory cytokines, depressed mood, and social disconnection in response to an inflammatory challenge. One hundred and fifteen healthy participants (69 female) completed this double-blind, placebo-controlled, randomized clinical trial in which participants were randomly assigned to receive either a single infusion of low-dose endotoxin (derived from Escherichia coli; 0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline). Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), depressed mood, and feelings of social disconnection were assessed hourly. Results showed that endotoxin (vs placebo) led to increases in proinflammatory cytokines (TNF-α, IL-6), depressed mood, and feelings of social disconnection. Females exposed to endotoxin showed greater increases in depressed mood and feelings of social disconnection. Furthermore, increases in TNF-α and IL-6 were correlated with increases in social disconnection for females but not for males. These sex differences in the relationships between inflammatory and socioemotional responses to an inflammatory challenge may be particularly important for understanding why females are two times as likely as males to develop depressive disorders. PMID:25598426

Histological evaluations and inflammatory responses of different dental implant abutment materials: A human histology pilot study.

PubMed

Sampatanukul, Teeratida; Serichetaphongse, Pravej; Pimkhaokham, Atiphan

2018-04-01

Improvements of soft tissue to the abutment surface results in more stable peri-implant conditions, however, few human histological studies have compared soft tissue responses around different abutment materials. To describe the peri-implant tissue around 3 abutment materials; titanium, zirconia, and gold alloy, over an 8-week healing period. Fifteen edentulous sites were treated with implants. Eight weeks later, peri-implant tissue was harvested and processed using a nonseparation resin embedded technique. The tissue attachment characteristics were assessed at clinical stages using the gingival index (GI) score, surgical stage (surgical score), and histological stage (histological attachment percentage). Additionally, the inflammatory responses were evaluated using inflammatory extent and inflammatory cellularity grades. Nonparametrical statistics were used to describe the GI and surgical scores, and analytical statistics were used to analyze the histological attachment percentages as well as the inflammatory extent and cellularity grades amongst the 3 groups. There were no statistically significant differences among the groups for GI score (P = .071) and surgical score (P = .262). Titanium and zirconia exhibited nearly similar mean histological attachment percentages while gold alloy had a significantly lower percentage (P = .004). For the inflammatory extent and cellularity grades, the odds of being one grade higher for gold alloy abutment was 5.18 and 17.8 times that of titanium abutment, respectively. However, for the zirconia abutment, the odds were 0.87 and 7.5 times higher than the titanium group. The tissue around the gold alloy abutments resulted in worse attachment conditions compared with the titanium and zirconia abutments. Inflammation tended to be higher in the tissue around the gold alloy abutments than the titanium and zirconia abutments. © 2017 Wiley Periodicals, Inc.

Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoEnull Mice

PubMed Central

Chukkapalli, Sasanka S.; Velsko, Irina M.; Rivera-Kweh, Mercedes F.; Zheng, Donghang; Lucas, Alexandra R.; Kesavalu, Lakshmyya

2015-01-01

Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoEnull mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoEnull hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoEnull mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model. PMID:26619277

Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE null Mice.

PubMed

Chukkapalli, Sasanka S; Velsko, Irina M; Rivera-Kweh, Mercedes F; Zheng, Donghang; Lucas, Alexandra R; Kesavalu, Lakshmyya

2015-01-01

Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE null mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE null hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE null mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.

Androgen Deprivation Accelerates the Prostatic Urethra Wound Healing After Thulium Laser Resection of the Prostate by Promoting Re-Epithelialization and Regulating the Macrophage Polarization.

PubMed

Wang, Xing-Jie; Zhuo, Jian; Luo, Guang-Heng; Zhu, Yi-Ping; Yu, Dian-Jun; Zhao, Rui-Zhe; Jiang, Chen-Yi; Shi, Yun-Feng; Li, Hao; Chen, Lei; Hao, Kui-Yuan; Han, Xia; Zhao, Sheng; Bei, Xiao-Yu; Jing, Yi-Feng; Xia, Shu-Jie

2017-05-01

Complications after a thulium laser resection of the prostate (TmLRP) are related to re-epithelialization of the prostatic urethra. Since prostate growth and development are induced by androgen, the aim of this study was to determine the role and explore the mechanism of androgen in wound healing of the prostatic urethra. Beagles that received TmLRPs were randomly distributed into a castration group, a testosterone undecanoate (TU) group, and a control group. The prostate wound was assessed once a week using a cystoscope. Histological analysis was then carried out to study the re-epithelialization of the prostatic urethra in each group. The inflammatory response in the wound tissue and urine was also investigated. The healing of the prostatic urethra after a TmLRP was more rapid in the castration group and slower in the TU group than that in the control group. Castration accelerated re-epithelialization by promoting basal cell proliferation in the wound surface and beneath the wound and by accelerating the differentiation of basal cells into urothelial cells. Castration reduced the duration of the inflammatory phase and induced the conversion of M1 macrophages to M2 macrophages, thus accelerating the maturation of the wound. By contrast, androgen supplementation enhanced the inflammatory response and prolonged the inflammatory phase. Moreover, the anti-inflammatory phase was delayed and weakened. Androgen deprivation promotes re-epithelialization of the wound, regulates the inflammatory response, and accelerates wound healing of the prostatic urethra after a TmLRP. Prostate 77:708-717, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Better cognitive control of emotional information is associated with reduced pro-inflammatory cytokine reactivity to emotional stress.

PubMed

Shields, Grant S; Kuchenbecker, Shari Young; Pressman, Sarah D; Sumida, Ken D; Slavich, George M

2016-01-01

Stress is strongly associated with several mental and physical health problems that involve inflammation, including asthma, cardiovascular disease, certain types of cancer, and depression. It has been hypothesized that better cognitive control of emotional information may lead to reduced inflammatory reactivity to stress and thus better health, but to date no studies have examined whether differences in cognitive control predict pro-inflammatory cytokine responses to stress. To address this issue, we conducted a laboratory-based experimental study in which we randomly assigned healthy young-adult females to either an acute emotional stress (emotionally evocative video) or no-stress (control video) condition. Salivary levels of the key pro-inflammatory cytokines IL-1β, IL-6, and IL-8 were measured before and after the experimental manipulation, and following the last cytokine sample, we assessed participants' cognitive control of emotional information using an emotional Stroop task. We also assessed participants' cortisol levels before and after the manipulation to verify that documented effects were specific to cytokines and not simply due to increased nonwater salivary output. As hypothesized, the emotional stressor triggered significant increases in IL-1β, IL-6, and IL-8. Moreover, even in fully adjusted models, better cognitive control following the emotional (but not control) video predicted less pronounced cytokine responses to that stressor. In contrast, no effects were observed for cortisol. These data thus indicate that better cognitive control specifically following an emotional stressor is uniquely associated with less pronounced pro-inflammatory cytokine reactivity to such stress. These findings may therefore help explain why superior cognitive control portends better health over the lifespan.

Morin protects gastric mucosa from nonsteroidal anti-inflammatory drug, indomethacin induced inflammatory damage and apoptosis by modulating NF-κB pathway.

PubMed

Sinha, Krishnendu; Sadhukhan, Pritam; Saha, Sukanya; Pal, Pabitra Bikash; Sil, Parames C

2015-04-01

Deregulation in prostaglandin (PG) biosynthesis, severe oxidative stress, inflammation and apoptosis contribute to the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. Unfortunately, most of the prescribed anti-ulcer drugs generate various side effects. In this scenario, we could consider morin as a safe herbal potential agent against IND-gastropathy and rationalize its action systematically. Rats were pretreated with morin for 30 min followed by IND (48 mgkg(-1)) administration for 4 h. The anti-ulcerogenic nature of morin was assessed by morphological and histological analysis. Its effects on the inflammatory (MPO, cytokines, adhesion molecules), ulcer-healing (COXs, PGE(2)), and signaling parameters (NF-κB and apoptotic signaling) were assessed by biochemical, RP-HPLC, immunoblots, IHC, RT-PCR, and ELISA at the time points of their maximal changes due to IND administration. IND induced NF-κB and apoptotic signaling in rat's gastric mucosa. These increased proinflammatory responses, but reduced the antioxidant enzymes and other protective factors. Morin reversed all the adverse effects to prevent IND-induced gastric ulceration in a PGE2 independent manner. Also, it did not affect the absorption and/or primary pharmacological activity of IND. The gastroprotective action of morin is primarily attributed to its potent antioxidant nature that also helps in controlling several IND-induced inflammatory responses. For the first time, the study reveals a mechanistic basis of morin mediated protective action against IND-induced gastropathy. As morin is a naturally abundant safe antioxidant, future detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as a gastroprotective agent. Copyright © 2015 Elsevier B.V. All rights reserved.

Lamellar pro-inflammatory cytokine expression patterns in laminitis at the developmental stage and at the onset of lameness: innate vs. adaptive immune response.

PubMed

Belknap, J K; Giguère, S; Pettigrew, A; Cochran, A M; Van Eps, A W; Pollitt, C C

2007-01-01

Recent research has indicated that inflammation plays a role in the early stages of laminitis and that, similar to organ failure in human sepsis, early inflammatory mechanisms may lead to downstream events resulting in lamellar failure. Characterisation of the type of immune response (i.e. innate vs. adaptive) is essential in order to develop therapeutic strategies to counteract these deleterious events. To quantitate gene expression of pro-inflammatory cytokines known to be important in the innate and adaptive immune response during the early stages of laminitis, using both the black walnut extract (BWE) and oligofructose (OF) models of laminitis. Real-time qPCR was used to assess lamellar mRNA expression of interleukins-1beta, 2, 4, 6, 8, 10, 12 and 18, and tumour necrosis factor alpha and interferon gamma at the developmental stage and at the onset of lameness. Significantly increased lamellar mRNA expression of cytokines important in the innate immune response were present at the developmental stage of the BWE model, and at the onset of acute lameness in both the BWE model and OF model. Of the cytokines characteristic of the Th1 and Th2 arms of the adaptive immune response, a mixed response was noted at the onset of acute lameness in the BWE model, whereas the response was skewed towards a Th1 response at the onset of lameness in the OF model. Lamellar inflammation is characterised by strong innate immune response in the developmental stages of laminitis; and a mixture of innate and adaptive immune responses at the onset of lameness. These results indicate that anti-inflammatory treatment of early stage laminitis (and the horse at risk of laminitis) should include not only therapeutic drugs that address prostanoid activity, but should also address the marked increases in lamellar cytokine expression.

Effects of wear particles of polyether-ether-ketone and cobalt-chromium-molybdenum on CD4- and CD8-T-cell responses

PubMed Central

Du, Zhe; Wang, Shujun; Yue, Bing; Wang, Ying; Wang, You

2018-01-01

T-cells, second only to macrophages, are often considered as the potential cells involved in debris-related failure of arthroplasty. Here, we assessed the effects of particulate wear debris on T-cells and inflammatory reactions. Blood samples from 25 donors were incubated with polyether-ether-ketone (PEEK) and cobalt-chromium-molybdenum (CoCrMo) particles generated by custom cryo-milling and pulverization. The T-cell phenotypes were assessed using immunostaining and flow cytometry. For the in vivo study, 0.1 mL of each particle suspension (approximately 1.0 × 108 wear particles) was injected into murine knee joints; the synovium and spleen were collected one week after the operation for histological examination and immunofluorescence staining. The T-cell responses observed included low-level activation of Th1, Th2, Th17, and CD8+ pathways after 72 h of co-culture of the particles with peripheral blood mononuclear cells. Obvious CD8+ T-cell responses were observed in local synovium and peripheral spleen, with higher inflammatory cytokine expression in the CoCrMo group. Relatively minor cytotoxic and immunological reactions were observed in vitro, with PEEK and CoCrMo particle-induced immune responses being primarily mediated by CD8+ T-cells, rather than CD4+ T-cells, in vivo. Overall, PEEK wear particles induced fewer inflammatory reactions than CoCrMo particles. This study verified that PEEK was suitable as a potential alternative for metals in total knee replacements in terms of the immunological reaction to PEEK particles, and shed light on the effects of wear particles from polymer and metal-based implants on immune responses. PMID:29541407

Effects of wear particles of polyether-ether-ketone and cobalt-chromium-molybdenum on CD4- and CD8-T-cell responses.

PubMed

Du, Zhe; Wang, Shujun; Yue, Bing; Wang, Ying; Wang, You

2018-02-16

T-cells, second only to macrophages, are often considered as the potential cells involved in debris-related failure of arthroplasty. Here, we assessed the effects of particulate wear debris on T-cells and inflammatory reactions. Blood samples from 25 donors were incubated with polyether-ether-ketone (PEEK) and cobalt-chromium-molybdenum (CoCrMo) particles generated by custom cryo-milling and pulverization. The T-cell phenotypes were assessed using immunostaining and flow cytometry. For the in vivo study, 0.1 mL of each particle suspension (approximately 1.0 × 10 8 wear particles) was injected into murine knee joints; the synovium and spleen were collected one week after the operation for histological examination and immunofluorescence staining. The T-cell responses observed included low-level activation of Th1, Th2, Th17, and CD8+ pathways after 72 h of co-culture of the particles with peripheral blood mononuclear cells. Obvious CD8+ T-cell responses were observed in local synovium and peripheral spleen, with higher inflammatory cytokine expression in the CoCrMo group. Relatively minor cytotoxic and immunological reactions were observed in vitro , with PEEK and CoCrMo particle-induced immune responses being primarily mediated by CD8+ T-cells, rather than CD4+ T-cells, in vivo . Overall, PEEK wear particles induced fewer inflammatory reactions than CoCrMo particles. This study verified that PEEK was suitable as a potential alternative for metals in total knee replacements in terms of the immunological reaction to PEEK particles, and shed light on the effects of wear particles from polymer and metal-based implants on immune responses.

Derivation and Validation of a Biomarker-Based Clinical Algorithm to Rule Out Sepsis From Noninfectious Systemic Inflammatory Response Syndrome at Emergency Department Admission: A Multicenter Prospective Study.

PubMed

Mearelli, Filippo; Fiotti, Nicola; Giansante, Carlo; Casarsa, Chiara; Orso, Daniele; De Helmersen, Marco; Altamura, Nicola; Ruscio, Maurizio; Castello, Luigi Mario; Colonetti, Efrem; Marino, Rossella; Barbati, Giulia; Bregnocchi, Andrea; Ronco, Claudio; Lupia, Enrico; Montrucchio, Giuseppe; Muiesan, Maria Lorenza; Di Somma, Salvatore; Avanzi, Gian Carlo; Biolo, Gianni

2018-05-07

To derive and validate a predictive algorithm integrating a nomogram-based prediction of the pretest probability of infection with a panel of serum biomarkers, which could robustly differentiate sepsis/septic shock from noninfectious systemic inflammatory response syndrome. Multicenter prospective study. At emergency department admission in five University hospitals. Nine-hundred forty-seven adults in inception cohort and 185 adults in validation cohort. None. A nomogram, including age, Sequential Organ Failure Assessment score, recent antimicrobial therapy, hyperthermia, leukocytosis, and high C-reactive protein values, was built in order to take data from 716 infected patients and 120 patients with noninfectious systemic inflammatory response syndrome to predict pretest probability of infection. Then, the best combination of procalcitonin, soluble phospholypase A2 group IIA, presepsin, soluble interleukin-2 receptor α, and soluble triggering receptor expressed on myeloid cell-1 was applied in order to categorize patients as "likely" or "unlikely" to be infected. The predictive algorithm required only procalcitonin backed up with soluble phospholypase A2 group IIA determined in 29% of the patients to rule out sepsis/septic shock with a negative predictive value of 93%. In a validation cohort of 158 patients, predictive algorithm reached 100% of negative predictive value requiring biomarker measurements in 18% of the population. We have developed and validated a high-performing, reproducible, and parsimonious algorithm to assist emergency department physicians in distinguishing sepsis/septic shock from noninfectious systemic inflammatory response syndrome.

Adoptively transferred dendritic cells restore primary cell-mediated inflammatory competence to acutely malnourished weanling mice.

PubMed

Hillyer, Lyn; Whitley, Charlene; Olver, Amy; Webster, Michelle; Steevels, Tessa; Woodward, Bill

2008-02-01

Immune depression associated with prepubescent malnutrition underlies a staggering burden of infection-related morbidity. This investigation centered on dendritic cells as potentially decisive in this phenomenon. C57BL/6J mice, initially 19 days old, had free access for 14 days to a complete diet or to a low-protein formulation that induced wasting deficits of protein and energy. Mice were sensitized by i.p. injection of sheep red blood cells on day 9, at which time one-half of the animals in each dietary group received a simultaneous injection of 10(6) syngeneic dendritic cells (JAWS II). All mice were challenged with the immunizing antigen in the right hind footpad on day 13, and the 24-hour delayed hypersensitivity response was assessed as percentage increase in footpad thickness. The low-protein diet reduced the inflammatory immune response, but JAWS cells, which exhibited immature phenotypic and functional characteristics, increased the response of both the malnourished group and the controls. By contrast, i.p. injection of 10(6) syngeneic T cells did not influence the inflammatory immune response of mice subjected to the low-protein protocol. Antigen-presenting cell numbers limited primary inflammatory cell-mediated competence in this model of wasting malnutrition, an outcome that challenges the prevailing multifactorial model of malnutrition-associated immune depression. Thus, a new dendritic cell-centered perspective emerges regarding the cellular mechanism underlying immune depression in acute pediatric protein and energy deficit.

Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study.

PubMed

Montón, C; Ewig, S; Torres, A; El-Ebiary, M; Filella, X; Rañó, A; Xaubet, A

1999-07-01

The aim of the study was to assess the potential role of glucocorticoids (GC) in modulating systemic and pulmonary inflammatory responses in mechanically ventilated patients with severe pneumonia. Twenty mechanically ventilated patients with pneumonia treated at a respiratory intensive care unit (RICU) of a 1,000-bed teaching hospital were prospectively studied. All patients had received prior antimicrobial treatment. Eleven patients received GC (mean+/-SD dose of i.v. methylprednisolone 677+/-508 mg for 9+/-7 days), mainly for bronchial dilatation. Serum and bronchoalveolar lavage fluid (BALF) tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and C-reactive protein levels were measured in all patients. The inflammatory response was attenuated in patients receiving GC, both systemically (IL-6 1,089+/-342 versus 630+/-385 pg x mL(-1), p=0.03; C-reactive protein 34+/-5 versus 19+/-5 mg x L(-1), p=0.04) and locally in BALF (TNF-alpha 118+/-50 versus 24+/-5 pg x mL(-1), p= 0.05; neutrophil count: 2.4+/-1.1 x 10(9) cells x L(-1) (93+/-3%) versus 1.9+/-1.8 x 10(9) cells x L(-1) (57+/-16%), p=0.03). Four of the 11 (36%) patients receiving GC died compared to six (67%) who were not receiving GC (p=0.37). The present pilot study suggests that glucocorticoids decrease systemic and lung inflammatory responses in mechanically ventilated patients with severe pneumonia receiving antimicrobial treatment.

Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease

PubMed Central

Scott, Frank I.; Lichtenstein, Gary R.

2014-01-01

While anti-TNF agents have had a marked impact in the treatment of inflammatory bowel disease, a significant number of patients lose their response to these medications over time. Clinical trials have demonstrated that antibodies against anti-TNF medications may impact treatment response and increase the risk of infusion reaction. Scheduled dosing and concurrent use of immunomodulators may help to mitigate these risks via inhibiting the formation of these antibodies. The recent availability of assays to measure anti-TNF drug levels and antibodies against anti-TNFs offer the opportunity to assess patients who have lost response with infliximab and adalimumab, and potentially determine the most appropriate therapeutic strategy. There is growing evidence that such testing improves patient outcomes and is cost-effective, although heterogeneity in the assays used in clinical and observational trials has resulted in mixed results. PMID:24452768

Evidence of the impact of systemic inflammation on neuroinflammation from a non-bacterial endotoxin animal model.

PubMed

Huang, Chunxia; Irwin, Michael Garnet; Wong, Gordon Tin Chun; Chang, Raymond Chuen Chung

2018-05-17

Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term. In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed. Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1β, IL-6, and TNF-α), and hippocampus (IL-1β and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus. Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.

Comparative analysis of histopathologic effects of synthetic meshes based on material, weight, and pore size in mice.

PubMed

Orenstein, Sean B; Saberski, Ean R; Kreutzer, Donald L; Novitsky, Yuri W

2012-08-01

While synthetic prosthetics have essentially become mandatory for hernia repair, mesh-induced chronic inflammation and scarring can lead to chronic pain and limited mobility. Mesh propensity to induce such adverse effects is likely related to the prosthetic's material, weight, and/or pore size. We aimed to compare histopathologic responses to various synthetic meshes after short- and long-term implantations in mice. Samples of macroporous polyester (Parietex [PX]), heavyweight microporous polypropylene (Trelex[TX]), midweight microporous polypropylene (ProLite[PL]), lightweight macroporous polypropylene (Ultrapro[UP]), and expanded polytetrafluoroethylene (DualMesh[DM]) were implanted subcutaneously in mice. Four and 12 wk post-implantation, meshes were assessed for inflammation, foreign body reaction (FBR), and fibrosis. All meshes induced varying levels of inflammatory responses. PX induced the greatest inflammatory response and marked FBR. DM induced moderate FBR and a strong fibrotic response with mesh encapsulation at 12 wk. UP and PL had the lowest FBR, however, UP induced a significant chronic inflammatory response. Although inflammation decreased slightly for TX, marked FBR was present throughout the study. Of the three polypropylene meshes, fibrosis was greatest for TX and slightly reduced for PL and UP. For UP and PL, there was limited fibrosis within each mesh pore. Polyester mesh induced the greatest FBR and lasting chronic inflammatory response. Likewise, marked fibrosis and encapsulation was seen surrounding ePTFE. Heavier polypropylene meshes displayed greater early and persistent fibrosis; the reduced-weight polypropylene meshes were associated with the least amount of fibrosis. Mesh pore size was inversely proportional to bridging fibrosis. Moreover, reduced-weight polypropylene meshes demonstrated the smallest FBR throughout the study. Overall, we demonstrated that macroporous, reduced-weight polypropylene mesh exhibited the highest degree of biocompatibility at sites of mesh implantation. Copyright © 2012 Elsevier Inc. All rights reserved.

Mycolactone displays anti-inflammatory effects on the nervous system

PubMed Central

Isaac, Caroline; Mauborgne, Annie; Grimaldi, Alfonso; Ade, Kemy; Pohl, Michel; Limatola, Cristina; Boucher, Yves; Demangel, Caroline

2017-01-01

Background Mycolactone is a macrolide produced by the skin pathogen Mycobacterium ulcerans, with cytotoxic, analgesic and immunomodulatory properties. The latter were recently shown to result from mycolactone blocking the Sec61-dependent production of pro-inflammatory mediators by immune cells. Here we investigated whether mycolactone similarly affects the inflammatory responses of the nervous cell subsets involved in pain perception, transmission and maintenance. We also investigated the effects of mycolactone on the neuroinflammation that is associated with chronic pain in vivo. Methodology/ Principle findings Sensory neurons, Schwann cells and microglia were isolated from mice for ex vivo assessment of mycolactone cytotoxicity and immunomodulatory activity by measuring the production of proalgesic cytokines and chemokines. In all cell types studied, prolonged (>48h) exposure to mycolactone induced significant cell death at concentrations >10 ng/ml. Within the first 24h treatment, nanomolar concentrations of mycolactone efficiently suppressed the cell production of pro-inflammatory mediators, without affecting their viability. Notably, mycolactone also prevented the pro-inflammatory polarization of cortical microglia. Since these cells critically contribute to neuroinflammation, we next tested if mycolactone impacts this pathogenic process in vivo. We used a rat model of neuropathic pain induced by chronic constriction of the sciatic nerve. Here, mycolactone was injected daily for 3 days in the spinal canal, to ensure its proper delivery to spinal cord. While this treatment failed to prevent injury-induced neuroinflammation, it decreased significantly the local production of inflammatory cytokines without inducing detectable cytotoxicity. Conclusion/ Significance The present study provides in vitro and in vivo evidence that mycolactone suppresses the inflammatory responses of sensory neurons, Schwann cells and microglia, without affecting the cell viability. Together with previous studies using peripheral blood leukocytes, our work implies that mycolactone-mediated analgesia may, at least partially, be explained by its anti-inflammatory properties. PMID:29149212

N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury.

PubMed

Wigenstam, Elisabeth; Koch, Bo; Bucht, Anders; Jonasson, Sofia

2015-02-03

Chlorine (Cl2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1h after Cl2-exposure could improve protection against acute lung injury in Cl2-exposed mice. BALB/c mice were exposed to 300 ppm Cl2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated. Copyright © 2014. Published by Elsevier Ireland Ltd.

A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies.

PubMed

Calder, P C; Ahluwalia, N; Albers, R; Bosco, N; Bourdet-Sicard, R; Haller, D; Holgate, S T; Jönsson, L S; Latulippe, M E; Marcos, A; Moreines, J; M'Rini, C; Müller, M; Pawelec, G; van Neerven, R J J; Watzl, B; Zhao, J

2013-01-01

To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation.

Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality.

PubMed

Osuchowski, Marcin F; Welch, Kathy; Siddiqui, Javed; Remick, Daniel G

2006-08-01

Mortality in sepsis remains unacceptably high and attempts to modulate the inflammatory response failed to improve survival. Previous reports postulated that the sepsis-triggered immunological cascade is multimodal: initial systemic inflammatory response syndrome (SIRS; excessive pro-, but no/low anti-inflammatory plasma mediators), intermediate homeostasis with a mixed anti-inflammatory response syndrome (MARS; both pro- and anti-inflammatory mediators) and final compensatory anti-inflammatory response syndrome (CARS; excessive anti-, but no/low proinflammatory mediators). To verify this, we examined the evolution of the inflammatory response during the early phase of murine sepsis by repetitive blood sampling of septic animals. Increased plasma concentrations of proinflammatory (IL-6, TNF, IL-1beta, KC, MIP-2, MCP-1, and eotaxin) and anti-inflammatory (TNF soluble receptors, IL-10, IL-1 receptor antagonist) cytokines were observed in early deaths (days 1-5). These elevations occurred simultaneously for both the pro- and anti-inflammatory mediators. Plasma levels of IL-6 (26 ng/ml), TNF-alpha (12 ng/ml), KC (33 ng/ml), MIP-2 (14 ng/ml), IL-1 receptor antagonist (65 ng/ml), TNF soluble receptor I (3 ng/ml), and TNF soluble receptor II (14 ng/ml) accurately predicted mortality within 24 h. In contrast, these parameters were not elevated in either the late-deaths (day 6-28) or survivors. Surprisingly, either pro- or anti-inflammatory cytokines were also reliable in predicting mortality up to 48 h before outcome. These data demonstrate that the initial inflammatory response directly correlates to early but not late sepsis mortality. This multifaceted response questions the use of a simple proinflammatory cytokine measurement for classifying the inflammatory status during sepsis.

Importance of basophils in eosinophilic asthma: the murine counterpart.

PubMed

Poddighe, D; Mathias, C B; Brambilla, I; Marseglia, G L; Oettgen, H C

2018-01-01

Several experimental studies in mice showed that basophils participate in the initiation of Th2 adaptive immune response, in addition to the effector phase. However, the role of basophils in allergic airway inflammation is less clear. The aim of this experiment was to assess the importance of basophils in recruiting inflammatory cells and, in particular, eosinophils in a murine model of asthma induced by Aspergillus fumigatus allergens. Additionally, bronchial reactivity was evaluated. Basophil depletion resulted in a reduction of inflammatory cells in the airways and eosinophil recruitment was significantly impaired. Also bronchial reactivity seemed to be impaired in basophil-depleted mice, but the result was not statistically significant. According to these preliminary data, basophils seem to influence the local eosinophilic response of allergic asthma.

Mechanisms of cell uptake, inflammatory potential and protein corona effects with gold nanoparticles.

PubMed

Li, Yang; Monteiro-Riviere, Nancy A

2016-12-01

To assess inflammation, cellular uptake and endocytic mechanisms of gold nanoparticles (AuNP) in human epidermal keratinocytes with and without a protein corona. Human epidermal keratinocytes were exposed to 40 and 80 nm AuNP with lipoic acid, polyethylene glycol (PEG) and branched polyethyleneimine (BPEI) coatings with and without a protein corona up to 48 h. Inhibitors were selected to characterize endocytosis. BPEI-AuNP showed the greatest uptake, while PEG-AuNP had the least. Protein coronas decreased uptake and affected their mechanism. AuNP uptake was energy-dependent, except for 40 nm lipoic-AuNP. Most AuNP were internalized by clathrin and lipid raft-mediated endocytosis, except for 40 nm PEG was by raft/noncaveolae mediated endocytosis. Coronas inhibited caveolae-mediated-endocytosis with lipoic acid and BPEI-AuNP and altered 40 nm PEG-AuNP from raft/noncaveolae to clathrin. Inflammatory responses decreased with a plasma corona. Results suggest protein coronas significantly affect cellular uptake and inflammatory responses of AuNP.

Chickenpox encephalitis and encephalopathy: evidence for differing pathogenesis.

PubMed Central

Shope, T. C.

1982-01-01

Retrospective assessment of hepatic and central nervous system involvement associated with chickenpox cases at a large metropolitan medical center reveals that 28 of 58 patients had biochemical, but not inflammatory, evidence of liver involvement. An additional 18 patients had biochemical liver abnormalities along with non-inflammatory encephalopathy (Reye syndrome) and 12 had clear evidence of central nervous system inflammatory involvement (encephalitis). There were no cases of solitary inflammatory liver involvement. Reviewed evidence suggests that the pathogenesis of hepatopathy and hepatoencephalopathy (Reye syndrome) is not caused by replication of virus in the involved organs, but instead is mediated through a cytotoxic mechanism and that the inflammatory brain disease is also not caused by viral replication in brain tissue, but appears to be tissue damage associated with immune cell responses (post-infectious encephalitis). The concept put forth in this essay is that a virus replicating in one organ (skin) could affect the macromolecular function of cells in another organ (liver, brain) bringing about both hepatopathy and hepatoencephalopathy. PMID:6295009

Cytokines and metabolic patterns in pediatric patients with critical illness.

PubMed

Briassoulis, George; Venkataraman, Shekhar; Thompson, Ann

2010-01-01

It is not known if cytokines, which are cell-derived mediators released during the host immune response to stress, affect metabolic response to stress during critical illness. The aim of this prospective study was to determine whether the metabolic response to stress is related to the inflammatory interleukin-6 (IL-6), 10 (IL-10), and other stress mediators' responses and to assess their relationships with different feeding patterns, nutritional markers, the severity of illness as assessed by the Multiple Organ System Failure (MOSF), the Pediatric Risk of Mortality Score (PRISM), systemic inflammatory response syndrome (SIRS), and mortality in critically ill children. Patients were classified as hypermetabolic, normometabolic, and hypometabolic when the measured resting energy expenditures (REE) were >110%, 90-110% and, <90% of the predicted basal metabolic rate, respectively. The initial predominance of the hypometabolic pattern (48.6%) declined within 1 week of acute stress (20%), and the hypermetabolic patterns dominated only after 2 weeks (60%). Only oxygen consumption (VO(2)) and carbon dioxide production (VCO(2)) (P < .0001) but none of the cytokines and nutritional markers, were independently associated with a hypometabolic pattern. REE correlated with the IL-10 but not PRISM. In the presence of SIRS or sepsis, CRP, IL-6, IL-10, Prognostic Inflammatory and Nutritional Index (NI), and triglycerides--but not glucose, VO(2), or VCO(2) increased significantly. High IL-10 levels (P = .0000) and low measured REE (P = .0000) were independently associated with mortality (11.7%), which was higher in the hypometabolic compared to other metabolic patterns (P < .005). Our results showed that only VO(2) and VCO(2), but not IL-6 or IL-10, were associated with a hypometabolic pattern which predominated the acute phase of stress, and was associated with increased mortality. Although in SIRS or sepsis, the cytokine response was reliably reflected by increases in NI and triglycerides, it was different from the metabolic (VO(2), VCO(2)) or glucose response.

Cytokines and Metabolic Patterns in Pediatric Patients with Critical Illness

PubMed Central

Briassoulis, George; Venkataraman, Shekhar; Thompson, Ann

2010-01-01

It is not known if cytokines, which are cell-derived mediators released during the host immune response to stress, affect metabolic response to stress during critical illness. The aim of this prospective study was to determine whether the metabolic response to stress is related to the inflammatory interleukin-6 (IL-6), 10 (IL-10), and other stress mediators' responses and to assess their relationships with different feeding patterns, nutritional markers, the severity of illness as assessed by the Multiple Organ System Failure (MOSF), the Pediatric Risk of Mortality Score (PRISM), systemic inflammatory response syndrome (SIRS), and mortality in critically ill children. Patients were classified as hypermetabolic, normometabolic, and hypometabolic when the measured resting energy expenditures (REE) were >110%, 90–110% and, <90% of the predicted basal metabolic rate, respectively. The initial predominance of the hypometabolic pattern (48.6%) declined within 1 week of acute stress (20%), and the hypermetabolic patterns dominated only after 2 weeks (60%). Only oxygen consumption (VO2) and carbon dioxide production (VCO2) (P < .0001) but none of the cytokines and nutritional markers, were independently associated with a hypometabolic pattern. REE correlated with the IL-10 but not PRISM. In the presence of SIRS or sepsis, CRP, IL-6, IL-10, Prognostic Inflammatory and Nutritional Index (NI), and triglycerides—but not glucose, VO2, or VCO2 increased significantly. High IL-10 levels (P = .0000) and low measured REE (P = .0000) were independently associated with mortality (11.7%), which was higher in the hypometabolic compared to other metabolic patterns (P < .005). Our results showed that only VO2 and VCO2, but not IL-6 or IL-10, were associated with a hypometabolic pattern which predominated the acute phase of stress, and was associated with increased mortality. Although in SIRS or sepsis, the cytokine response was reliably reflected by increases in NI and triglycerides, it was different from the metabolic (VO2, VCO2) or glucose response. PMID:20490277

Indole-3-carbinol inhibits LPS-induced inflammatory response by blocking TRIF-dependent signaling pathway in macrophages.

PubMed

Jiang, Jun; Kang, Tae Bong; Shim, Do Wan; Oh, Na Hyun; Kim, Tack Joong; Lee, Kwang Ho

2013-07-01

Indole-3-carbinol (I3C), a natural hydrolysis product of glucobrassicin, is a member of the Brassica family of vegetables and is known to have various anti-cancer activities. In the present study, we assessed in vitro and in vivo anti-inflammatory effects of I3C and its molecular mechanisms. I3C attenuated the production of pro-inflammatory mediators such as NO, IL-6, and IL-1β in LPS-induced Raw264.7 cells and THP-1 cells through attenuation of the TRIF-dependent signaling pathway. Furthermore, I3C suppressed the infiltration of immune cells into the lung and pro-inflammatory cytokine production such as IL-6, TNF-α in broncho-alveolar lavage fluid (BALF) in the LPS-induced acute lung injury mouse model. I3C also suppressed IL-1β secretion in nigericin treated in vivo model. I3C has potent anti-inflammatory effects through regulating TRIF-dependent signaling pathways, suggesting that I3C may provide a valuable therapeutic strategy in treating various inflammatory diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

Local and Systemic Inflammatory Responses to Experimentally Induced Gingivitis

PubMed Central

Leishman, Shaneen J.; Seymour, Gregory J.; Ford, Pauline J.

2013-01-01

This study profiled the local and systemic inflammatory responses to experimentally induced gingivitis. Eight females participated in a 21-day experimental gingivitis model followed by a 14-day resolution phase. Bleeding on probing and plaque index scores were assessed before, during, and after resolution of gingival inflammation, and samples of saliva, GCF, and plasma were collected. Samples were assessed for biomarkers of inflammation using the BioPlex platform and ELISA. There were no significant changes in GCF levels of cytokines during the experimental phase; however, individual variability in cytokine profiles was noted. During resolution, mean GCF levels of IL-2, IL-6, and TNF-α decreased and were significantly lower than baseline levels (P = 0.003, P = 0.025, and P = 0.007, resp.). Furthermore, changes in GCF levels of IL-2, IL-6, and TNF-α during resolution correlated with changes in plaque index scores (r = 0.88, P = 0.004; r = 0.72, P = 0.042; r = 0.79, P = 0.019, resp.). Plasma levels of sICAM-1 increased significantly during the experimental phase (P = 0.002) and remained elevated and significantly higher than baseline levels during resolution (P < 0.001). These results support the concept that gingivitis adds to the systemic inflammatory burden of an individual. PMID:24227893

Local and systemic inflammatory responses to experimentally induced gingivitis.

PubMed

Leishman, Shaneen J; Seymour, Gregory J; Ford, Pauline J

2013-01-01

This study profiled the local and systemic inflammatory responses to experimentally induced gingivitis. Eight females participated in a 21-day experimental gingivitis model followed by a 14-day resolution phase. Bleeding on probing and plaque index scores were assessed before, during, and after resolution of gingival inflammation, and samples of saliva, GCF, and plasma were collected. Samples were assessed for biomarkers of inflammation using the BioPlex platform and ELISA. There were no significant changes in GCF levels of cytokines during the experimental phase; however, individual variability in cytokine profiles was noted. During resolution, mean GCF levels of IL-2, IL-6, and TNF-α decreased and were significantly lower than baseline levels (P = 0.003, P = 0.025, and P = 0.007, resp.). Furthermore, changes in GCF levels of IL-2, IL-6, and TNF-α during resolution correlated with changes in plaque index scores (r = 0.88, P = 0.004; r = 0.72, P = 0.042; r = 0.79, P = 0.019, resp.). Plasma levels of sICAM-1 increased significantly during the experimental phase (P = 0.002) and remained elevated and significantly higher than baseline levels during resolution (P < 0.001). These results support the concept that gingivitis adds to the systemic inflammatory burden of an individual.

Assessment of adrenocortical reserve capacity and inflammatory parameters in critically ill dogs.

PubMed

Csöndes, Judit; Fábián, Ibolya; Szabó, Bernadett; Máthé, Ákos; Vajdovich, Péter

2017-12-01

Inflammatory markers and adrenocorticotropic hormone (ACTH) stimulation test results may help us recognise critically ill dogs with poor disease outcome. Systemic inflammatory response syndrome (SIRS) criteria, the fast version of the Acute Patient Physiologic and Laboratory Evaluation Score (APPLE fast ), complete blood count, albumin and C-reactive protein (CRP) levels, baseline and stimulated cortisol levels and Δcortisol value were recorded in 50 client-owned dogs admitted to the Small Animal Hospital of the University of Veterinary Medicine Budapest with various inflammatory or neoplastic conditions. Increasing APPLE fast score was associated with a decreasing chance of survival (P = 0.0420). The Δcortisol value was significantly higher in SIRS dogs than in non-SIRS dogs (mean ± SD Δcortisol SIRS : 342.5 ± 273.96; mean ± SD Δcortisol non-SIRS : 175.3 ± 150.35; P = 0.0443). Elevated baseline or stimulated cortisol levels were associated with a higher chance of non-survival (P = 0.0135 and P = 0.0311, respectively). These data indicate that pathologically higher baseline and stimulated cortisol levels represent an exaggerated stress response in critically ill dogs, which is negatively associated with survival.

Inflammatory parameters in Caco-2 cells: effect of stimuli nature, concentration, combination and cell differentiation.

PubMed

Van De Walle, Jacqueline; Hendrickx, Aurélie; Romier, Béatrice; Larondelle, Yvan; Schneider, Yves-Jacques

2010-08-01

Enterocytes regulate gut maintenance and defence by secreting and responding to inflammatory mediators and by modulating the intestinal epithelial permeability. In order to develop an in vitro model of the acute phase of intestinal inflammation, Caco-2 cells were exposed to the inflammatory mediators IL-1beta, TNF-alpha, IFN-gamma and LPS, and the importance of several experimental parameters, i.e. cell differentiation, stimulus nature, concentration and combination on the inflammatory response was assessed by measuring the production of IL-6, IL-8, PGE-2 and NO and by evaluating the monolayer permeability. A maximal increase in IL-8, IL-6 and PGE-2 production and monolayer permeability was observed when using the cytokines simultaneously at their highest level, but this relied mainly on IL-1beta. The effects of TNF-alpha on IL-8 and IL-6 or NO production were stronger upon combination with IL-1beta or IFN-gamma, respectively, whereas cells were unaffected by the presence of LPS. Although NO production, induced by IFN-gamma-containing combinations, was observed only in differentiated cells, general inflammatory response was higher in proliferating cells. The use of a mixture of IL-1beta, TNF-alpha and IFN-gamma thus accurately mimics intestinal inflammatory processes, but cell differentiation and stimuli combination are important parameters to take into account for in vitro studies on intestinal inflammation. Copyright (c) 2010. Published by Elsevier Ltd.

Inflammatory responses and intestinal injury development during acute Trypanosoma cruzi infection are associated with the parasite load.

PubMed

Vazquez, Bruna Perez; Vazquez, Thaís Perez; Miguel, Camila Botelho; Rodrigues, Wellington Francisco; Mendes, Maria Tays; de Oliveira, Carlo José Freire; Chica, Javier Emílio Lazo

2015-04-03

Chagas disease is caused by the protozoan Trypanosoma cruzi and is characterized by cardiac, gastrointestinal, and nervous system disorders. Although much about the pathophysiological process of Chagas disease is already known, the influence of the parasite burden on the inflammatory process and disease progression remains uncertain. We used an acute experimental disease model to evaluate the effect of T. cruzi on intestinal lesions and assessed correlations between parasite load and inflammation and intestinal injury at 7 and 14 days post-infection. Low (3 × 10(2)), medium (3 × 10(3)), and high (3 × 10(4)) parasite loads were generated by infecting C57BL/6 mice with "Y"-strain trypomastigotes. Statistical analysis was performed using analysis of variance with Tukey's multiple comparison post-test, Kruskal-Wallis test with Dunn's multiple comparison, χ2 test and Spearman correlation. High parasite load-bearing mice more rapidly and strongly developed parasitemia. Increased colon width, inflammatory infiltration, myositis, periganglionitis, ganglionitis, pro-inflammatory cytokines (e.g., TNF-α, INF-γ, IL-2, IL-17, IL-6), and intestinal amastigote nests were more pronounced in high parasite load-bearing animals. These results were remarkable because a positive correlation was observed between parasite load, inflammatory infiltrate, amastigote nests, and investigated cytokines. These experimental data support the idea that the parasite load considerably influences the T. cruzi-induced intestinal inflammatory response and contributes to the development of the digestive form of the disease.

Establishing a Th17 based mouse model for preclinical assessment of the toxicity of candidate microbicides.

PubMed

Li, Liang-Zhu; Yang, Yu; Yuan, Song-Hua; Wan, Yan-Min; Qiu, Chao; Feng, Yan-Ling; Xu, Jian-Qing; Zhang, Xiao-Yan

2010-12-01

To effectively block the invasion of human immunodeficiency virus (HIV)-1 on mucosal surface, vaginal anti-HIV-1 microbicides should avoid inflammatory responses and disruption of mucosa integrity because these will facilitate transepithelial viral penetration and replication. However, existing models fail to predict and evaluate vaginal mucosal toxicity induced by microbicides, and most importantly, they are unable to identify subtle or subclinical inflammatory reactions. This study was designed to develop a cost-effective in vivo model to evaluate microbicide safety in a preclinical study which can recapitulate the mucosal topical reaction. A murine model was employed with nonoxynol-9 (N-9) as the topical stimulant within the vagina. Different concentrations of N-9 (1%, 3%, and 4%) were topically applied to the vagina for five consecutive days. A panel of inflammatory cytokines including interleukine-2 (IL-2), IL-4, IL-6, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and immuno-regulatory IL-10 were assayed in vaginal lavage. Cytokines were quantified by using cytometric bead array (CBA) and reverse transcript (RT) real-time PCR. Histopathological evaluation of vaginal tissues was conducted on hematoxylin-eosin stained slides and scored with a semi-quantitative system according to the severity of epithelial disruption, leucocyte infiltration, edema, and vascular injection. The association between the cytokines and histopathological scores was assessed by linear regression analysis. All three concentrations of N-9 induced inflammatory cytokine production. The 4% N-9 application resulted in a consistent production of cytokines in a time-dependent manner. The cytokines reached peak expression on day three with the exception of IL-4 which reached its peak on day one. Histopathological examination of 4% N-9 treated cervicovaginal tissues on day three showed intensive damage in four mice (sores: 10 - 13) and moderate damage in one mouse (score: 8), which were significantly associated with both inflammatory cytokines IL-17A and IL-6 and anti-inflammatory cytokines IL-4 and IL-10. Interestingly, IL-17A showed significant positive association with inflammatory cytokine TNF-α (r = 0.739; P < 0.05), anti-inflammatory cytokines IL-10 (r = 0.804; P < 0.01) and IL-4 (r = 0.668; P < 0.05). Our data demonstrate that a panel of cytokines (IL-17A, IL-6, IL-4 and IL-10) could be used as surrogate biomarkers to predict the histopathological damage. Th17 may play a central role in orchestrating inflammatory cytokine responses. This Th17 based mouse model is cost-effective and suitable to assess the toxicity of candidate microbicides in preclinical studies.

Impact of intraoperative cytokine adsorption on outcome of patients undergoing orthotopic heart transplantation-an observational study.

PubMed

Nemeth, Endre; Kovacs, Eniko; Racz, Kristof; Soltesz, Adam; Szigeti, Szabolcs; Kiss, Nikolett; Csikos, Gergely; Koritsanszky, Kinga B; Berzsenyi, Viktor; Trembickij, Gabor; Fabry, Szabolcs; Prohaszka, Zoltan; Merkely, Bela; Gal, Janos

2018-04-01

The aim of this study was to assess the influence of intraoperative cytokine adsorption on the perioperative vasoplegia, inflammatory response and outcome during orthotopic heart transplantation (OHT). Eighty-four OHT patients were separated into the cytokine adsorption (CA)-treated group or controls. Vasopressor demand, inflammatory response described by procalcitonin and C-reactive protein, and postoperative outcome were assessed performing propensity score matching. In the 16 matched pairs, the median noradrenaline requirement was significantly less in the CA-treated patients than in the controls on the first and second postoperative days (0.14 vs 0.3 μg*kg -1 *min -1 , P = .039 and 0.06 vs 0.32 μg*kg -1 *min -1 , P = .047). The inflammatory responses were similar in the two groups. There was a trend toward shorter length of mechanical ventilation and intensive care unit (ICU) stay in the CA-treated group compared to the controls. No difference in adverse events was observed between the two groups. However, the frequency of renal replacement therapy was significantly less in the CA-treated patients than in the controls (P = .031). Intraoperative CA treatment was associated with reduced vasopressor demand and less frequent renal replacement therapy with a favorable tendency in length of mechanical ventilation and ICU stay. CA treatment was not linked to higher rates of adverse events. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Prenatal vitamin A deficiency impairs adaptive immune responses to pentavalent rotavirus vaccine (RotaTeq®) in a neonatal gnotobiotic pig model.

PubMed

Kandasamy, Sukumar; Chattha, Kuldeep S; Vlasova, Anastasia N; Saif, Linda J

2014-02-07

Vitamin A deficiency (VAD) is associated with increased childhood mortality and morbidity in impoverished Asian and African countries, but the impact of VAD on rotavirus (RV) vaccine or infection is poorly understood. We assessed effects of gestational and dietary induced pre- and post-natal VAD and vitamin A supplementation on immune responses to a pentavalent rotavirus vaccine, RotaTeq(®) in a neonatal gnotobiotic pig model. Vaccine efficacy was assessed against virulent G1P[8] human rotavirus (HRV) challenge. VAD and vitamin A sufficient (VAS) piglets were derived from dietary VAD and VAS sows, respectively. VAD piglets had significantly lower levels of hepatic vitamin A compared to that of VAS piglets. RotaTeq(®)-vaccinated VAD piglets had 350-fold higher fecal virus shedding titers compared to vaccinated VAS piglets post-challenge. Only 25% of vaccinated non-vitamin A supplemented VAD piglets were protected against diarrhea compared with 100% protection rate in vaccinated non-supplemented VAS piglets post-challenge. Intestinal HRV specific immune responses were compromised in VAD piglets. Vaccinated VAD piglets had significantly lower ileal HRV IgG antibody secreting cell (ASC) responses (pre-challenge) and duodenal HRV IgA ASC responses (post-challenge) compared to vaccinated VAS piglets. Also, intestinal HRV IgA antibody titers were 11-fold lower in vaccinated VAD compared to vaccinated VAS piglets post-challenge. Persistently elevated levels of IL-8, a pro-inflammatory mediator, and lower IL-10 responses (anti-inflammatory) in vaccinated VAD compared to VAS piglets suggest more severe inflammatory responses in VAD piglets post-challenge. Moreover higher IFN-γ responses pre-challenge were observed in VAD compared to VAS piglets. The impaired vaccine-specific intestinal antibody responses and decreased immunoregulatory cytokine responses coincided with reduced protective efficacy of the RV vaccine against virulent HRV challenge in VAD piglets. In conclusion, VAD impaired antibody responses to RotaTeq(®) and vaccine efficacy. Oral supplementation of 100,000 IU vitamin A concurrent with RV vaccine failed to increase the vaccine efficacy in VAD piglets. Copyright © 2014 Elsevier Ltd. All rights reserved.

Role of inflammasomes in inflammatory autoimmune rheumatic diseases.

PubMed

Yi, Young-Su

2018-01-01

Inflammasomes are intracellular multiprotein complexes that coordinate anti-pathogenic host defense during inflammatory responses in myeloid cells, especially macrophages. Inflammasome activation leads to activation of caspase-1, resulting in the induction of pyroptosis and the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Although the inflammatory response is an innate host defense mechanism, chronic inflammation is the main cause of rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and Sjögren's syndrome (SS). Since rheumatic diseases are inflammatory/autoimmune disorders, it is reasonable to hypothesize that inflammasomes activated during the inflammatory response play a pivotal role in development and progression of these diseases. Indeed, previous studies have provided important observations that inflammasomes are actively involved in the pathogenesis of inflammatory/autoimmune rheumatic diseases. In this review, we summarize the current knowledge on several types of inflammasomes during macrophage-mediated inflammatory responses and discuss recent research regarding the role of inflammasomes in the pathogenesis of inflammatory/autoimmune rheumatic diseases. This avenue of research could provide new insights for the development of promising therapeutics to treat inflammatory/autoimmune rheumatic diseases.

Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation.

PubMed

Irwin, Michael R; Wang, Minge; Campomayor, Capella O; Collado-Hidalgo, Alicia; Cole, Steve

2006-09-18

Inflammation is associated with increased risk of cardiovascular disorders, arthritis, diabetes mellitus, and mortality. The effects of sleep loss on the cellular and genomic mechanisms that contribute to inflammatory cytokine activity are not known. In 30 healthy adults, monocyte intracellular proinflammatory cytokine production was repeatedly assessed during the day across 3 baseline periods and after partial sleep deprivation (awake from 11 pm to 3 am). We analyzed the impact of sleep loss on transcription of proinflammatory cytokine genes and used DNA microarray analyses to characterize candidate transcription-control pathways that might mediate the effects of sleep loss on leukocyte gene expression. In the morning after a night of sleep loss, monocyte production of interleukin 6 and tumor necrosis factor alpha was significantly greater compared with morning levels following uninterrupted sleep. In addition, sleep loss induced a more than 3-fold increase in transcription of interleukin 6 messenger RNA and a 2-fold increase in tumor necrosis factor alpha messenger RNA. Bioinformatics analyses suggested that the inflammatory response was mediated by the nuclear factor kappaB inflammatory signaling system as well as through classic hormone and growth factor response pathways. Sleep loss induces a functional alteration of the monocyte proinflammatory cytokine response. A modest amount of sleep loss also alters molecular processes that drive cellular immune activation and induce inflammatory cytokines; mapping the dynamics of sleep loss on molecular signaling pathways has implications for understanding the role of sleep in altering immune cell physiologic characteristics. Interventions that target sleep might constitute new strategies to constrain inflammation with effects on inflammatory disease risk.

The effect of the systemic inflammatory response on plasma zinc and selenium adjusted for albumin.

PubMed

Ghashut, Rawia A; McMillan, Donald C; Kinsella, John; Vasilaki, Aikaterini T; Talwar, Dinesh; Duncan, Andrew

2016-04-01

The magnitude of systemic inflammatory response, as evidenced by C-reactive protein (CRP), is a major factor associated with lower zinc and selenium. They may also be influenced by their binding proteins, such as albumin. The aim of the present study was to examine the relationships between plasma zinc, selenium and the systemic inflammatory response in a large cohort of patients referred for nutritional screen and also to examine these relationships in patients with critical illness. Patients referred for nutritional assessment of zinc (n = 743) and selenium (n = 833) and 114 patients with critical illness were examined. Intra-assay imprecision was <10% for these analytes. In the nutritional screen cohort, plasma zinc was significantly associated with CRP (rs = -0.404, p < 0.001) and albumin (rs = 0.588, p < 0.001). For each CRP category (≤10, 11-80, >80 mg/l) the zinc/albumin ratio x100 was similar (31, 33 and 32 respectively, p = 0.029). Plasma selenium was significantly associated with CRP (rs = -0.489, p < 0.001) and albumin (rs = 0.600, p < 0.001). With increasing CRP category (≤10, 11-80, >80 mg/l) the selenium/albumin ratio ×100 was lower (2.3, 2.1 and 1.8 respectively, p < 0.001). Similar relationships were also observed in the cohort of patients with critical illness. Plasma zinc was associated with both CRP and albumin. The impact of the systemic inflammatory response could be largely adjusted by albumin concentrations. Plasma selenium was associated with both CRP and albumin. The impact of the systemic inflammatory response on plasma selenium concentrations could not be reasonably adjusted by albumin concentrations. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment.

PubMed

Cassano, Jennifer M; Schnabel, Lauren V; Goodale, Margaret B; Fortier, Lisa A

2018-04-03

Inflammatory licensed mesenchymal stem cells (MSCs) have the ability to promote functional tissue repair. This study specifically sought to understand how the recipient tissue environment reciprocally affects MSC function. Inflammatory polarized macrophages, modeling an injured tissue environment, were exposed to licensed MSCs, and the resultant effects of MSC immunomodulation and functionality of the MSC secretome on chondrocyte homeostasis were studied. Inflammatory licensed MSCs were generated through priming with either IFN-γ or polyinosinic:polycytidylic acid (poly I:C). Macrophages were polarized to an inflammatory phenotype using IFN-γ. Licensed MSCs were co-cultured with inflammatory macrophages and immunomodulation of MSCs was assessed in a T-cell proliferation assay. MSC gene expression was analyzed for changes in immunogenicity (MHC-I, MHC-II), immunomodulation (IDO, PTGS2, NOS2, TGF-β1), cytokine (IL-6, IL-8), and chemokine (CCL2, CXCL10) expression. Macrophages were assessed for changes in cytokine (IL-6, IL-10, TNF-α, IFN-γ) and chemokine (CCL2, CXCL10) expression. Conditioned medium representing the secretome from IFN-γ or poly I:C-primed MSCs was applied to IL-1β-stimulated chondrocytes, which were analyzed for catabolic (IL-6, TNF-α, CCL2, CXCL10, MMP-13, PTGS2) and matrix synthesis (ACAN, COL2A1) genes. IFN-γ-primed MSCs had a superior ability to suppress T-cell proliferation compared to naïve MSCs, and this ability was maintained following exposure to proinflammatory macrophages. In naïve and licensed MSCs exposed to inflammatory macrophages, MHC-I and MHC-II gene expression was upregulated. The secretome from licensed MSCs was chondroprotective and downregulated inflammatory gene expression in IL-1β-stimulated chondrocytes. In-vitro inflammatory licensing agents enhanced the immunomodulatory ability of MSCs exposed to inflammatory macrophages, and the resultant secretome was biologically active, protecting chondrocytes from catabolic stimulation. Use of licensing agents produced a more consistent immunomodulatory MSC population compared to exposure to inflammatory macrophages. The clinical implications of this study are that in-vitro licensing prior to therapeutic application could result in a more predictable immunomodulatory and reparative response to MSC therapy compared to in-vivo inflammatory licensing by the recipient environment.

Intervention effect and dose-dependent response of tanreqing injection on airway inflammation in lipopolysaccharide-induced rats.

PubMed

Dong, Shoujin; Zhong, Yunqing; Yang, Kun; Xiong, Xiaoling; Mao, Bing

2013-08-01

To assess the effect of Tanreqing injection on airway inflammation in rats. A rat model of airway inflammation was generated with lipopolysaccharide (LPS). Tanreqing injection was given by intratracheal instillation, and bronchoalveolar lavage fluid (BALF) from the right lung was collected. BALF total cell and neutrophil counts were then determined. In addition, BALF levels of inflammatory cytokines interleukin-13, cytokine-induced neutrophil chemoat-tractant-1, and tumor necrosis factor-alpha were measured using enzyme linked immunosorbent assay. The middle lobe of the right lung was stained with hematoxylin-eosin and histological changes examined. LPS increased airway inflammation, decreased BALF inflammatory cell count, inflammatory cytokine levels, and suppressed leukocyte influx of the lung. The LPS-induced airway inflammation peaked at 24 h, decreased beginning at 48 h, and had decreased markedly by 96 h. Tanreqing injection contains anti-inflammatory properties, and inhibits airway inflammation in a dose-dependent manner.

Optical Molecular Imaging for Diagnosing Intestinal Diseases

PubMed Central

Kim, Sang-Yeob

2013-01-01

Real-time visualization of the molecular signature of cells can be achieved with advanced targeted imaging techniques using molecular probes and fluorescence endoscopy. This molecular optical imaging in gastrointestinal endoscopy is promising for improving the detection of neoplastic lesions, their characterization for patient stratification, and the assessment of their response to molecular targeted therapy and radiotherapy. In inflammatory bowel disease, this method can be used to detect dysplasia in the presence of background inflammation and to visualize inflammatory molecular targets for assessing disease severity and prognosis. Several preclinical and clinical trials have applied this method in endoscopy; however, this field has just started to evolve. Hence, many problems have yet to be solved to enable the clinical application of this novel method. PMID:24340254

Mycoplasma hyopneumoniae does not affect the interferon-related anti-viral response but predisposes the pig to a higher level of inflammation following swine influenza virus infection.

PubMed

Deblanc, Céline; Delgado-Ortega, Mario; Gorin, Stéphane; Berri, Mustapha; Paboeuf, Frédéric; Berthon, Patricia; Herrler, Georg; Meurens, François; Simon, Gaëlle

2016-10-01

In pigs, influenza A viruses and Mycoplasma hyopneumoniae (Mhp) are major contributors to the porcine respiratory disease complex. Pre-infection with Mhp was previously shown experimentally to exacerbate the clinical outcomes of H1N1 infection during the first week after virus inoculation. In order to better understand the interactions between these pathogens, we aimed to assess very early responses (at 5, 24 and 48 h) after H1N1 infection in pigs pre-infected or not with Mhp. Clinical signs and macroscopic lung lesions were similar in both infected groups at early times post-H1N1 infection; and Mhp pre-infection affected neither the influenza virus replication nor the IFN-induced antiviral responses in the lung. However, it predisposed the animals to a higher inflammatory response to H1N1 infection, as revealed by the massive infiltration of neutrophils and macrophages into the lungs and the increased production of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α). Thus, it seems it is this marked inflammatory state that would play a role in exacerbating the clinical signs subsequent to H1N1 infection.

The Role of Inflammasome in Inflammatory Macrophage in Mycobacterium Avium Complex-lung Disease and Mycobacterium Abscessus-lung Disease

ClinicalTrials.gov

2014-06-27

To Investigate the Inflammasome Response of Inflammatory and Resting Macrophage; To Compare the Difference of Inflammasome Response of Inflammatory Macrophage; To Study the Diagnostic Aid From Immunological Markers in Inflammasome Response

Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

PubMed Central

Yi, Young-Su; Son, Young-Jin; Ryou, Chongsuk; Sung, Gi-Ho; Kim, Jong-Hoon; Cho, Jae Youl

2014-01-01

Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk) was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases. PMID:25045209

Colonization with Heligmosomoides polygyrus suppresses mucosal IL-17 production

USDA-ARS?s Scientific Manuscript database

Helminth exposure appears to protect hosts from inappropriate inflammatory responses, such as those causing inflammatory bowel disease. A recently identified, strongly pro-inflammatory limb of the immune response is characterized by T cell IL-17 production. Many autoimmune-type inflammatory diseases...

Naringin attenuates the development of carrageenan-induced acute lung inflammation through inhibition of NF-κb, STAT3 and pro-inflammatory mediators and enhancement of IκBα and anti-inflammatory cytokines.

PubMed

Ahmad, Sheikh Fayaz; Attia, Sabry M; Bakheet, Saleh A; Zoheir, Khairy M A; Ansari, Mushtaq Ahmad; Korashy, Hesham M; Abdel-Hamied, Hala E; Ashour, Abdelkader E; Abd-Allah, Adel R A

2015-04-01

Naringin has been reported to possess diverse pharmacological properties, including anti-arthritic and anti-inflammatory activities. The aim of the present study was to determine the potential anti-inflammatory effect of naringin in a mouse model of carrageenan-induced pleurisy. A single dose of naringin (40 and 80 mg/kg) was administered per oral (p.o.) 1 h before carrageenan (Cg) administration. Pro- and anti-inflammatory cytokines were analysed in pleural fluid. We also assessed the effects of naringin on the expression levels of iNOS, inducible cyclooxygenase isoform (COX-2), ICAM-1, MIP-2, PGE2, STAT3, TGF-β1, nuclear factor kappa B (NF-κB) and inhibitor of kappa B (IκBα) in lung tissue. The histological examinations revealed anti-inflammatory effect of naringin while Cg group deteriorated. Naringin downregulated Th1 and upregulated Th2 cytokines. Western blot analyses revealed increased protein expression of NF-κB, STAT3 and COX-2 and decreased IκBα in response to Cg treatment, which were reversed by the treatment with naringin. In the Cg group, mRNA expression levels of pro-inflammatory mediators upregulated and anti-inflammatory mediators downregulated. Naringin reversed these actions.

Rose geranium essential oil as a source of new and safe anti-inflammatory drugs

PubMed Central

Boukhatem, Mohamed Nadjib; Kameli, Abdelkrim; Ferhat, Mohamed Amine; Saidi, Fairouz; Mekarnia, Maamar

2013-01-01

Background Since the available anti-inflammatory drugs exert an extensive variety of side effects, the search for new anti-inflammatory agents has been a priority of pharmaceutical industries. Aims The aim of the present study was to assess the anti-inflammatory activities of the essential oil of rose geranium (RGEO). Methods The chemical composition of the RGEO was investigated by gas chromatography. The major components were citronellol (29.13%), geraniol (12.62%), and citronellyl formate (8.06%). In the carrageenan-induced paw edema, five different groups were established and RGEO was administered orally in three different doses. Results RGEO (100 mg/kg) was able to significantly reduce the paw edema with a comparable effect to that observed with diclofenac, the positive control. In addition, RGEO showed a potent anti-inflammatory activity by topical treatment in the method of croton oil-induced ear edema. When the dose was 5 or 10 µl of RGEO per ear, the inflammation was reduced by 73 and 88%, respectively. This is the first report to demonstrate a significant anti-inflammatory activity of Algerian RGEO. In addition, histological analysis confirmed that RGEO inhibited the inflammatory responses in the skin. Conclusion Our results indicate that RGEO may have significant potential for the development of novel anti-inflammatory drugs with improved safety profile. PMID:24103319

Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury.

PubMed

Chen, Xiangrong; Wu, Shukai; Chen, Chunnuan; Xie, Baoyuan; Fang, Zhongning; Hu, Weipeng; Chen, Junyan; Fu, Huangde; He, Hefan

2017-07-24

Microglial activation and the subsequent inflammatory response in the central nervous system play important roles in secondary damage after traumatic brain injury (TBI). High-mobility group box 1 (HMGB1) protein, an important mediator in late inflammatory responses, interacts with transmembrane receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) to activate downstream signaling pathways, such as the nuclear factor (NF)-κB signaling pathway, leading to a cascade amplification of inflammatory responses, which are related to neuronal damage after TBI. Omega-3 polyunsaturated fatty acid (ω-3 PUFA) is a commonly used clinical immunonutrient, which has antioxidative and anti-inflammatory effects. However, the effects of ω-3 PUFA on HMGB1 expression and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway are not clear. The Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglial activation in lesioned sites and protein markers for proinflammatory, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and HMGB1 were used to evaluate neuroinflammatory responses and anti-inflammation effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1-mediated activation of the TLR4/NF-κB signaling pathway to evaluate the effects of ω-3 PUFA supplementation and gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI. It was found that ω-3 PUFA supplementation inhibited TBI-induced microglial activation and expression of inflammatory factors (TNF-α, IL-1β, IL-6, and IFN-γ), reduced brain edema, decreased neuronal apoptosis, and improved neurological functions after TBI. We further demonstrated that ω-3 PUFA supplementation inhibited HMGB1 nuclear translocation and secretion and decreased expression of HMGB1 in neurons and microglia in the lesioned areas. Moreover, ω-3 PUFA supplementation inhibited microglial activation and the subsequent inflammatory response by regulating HMGB1 and the TLR4/NF-κB signaling pathway. The results of this study suggest that microglial activation and the subsequent neuroinflammatory response as well as the related HMGB1/TLR4/NF-κB signaling pathway play essential roles in secondary injury after TBI. Furthermore, ω-3 PUFA supplementation inhibited TBI-induced microglial activation and the subsequent inflammatory response by regulating HMGB1 nuclear translocation and secretion and also HMGB1-mediated activation of the TLR4/NF-κB signaling pathway, leading to neuroprotective effects.

Development of optical probes for in vivo imaging of polarized macrophages during foreign body reactions

PubMed Central

Tsai, Yi-Ting; Patty, Kaitlen M; Weng, Hong; Tang, Ewin N.; Nair, Ashwin; Hu, Wen-Jing; Tang, Liping

2014-01-01

Plasticity of macrophages (MΦ) phenotypes exist in a spectrum from classically activated (M1) cells, to alternatively activated (M2) cells, contributing to both the normal healing of tissues and the pathogenesis of implant failure. Here, folate- and mannose-based optical probes were fabricated to simultaneously determine the degree of MΦ polarization. In vitro tests show the ability of these probes to specifically target M1 and M2 cells. In an in vivo murine model, they were able to distinguish between M1-dominated inflammatory response to infection and M2-dominated regenerative response to particle implants. Finally, the probes were used to assess the inflammatory/ regenerative property of biomaterial implants. Our results show that these probes can be used to monitor and quantify the dynamic processes of MΦ polarization and their role in cellular responses in real time. PMID:24726956

Self-management of older adolescents with inflammatory bowel disease: a pilot study of behavior and knowledge as prelude to transition.

PubMed

Fishman, Laurie N; Barendse, Renée M; Hait, Elizabeth; Burdick, Cynthia; Arnold, Janis

2010-12-01

Patients gradually assume responsibility for self-management. This study sought to determine whether adolescents with inflammatory bowel disease (IBD) have developed key skills of self-management prior to the age at which many transfer to adult care. Adolescents aged 16 to 18 years old in the Children's Hospital Boston IBD database (94 total) received a mailed survey assessing knowledge and confidence of their own health information and behaviors. Respondents (43%) could name medication and dose with confidence but had very poor knowledge of important side effects. Most patients deferred responsibility mostly or completely to parents for scheduling appointments (85%), requesting refills (75%), or contacting provider between visits (74%). Older adolescents with IBD have good recall of medications but not of side effects. Parents remain responsible for the majority of tasks related to clinic visits and the acquisition of medications.

Measurements of intracellular calcium signals in polarized primary cultures of normal and cystic fibrosis human airway epithelia.

PubMed

Ribeiro, Carla M P

2011-01-01

The airways are continuously challenged by a variety of stimuli including bacteria, viruses, allergens, and inflammatory factors that act as agonists for G protein-coupled receptors (GPCR). Intracellular calcium (Ca(2+) (i)) mobilization in airway epithelia in response to extracellular stimuli regulates key airway innate defense functions, e.g., Ca(2+)-activated Cl(-) secretion, ciliary beating, mucin secretion, and inflammatory responses. Because Ca(2+) (i) mobilization in response to luminal stimuli is larger in CF vs. normal human airway epithelia, alterations in Ca(2+) (i) signals have been associated with the pathogenesis of CF airway disease. Hence, assessment of Ca(2+) (i) signaling has become an important area of CF research. This chapter will focus on measurements of cytoplasmic and mitochondrial Ca(2+) signals resulting from GPCR activation in polarized primary cultures of normal and CF human bronchial epithelia (HBE).

Loss of the Sexually Dimorphic Neuro-Inflammatory Response in a Transgenic Mouse Model of Huntington's Disease.

PubMed

Renoir, Thibault; Pang, Terence Y; Shikano, Yoshiko; Li, Shanshan; Hannan, Anthony J

2015-01-01

We previously reported sex differences in depression-like behaviours in a mouse model of Huntington's disease (HD). We hypothesized that immune response could also be altered in HD mice in a sex-dependent manner. Here, we assessed the molecular effects of an acute challenge with lipopolysaccharides (LPS) in female versus male R6/1 transgenic HD mice. We found an enhancement of LPS-induced TNF-α gene expression in the hypothalamus of female HD mice. TNF-α serum levels following LPS administration were also higher in female HD mice compared to WT animals. In contrast, male HD mice exhibited reduced LPS-induced TNF-α gene expression compared to WT animals. Our findings suggest that immune response to LPS is altered in HD mice in a sex-dependent manner. These pro-inflammatory abnormalities may contribute to the sexually dimorphic depression-like behaviours displayed by this mouse model of HD.

Time course of lung inflammatory and fibrogenic responses during protective mechanical ventilation in healthy rats.

PubMed

Krebs, Joerg; Pelosi, Paolo; Tsagogiorgas, Charalambos; Haas, Jenny; Yard, Benito; Rocco, Patricia R M; Luecke, Thomas

2011-09-15

This study aimed to assess pulmonary inflammatory and fibrogenic responses and their impact on lung mechanics and histology in healthy rats submitted to protective mechanical ventilation for different experimental periods. Eighteen Wistar rats were randomized to undergo open lung-mechanical ventilation (OL-MV) for 1, 6 or 12 h. Following a recruitment maneuver, a decremental PEEP trial was performed and PEEP set according to the minimal respiratory system static elastance. Respiratory system, lung, and chest-wall elastance and gas-exchange were maintained throughout the 12 h experimental period. Histological lung injury score remained low at 1 and 6 h, but was higher at 12 h due to overinflation. A moderate inflammatory response was observed with a distinct peak at 6h. Compared to unventilated controls, type I procollagen mRNA expression was decreased at 1 and 12h, while type III procollagen expression decreased throughout the 12h experimental period. In conclusion, OL-MV in healthy rats yielded overinflation after 6 h even though respiratory elastance and gas-exchange were preserved for up to 12 h. Copyright © 2011 Elsevier B.V. All rights reserved.

Transcriptional Analysis of PRRSV-Infected Porcine Dendritic Cell Response to Streptococcus suis Infection Reveals Up-Regulation of Inflammatory-Related Genes Expression

PubMed Central

Auray, Gaël; Lachance, Claude; Wang, Yingchao; Gagnon, Carl A.; Segura, Mariela; Gottschalk, Marcelo

2016-01-01

The porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important swine pathogens and often serves as an entry door for other viral or bacterial pathogens, of which Streptococcus suis is one of the most common. Pre-infection with PRRSV leads to exacerbated disease caused by S. suis infection. Very few studies have assessed the immunological mechanisms underlying this higher susceptibility. Since antigen presenting cells play a major role in the initiation of the immune response, the in vitro transcriptional response of bone marrow-derived dendritic cells (BMDCs) and monocytes in the context of PRRSV and S. suis co-infection was investigated. BMDCs were found to be more permissive than monocytes to PRRSV infection; S. suis phagocytosis by PRRSV-infected BMDCs was found to be impaired, whereas no effect was found on bacterial intracellular survival. Transcription profile analysis, with a major focus on inflammatory genes, following S. suis infection, with and without pre-infection with PRRSV, was then performed. While PRRSV pre-infection had little effect on monocytes response to S. suis infection, a significant expression of several pro-inflammatory molecules was observed in BMDCs pre-infected with PRRSV after a subsequent infection with S. suis. While an additive effect could be observed for CCL4, CCL14, CCL20, and IL-15, a distinct synergistic up-regulatory effect was observed for IL-6, CCL5 and TNF-α after co-infection. This increased pro-inflammatory response by DCs could participate in the exacerbation of the disease observed during PRRSV and S. suis co-infection. PMID:27213692

Mass or total surface area with aerosol size distribution as exposure metrics for inflammatory, cytotoxic and oxidative lung responses in rats exposed to titanium dioxide nanoparticles.

PubMed

Noël, A; Truchon, G; Cloutier, Y; Charbonneau, M; Maghni, K; Tardif, R

2017-04-01

There is currently no consensus on the best exposure metric(s) for expressing nanoparticle (NP) dose. Although surface area has been extensively studied for inflammatory responses, it has not been as thoroughly validated for cytotoxicity or oxidative stress effects. Since inhaled NPs deposit and interact with lung cells based on agglomerate size, we hypothesize that mass concentration combined with aerosol size distribution is suitable for NP risk assessment. The objective of this study was to evaluate different exposure metrics for inhaled 5 nm titanium dioxide aerosols composed of small (SA < 100 nm) or large (LA > 100 nm) agglomerates at 2, 7, and 20 mg/m 3 on rat lung inflammatory, cytotoxicity, and oxidative stress responses. We found a significant positive correlation ( r = 0.98, p < 0.01) with the inflammatory reaction, measured by the number of neutrophils and the mass concentration when considering all six (SA + LA) aerosols. This correlation was similar ( r = 0.87) for total surface area. Regarding cytotoxicity and oxidative stress responses, measured by lactate dehydrogenase and 8-isoprostane, respectively, and mass or total surface area as an exposure metric, we observed significant positive correlations only with SA aerosols for both the mass concentration and size distribution ( r > 0.91, p < 0.01), as well as for the total surface area ( r > 0.97, p < 0.01). These data show that mass or total surface area concentrations alone are insufficient to adequately predict oxidant and cytotoxic pulmonary effects. Overall, our study indicates that considering NP size distribution along with mass or total surface area concentrations contributes to a more mechanistic discrimination of pulmonary responses to NP exposure.

Pro-inflammatory AGE-RAGE signaling is activated during arousal from hibernation in ground squirrel adipose.

PubMed

Logan, Samantha M; Storey, Kenneth B

2018-01-01

Inflammation is generally suppressed during hibernation, but select tissues (e.g. lung) have been shown to activate both antioxidant and pro-inflammatory pathways, particularly during arousal from torpor when breathing rates increase and oxidative metabolism fueling the rewarming process produces more reactive oxygen species. Brown and white adipose tissues are now understood to be major hubs for the regulation of immune and inflammatory responses, yet how these potentially damaging processes are regulated by fat tissues during hibernation has hardly been studied. The advanced glycation end-product receptor (RAGE) can induce pro-inflammatory responses when bound by AGEs (which are glycated and oxidized proteins, lipids, or nucleic acids) or damage associated molecular pattern molecules (DAMPs, which are released from dying cells). Since gene expression and protein synthesis are largely suppressed during torpor, increases in AGE-RAGE pathway proteins relative to a euthermic control could suggest some role for these pro-inflammatory mediators during hibernation. This study determined how the pro-inflammatory AGE-RAGE signaling pathway is regulated at six major time points of the torpor-arousal cycle in brown and white adipose from a model hibernator, Ictidomys tridecemlineatus . Immunoblotting, RT-qPCR, and a competitive ELISA were used to assess the relative gene expression and protein levels of key regulators of the AGE-RAGE pathway during a hibernation bout. The results of this study revealed that RAGE is upregulated as animals arouse from torpor in both types of fat, but AGE and DAMP levels either remain unchanged or decrease. Downstream of the AGE-RAGE cascade, nfat5 was more highly expressed during arousal in brown adipose. An increase in RAGE protein levels and elevated mRNA levels of the downstream transcription factor nfat5 during arousal suggest the pro-inflammatory response is upregulated in adipose tissue of the hibernating ground squirrel. It is unlikely that this cascade is activated by AGEs or DAMPs. This research sheds light on how a fat-but-fit organism with highly regulated metabolism may control the pro-inflammatory AGE-RAGE pathway, a signaling cascade that is often dysregulated in other obese organisms.

Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models.

PubMed

O'Neill, Jessica; Sikandar, Shafaq; McMahon, Stephen B; Dickenson, Anthony H

2015-09-01

Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively. The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of rat dorsal horn neurones and enhanced perceptual responses of human subjects to both mechanical and thermal stimulation. Additional heat rekindling produces markers of central sensitisation in both species, including enhanced receptive field sizes. Importantly, we also showed a correlation in the evoked activity of rat spinal neurones to human thermal pain thresholds. The parallel results in rats and humans validate the translational use of both models and the potential for such models for preclinical assessment of prospective analgesics in inflammatory pain states. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

COMPARATIVE TOXICITY OF SIZE FRACTIONATED AIRBORNE PARTICULATE MATTER OBTAINED FROM DIFFERENT CITIES IN THE USA

EPA Science Inventory

This paper is the result of a collaboration to assess effects of size fractionated PM from different locations on murine pulmonary inflammatory responses. In the course of this, they also determined the chemical makeup of each of the samples.

Inflammatory Cytokine Response to Ambient Particles Varies due to Field Collection Procedures

EPA Science Inventory

In-vitro assays of biological activity induced by particulate matter (PM) are a tool for investigating mechanisms of PM health effects. They have potential application to exposure assessment in chronic disease epidemiology. However, there has been little reporting of the impact o...

Obesity-associated metabolic syndrome spontaneously induces infiltration of pro-inflammatory macrophage in synovium and promotes osteoarthritis

PubMed Central

Sun, Antonia RuJia; Panchal, Sunil K.; Friis, Thor; Sekar, Sunderajhan; Crawford, Ross; Brown, Lindsay; Xiao, Yin

2017-01-01

Objectives Epidemiological and experimental studies have established obesity to be an important risk factor for osteoarthritis (OA), however, the mechanisms underlying this link remains largely unknown. Here, we studied local inflammatory responses in metabolic-OA. Methods Wistar rats were fed with control diet (CD) and high-carbohydrate, high-fat diet (HCHF) for period of 8 and 16 weeks. After euthanasia, the knees were examined to assess the articular cartilage changes and inflammation in synovial membrane. Further IHC was conducted to determine the macrophage-polarization status of the synovium. In addition, CD and HCHF synovial fluid was co-cultured with bone marrow-derived macrophages to assess the effect of synovial fluid inflammation on macrophage polarisation. Results Our study showed that, obesity induced by a high-carbohydrate, high-fat (HCHF) diet is associated with spontaneous and local inflammation of the synovial membranes in rats even before the cartilage degradation. This was followed by increased synovitis and increased macrophage infiltration into the synovium and a predominant elevation of pro-inflammatory M1 macrophages. In addition, bone marrow derived macrophages, cultured with synovial fluid collected from the knees of obese rats exhibited a pro-inflammatory M1 macrophage phenotype. Conclusion Our study demonstrate a strong association between obesity and a dynamic immune response locally within synovial tissues. Furthermore, we have also identified synovial resident macrophages to play a vital role in the inflammation caused by the HCHF diet. Therefore, future therapeutic strategies targeted at the synovial macrophage phenotype may be the key to break the link between obesity and OA. PMID:28859108

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsou, Tsui-Chun, E-mail: tctsou@nhri.org.tw; Liou, Saou-Hsing; Yeh, Szu-Ching

Our previous studies indicated that zinc induced inflammatory response in both vascular endothelial cells and promonocytes. Here, we asked if other metals could cause the similar effect on vascular endothelial cells and tried to determine its underlying mechanism. Following screening of fifteen metals, zinc and nickel were identified with a marked proinflammatory effect, as determined by ICAM-1 and IL-8 induction, on human umbilical vein endothelial cells (HUVECs). Inhibiting protein expression of myeloid differentiation primary response protein-88 (MyD88), a Toll-like receptor (TLR) adaptor acting as a TLR-signaling transducer, significantly attenuated the zinc/nickel-induced inflammatory response, suggesting the critical roles of TLRs inmore » the inflammatory response. Blockage of TLR-4 signaling by CLI-095, a TLR-4 inhibitor, completely inhibited the nickel-induced ICAM-1 and IL-8 expression and NFκB activation. The same CLI-095 treatment significantly blocked the zinc-induced IL-8 expression, however with no significant effect on the ICAM-1 expression and a minor inhibitory effect on the NFκB activation. The finding demonstrated the differential role of TLR-4 in regulation of the zinc/nickel-induced inflammatory response, where TLR-4 played a dominant role in NFκB activation by nickel, but not by zinc. Moreover, inhibition of NFκB by adenovirus-mediated IκBα expression and Bay 11-7025, an inhibitor of cytokine-induced IκB-α phosphorylation, significantly attenuated the zinc/nickel-induced inflammatory responses, indicating the critical of NFκB in the process. The study demonstrates the crucial role of TLRs in the zinc/nickel-induced inflammatory response in vascular endothelial cells and herein deciphers a potential important difference in NFκB activation via TLRs. The study provides a molecular basis for linkage between zinc/nickel exposure and pathogenesis of the metal-related inflammatory vascular disease. - Highlights: • Both zinc and nickel cause ICAM-1/IL‑8 expression in endothelial cells via TLRs. • Nickel induces the inflammatory responses via a TLR-4/NF-κB pathway. • Zinc causes the inflammatory responses via a broader TLRs/NF-κB signaling. • Nickel shows a significantly higher inflammatory effect than zinc. • NF-κB activation is the primary mechanism involved in the inflammatory responses.« less

11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

PubMed

Hardy, Rowan S; Doig, Craig L; Hussain, Zahrah; O'Leary, Mary; Morgan, Stuart A; Pearson, Mark J; Naylor, Amy; Jones, Simon W; Filer, Andrew; Stewart, Paul M; Buckley, Christopher D; Lavery, Gareth G; Cooper, Mark S; Raza, Karim

2016-12-01

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bidirectional GC-activating enzyme that is potently upregulated by inflammation within mesenchymal-derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11β-HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of tumour necrosis factor (TNF)-α within tissues, including muscle. The inflammatory regulation and functional consequences of 11β-HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11β-HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF-Tg mouse on an 11β-HSD1 null background. 11β-HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF-Tg mice. In human and murine primary myotubes, 11β-HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF-α (mRNA, 7.6-fold, p < 0.005; activity, 4.1-fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11β-HSD1 suppressed proinflammatory cytokine output (interkeukin-6, TNF-α, and interferon-γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11β-11β-HSD1 knockout background developed greater muscle wasting than their TNF-Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF-Tg mice with normal 11β-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11β-HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF-α-driven model, local endogenous GC activation appears to be an important anti-inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Muscle-specific deletion of SOCS3 increases the early inflammatory response but does not affect regeneration after myotoxic injury.

PubMed

Swiderski, Kristy; Thakur, Savant S; Naim, Timur; Trieu, Jennifer; Chee, Annabel; Stapleton, David I; Koopman, René; Lynch, Gordon S

2016-01-01

Muscles of old animals are injured more easily and regenerate poorly, attributed in part to increased levels of circulating pro-inflammatory cytokines. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling cascade is a key mediator of inflammatory cytokine action, and signaling via this pathway is increased in muscles with aging. As a negative regulator of JAK/STAT signaling, a key mediator of myogenic proliferation and differentiation, altered expression of suppressor of cytokine signaling (SOCS3) is likely to have important consequences for muscle regeneration. To model this scenario, we investigated the effect of SOCS3 deletion within mature muscle fibers on injury and repair. We tested the hypothesis that reduced SOCS3 function would alter the inflammatory response and impair muscle regeneration after myotoxic injury. Mice with a specific deletion of SOCS3 within mature skeletal muscle fibers were used to assess the effect of SOCS3 deletion on muscle injury and repair. Twelve-week-old or 24-month-old SOCS3 muscle-specific knockout (SOCS3 MKO) mice and littermate controls were either left uninjured or injured with a single injection of notexin (10 μg/ml) into the right tibialis anterior (TA) muscle. At 1, 2, 3, 5, 7, or 14 days post-injury, the right TA muscle was excised and subjected to histological, western immunoblotting, and gene expression analyses. Force production and fatigue were assessed in uninjured muscles and at 7 days post-notexin injury. In uninjured muscles, SOCS3 deletion decreased force production during fatigue but had no effect on the gross or histological appearance of the TA muscles. After notexin injury, deletion of SOCS3 increased STAT3 phosphorylation at day 1 and increased the mRNA expression of the inflammatory cytokine TNF-α , and the inflammatory cell markers F4/80 and CD68 at day 2. Gene expression analysis of the regeneration markers Pax7 , MyoD , and Myogenin indicated SOCS3 deletion had no effect on the progression of muscle repair after notexin injury. Inflammation and regeneration were also unchanged in the muscles of 24-month-old SOCS3 MKO mice compared with control. Loss of SOCS3 expression in mature muscle fibers increased the inflammatory response to myotoxic injury but did not impair muscle regeneration in either adult or old mice. Therefore, reduced SOCS3 expression in muscle fibers is unlikely to underlie impaired muscle regeneration. Further investigation into the role of SOCS3 in other cell types involved in muscle repair is warranted.

Circadian molecular clock in lung pathophysiology

PubMed Central

Sundar, Isaac K.; Yao, Hongwei; Sellix, Michael T.

2015-01-01

Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology. PMID:26361874

Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines.

PubMed

Dashdorj, Amarjargal; Jyothi, K R; Lim, Sangbin; Jo, Ara; Nguyen, Minh Nam; Ha, Joohun; Yoon, Kyung-Sik; Kim, Hyo Jong; Park, Jae-Hoon; Murphy, Michael P; Kim, Sung Soo

2013-08-06

MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation. Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed. Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells. Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.

Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines

PubMed Central

2013-01-01

Background MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation. Methods Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed. Results Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells. Conclusion Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease. PMID:23915129

Systemic inflammatory response following acute myocardial infarction

PubMed Central

Fang, Lu; Moore, Xiao-Lei; Dart, Anthony M; Wang, Le-Min

2015-01-01

Acute cardiomyocyte necrosis in the infarcted heart generates damage-associated molecular patterns, activating complement and toll-like receptor/interleukin-1 signaling, and triggering an intense inflammatory response. Inflammasomes also recognize danger signals and mediate sterile inflammatory response following acute myocardial infarction (AMI). Inflammatory response serves to repair the heart, but excessive inflammation leads to adverse left ventricular remodeling and heart failure. In addition to local inflammation, profound systemic inflammation response has been documented in patients with AMI, which includes elevation of circulating inflammatory cytokines, chemokines and cell adhesion molecules, and activation of peripheral leukocytes and platelets. The excessive inflammatory response could be caused by a deregulated immune system. AMI is also associated with bone marrow activation and spleen monocytopoiesis, which sustains a continuous supply of monocytes at the site of inflammation. Accumulating evidence has shown that systemic inflammation aggravates atherosclerosis and markers for systemic inflammation are predictors of adverse clinical outcomes (such as death, recurrent myocardial infarction, and heart failure) in patients with AMI. PMID:26089856

Depression, daily stressors and inflammatory responses to high-fat meals: when stress overrides healthier food choices.

PubMed

Kiecolt-Glaser, J K; Fagundes, C P; Andridge, R; Peng, J; Malarkey, W B; Habash, D; Belury, M A

2017-03-01

Depression, stress and diet can all alter inflammation. This double-blind, randomized crossover study addressed the impact of daily stressors and a history of major depressive disorder (MDD) on inflammatory responses to high-fat meals. During two separate 9.5 h admissions, 58 healthy women (38 breast cancer survivors and 20 demographically similar controls), mean age 53.1 years, received either a high saturated fat meal or a high oleic sunflower oil meal. The Daily Inventory of Stressful Events assessed prior day stressors and the Structured Clinical Interview for DSM-IV evaluated MDD. As expected, for a woman with no prior day stressors, C-reactive protein (CRP), serum amyloid A (SAA), intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were higher following the saturated fat meal than the high oleic sunflower oil meal after controlling for pre-meal measures, age, trunk fat and physical activity. But if a woman had prior day stressors, these meal-related differences disappeared-because the stressors heightened CRP, SAA, sICAM-1 and sVCAM-1 responses to the sunflower oil meal, making it look more like the responses to the saturated fat meal. In addition, women with an MDD history had higher post-meal blood pressure responses than those without a similar history. These data show how recent stressors and an MDD history can reverberate through metabolic alterations, promoting inflammatory and atherogenic responses.

Phycocyanobilin promotes PC12 cell survival and modulates immune and inflammatory genes and oxidative stress markers in acute cerebral hypoperfusion in rats.

PubMed

Marín-Prida, Javier; Pavón-Fuentes, Nancy; Llópiz-Arzuaga, Alexey; Fernández-Massó, Julio R; Delgado-Roche, Liván; Mendoza-Marí, Yssel; Santana, Seydi Pedroso; Cruz-Ramírez, Alieski; Valenzuela-Silva, Carmen; Nazábal-Gálvez, Marcelo; Cintado-Benítez, Alberto; Pardo-Andreu, Gilberto L; Polentarutti, Nadia; Riva, Federica; Pentón-Arias, Eduardo; Pentón-Rol, Giselle

2013-10-01

Since the inflammatory response and oxidative stress are involved in the stroke cascade, we evaluated here the effects of Phycocyanobilin (PCB, the C-Phycocyanin linked tetrapyrrole) on PC12 cell survival, the gene expression and the oxidative status of hypoperfused rat brain. After the permanent bilateral common carotid arteries occlusion (BCCAo), the animals were treated with saline or PCB, taking samples 24h post-surgery. Global gene expression was analyzed with GeneChip Rat Gene ST 1.1 from Affymetrix; the expression of particular genes was assessed by the Fast SYBR Green RT-PCR Master Mix and Bioplex methods; and redox markers (MDA, PP, CAT, SOD) were evaluated spectrophotometrically. The PCB treatment prevented the H2O2 and glutamate induced PC12 cell injury assessed by the MTT assay, and modulated 190 genes (93 up- and 97 down-regulated) associated to several immunological and inflammatory processes in BCCAo rats. Furthermore, PCB positively modulated 19 genes mostly related to a detrimental pro-inflammatory environment and counteracted the oxidative imbalance in the treated BCCAo animals. Our results support the view of an effective influence of PCB on major inflammatory mediators in acute cerebral hypoperfusion. These results suggest that PCB has a potential to be a treatment for ischemic stroke for which further studies are needed. Copyright © 2013 Elsevier Inc. All rights reserved.

The relationship between deiodinase activity and inflammatory responses under the stimulation of uremic toxins.

PubMed

Xu, Gaosi; Tu, Weiping; Qin, Shulan

2014-08-31

It is unclear to what extent uremic toxins participate in inflammatory responses and the activities of deiodinases, as well as the effects of deiodinases on inflammatory cytokines. Hepatocellular carcinoma cell lines (HepG2) were transfected with small interfering ribonucleic acid (siRNA) specific for deiodinase type 1 (DIO1) and cultured with or without uremic toxins. The mRNA expression of DIO1, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α was detected by quantitative real-time PCR. The presence of selenoprotein M (SelM) and DIO1 was assessed by western blotting. Sonicate deiodinase activities in HepG2 cells were measured by a dithiothreitol-stimulated assay. The NF-κB, AP-1 and CREB-1 inflammatory signal pathways were confirmed by EMSA. After culturing for 24 h, the mRNA expression of DIO1 was significantly decreased by the specific siRNA (reduced by 76%, P = 0.0002). Uremic toxins significantly increased the mRNA expression (P < 0.01) of IL-1β, IL-6 and TNF-α and inhibited DIO1 mRNA expression (P < 0.01) compared with controls. Suppression of DIO1 by siRNA significantly decreased the mRNA expression of IL-1β and IL-6 (P < 0.05) but not TNF-α (P = 0.093). Uremic toxins and specific siRNA synchronously reduced the protein expression of SelM and DIO1. Uremic toxins activate the expression of inflammatory cytokines. The major findings of this study indicate that the uremic toxins, more than inflammatory cytokines, play direct inhibitory roles in DIO1 enzyme activity, which then provides a negative feedback to the growing accumulation of inflammatory cytokines.

Src kinase-targeted anti-inflammatory activity of davallialactone from Inonotus xeranticus in lipopolysaccharide-activated RAW264.7 cells.

PubMed

Lee, Y G; Lee, W M; Kim, J Y; Lee, J Y; Lee, I-K; Yun, B-S; Rhee, M H; Cho, J Y

2008-06-01

Mushrooms are popular both as food and as a source of natural compounds of biopharmaceutical interest. Some mushroom-derived compounds such as beta-glucan have been shown to be immunostimulatory; this study explores the anti-inflammatory properties of hispidin analogues derived from the mushroom, Inonotus xeranticus. We sought to identify the molecular mechanism of action of these hispidin analogues by determining their effects on lipopolysaccharide (LPS)-mediated inflammatory responses in a macrophage cell line. The production of inflammatory mediators was determined by Griess assay, reverse transcription-PCR and ELISA. The inhibitory effect of davalliactone on LPS-induced activation of signalling cascades was assessed by western blotting, immunoprecipitation and direct kinase assay. In activated RAW264.7 cells, davallialactone strongly downregulated LPS-mediated inflammatory responses, including NO production, prostaglandin E2 release, expression of proinflammatory cytokine genes and cell surface expression of co-stimulatory molecules. Davallialactone treatment did not alter cell viability or morphology. Davallialactone was found to exert its anti-inflammatory effects by inhibiting a signalling cascade that activates nuclear factor kappa B via PI3K, Akt and IKK, but not mitogen-activated protein kinases. Treatment with davallialactone affected the phosphorylation of these signalling proteins, but not their level of expression. These inhibitory effects were not due to the interruption of toll-like receptor 4 binding to CD14. In particular, davallialactone strongly inhibited the LPS-induced phosphorylation and kinase activity of Src, implying that Src may be a potential pharmacological target of davallialactone. Our data suggest that davallialactone, a small molecule found in edible mushrooms, has anti-inflammatory activity. Davallialactone can be developed as a pharmaceutically valuable anti-Src kinase agent.

The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activator dh404 protects against diabetes-induced endothelial dysfunction.

PubMed

Sharma, Arpeeta; Rizky, Luddwi; Stefanovic, Nada; Tate, Mitchel; Ritchie, Rebecca H; Ward, Keith W; de Haan, Judy B

2017-03-03

Vascular dysfunction is a pivotal event in the development of diabetes-associated vascular disease. Increased inflammation and oxidative stress are major contributors to vascular dysfunction. Nrf2, a master regulator of several anti-oxidant genes and a suppressor of inflammatory NF-κB, has potential as a target to combat oxidative stress and inflammation. The aim of this study was to investigate the effects of a novel Nrf2 activator, the bardoxolone methyl derivative dh404, on endothelial function in vitro and in vivo. dh404 at 3 mg/kg was administered to male Akita mice, an established diabetic mouse model of insulin insufficiency and hyperglycemia, from 6 weeks of age. At 26 weeks of age, vascular reactivity was assessed by wire myography, pro-inflammatory expression was assessed in the aortas by qRT-PCR and immunohistochemistry, and systemic and vascular oxidative stress measurements were determined. Additionally, studies in human aortic endothelial cells (HAECs) derived from normal and diabetic patients in the presence or absence of dh404 included assessment of pro-inflammatory genes by qRT-PCR and western blotting. Oxidative stress was assessed by three methods; L-012, DCFDA and amplex red. Static adhesion assays were performed to determine the leukocyte-endothelial interaction in the presence or absence of dh404. Dh404 significantly attenuated endothelial dysfunction in diabetic Akita mice characterized by reduced contraction in response to phenylephrine and the downregulation of inflammatory genes (VCAM-1, ICAM-1, p65, IL-1β) and pro-oxidant genes (Nox1 and Nox2). Furthermore, reduced systemic and vascular oxidative stress levels were observed in diabetic Akita mice. dh404 exhibited cytoprotective effects in diabetic HAECs in vitro, reflected by significant upregulation of Nrf2-responsive genes, NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), reduction of oxidative stress markers (O 2 ·- and H 2 O 2 ), inhibition of inflammatory genes (VCAM-1 and the p65 subunit of NF-κB) and attenuation of leukocyte-endothelial interactions (P < 0.05 for all in vitro and in vivo parameters; one or two-way ANOVA as appropriate with post hoc testing). These studies demonstrate that upregulation of Nrf2 by dh404 represents a novel therapeutic strategy to limit diabetes-associated vascular injury.

Droplet digital PCR quantifies host inflammatory transcripts in feces reliably and reproducibly

USDA-ARS?s Scientific Manuscript database

The gut is the most extensive, interactive, and complex interface between the human host and the environment and therefore a critical site of immunological activity. Non-invasive methods to assess the host response in this organ are currently lacking. Feces are the available analyte which have been ...

Extracorporeal membrane oxygenation and cytokine adsorption

PubMed Central

Träger, Karl

2018-01-01

Extracorporeal membrane oxygenation (ECMO) is an increasingly used technology for mechanical support of respiratory and cardio-circulatory failure. Excessive systemic inflammatory response is observed during sepsis and after cardiopulmonary bypass (CPB) with similar clinical features. The overwhelming inflammatory response is characterized by highly elevated pro- and anti-inflammatory cytokine levels. The excessive cytokine release during the overwhelming inflammatory response may result in multiple organ damage and failure. During ECMO therapy activation of complement and contact systems occur which may be followed by cytokine release. Controlling excessively increased cytokines may be considered as a valuable treatment option. Hemoadsorption therapy may be used to decrease cytokine levels in case of excessive inflammatory response and due to its unspecific adsorptive characteristics also substances like myoglobin, free hemoglobin or bilirubin. Controlling pro-inflammatory response with hemoadsorption may have positive impact on the endothelial glycocalix and also may be advantageous for maintenance of the vascular barrier function which plays a pivotal role in the development of tissue edema and oxygen mismatch. Hemoadsorption therapy seems to offer a promising new option for the treatment of patients with overwhelming inflammatory response leading to faster hemodynamic and metabolic stabilization finally resulting in preserved organ functions. PMID:29732183

Extracorporeal membrane oxygenation and cytokine adsorption.

PubMed

Datzmann, Thomas; Träger, Karl

2018-03-01

Extracorporeal membrane oxygenation (ECMO) is an increasingly used technology for mechanical support of respiratory and cardio-circulatory failure. Excessive systemic inflammatory response is observed during sepsis and after cardiopulmonary bypass (CPB) with similar clinical features. The overwhelming inflammatory response is characterized by highly elevated pro- and anti-inflammatory cytokine levels. The excessive cytokine release during the overwhelming inflammatory response may result in multiple organ damage and failure. During ECMO therapy activation of complement and contact systems occur which may be followed by cytokine release. Controlling excessively increased cytokines may be considered as a valuable treatment option. Hemoadsorption therapy may be used to decrease cytokine levels in case of excessive inflammatory response and due to its unspecific adsorptive characteristics also substances like myoglobin, free hemoglobin or bilirubin. Controlling pro-inflammatory response with hemoadsorption may have positive impact on the endothelial glycocalix and also may be advantageous for maintenance of the vascular barrier function which plays a pivotal role in the development of tissue edema and oxygen mismatch. Hemoadsorption therapy seems to offer a promising new option for the treatment of patients with overwhelming inflammatory response leading to faster hemodynamic and metabolic stabilization finally resulting in preserved organ functions.

Targeted Overexpression of Inducible 6-Phosphofructo-2-kinase in Adipose Tissue Increases Fat Deposition but Protects against Diet-induced Insulin Resistance and Inflammatory Responses*

PubMed Central

Huo, Yuqing; Guo, Xin; Li, Honggui; Xu, Hang; Halim, Vera; Zhang, Weiyu; Wang, Huan; Fan, Yang-Yi; Ong, Kuok Teong; Woo, Shih-Lung; Chapkin, Robert S.; Mashek, Douglas G.; Chen, Yanming; Dong, Hui; Lu, Fuer; Wei, Lai; Wu, Chaodong

2012-01-01

Increasing evidence demonstrates the dissociation of fat deposition, the inflammatory response, and insulin resistance in the development of obesity-related metabolic diseases. As a regulatory enzyme of glycolysis, inducible 6-phosphofructo-2-kinase (iPFK2, encoded by PFKFB3) protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance independently of adiposity. Using aP2-PFKFB3 transgenic (Tg) mice, we explored the ability of targeted adipocyte PFKFB3/iPFK2 overexpression to modulate diet-induced inflammatory responses and insulin resistance arising from fat deposition in both adipose and liver tissues. Compared with wild-type littermates (controls) on a high fat diet (HFD), Tg mice exhibited increased adiposity, decreased adipose inflammatory response, and improved insulin sensitivity. In a parallel pattern, HFD-fed Tg mice showed increased hepatic steatosis, decreased liver inflammatory response, and improved liver insulin sensitivity compared with controls. In both adipose and liver tissues, increased fat deposition was associated with lipid profile alterations characterized by an increase in palmitoleate. Additionally, plasma lipid profiles also displayed an increase in palmitoleate in HFD-Tg mice compared with controls. In cultured 3T3-L1 adipocytes, overexpression of PFKFB3/iPFK2 recapitulated metabolic and inflammatory changes observed in adipose tissue of Tg mice. Upon treatment with conditioned medium from iPFK2-overexpressing adipocytes, mouse primary hepatocytes displayed metabolic and inflammatory responses that were similar to those observed in livers of Tg mice. Together, these data demonstrate a unique role for PFKFB3/iPFK2 in adipocytes with regard to diet-induced inflammatory responses in both adipose and liver tissues. PMID:22556414

Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cover, Cathleen; Liu Jie; Farhood, Anwar

Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2)more » was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.« less

Involvement of heat shock protein a4/apg-2 in refractory inflammatory bowel disease.

PubMed

Adachi, Teppei; Sakurai, Toshiharu; Kashida, Hiroshi; Mine, Hiromasa; Hagiwara, Satoru; Matsui, Shigenaga; Yoshida, Koji; Nishida, Naoshi; Watanabe, Tomohiro; Itoh, Katsuhiko; Fujita, Jun; Kudo, Masatoshi

2015-01-01

Expression of heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, is induced by several forms of stress. The physiological and pathological functions of HSPA4 in the intestine remain to be elucidated. We assessed HSPA4 expression and function by generating HSPA4-deficient mice and using 214 human intestinal mucosa samples from patients with inflammatory bowel disease (IBD). In the colonic mucosa of patients with IBD, a significant correlation was observed between the expression of HSPA4 and antiapoptotic protein Bcl-2, a T-cell-derived cytokine IL-17 or stem cell markers, such as Sox2. In refractory ulcerative colitis, a condition associated with increased cancer risk, expression of HSPA4 and Bcl-2 was increased in inflammatory cells of colonic mucosae. HSPA4 was overexpressed both in cancer cells and immune cells of human colorectal cancers. Patients with high expression of HSPA4 or Bmi1 showed significantly lower response rates upon subsequent steroid therapy as compared with patients with low expression of each gene. HSPA4-deficient mice exhibit more apoptosis and less expression of IL-17/IL-23 in inflammatory cells and less number of Sox2 cells after administration of dextran sodium sulfate than control mice. Transduction of HspaA4 bone marrow into wild-type mice reduced the immune response. Upregulation of Bcl-2 and IL-17 by HSPA4 would control apoptosis of inflammatory cells and immune response in the gut, which might develop treatment resistance in IBD. HSPA4 and Bmi1 would be a useful biomarker for refractory clinical course and a promising approach for a therapeutic strategy in patients with IBD.

Age-related differences in interferon regulatory factor-4 and -5 signaling in ischemic brains of mice.

PubMed

Zhao, Shou-Cai; Wang, Chun; Xu, Heng; Wu, Wen-Qian; Chu, Zhao-Hu; Ma, Ling-Song; Zhang, Ying-Dong; Liu, Fudong

2017-11-01

Stroke is a disease that mainly affects the elderly. Since the age-related differences in stroke have not been well studied, modeling stroke in aged animals is clinically more relevant. The inflammatory responses to stroke are a fundamental pathological procedure, in which microglial activation plays an important role. Interferon regulatory factor-5 (IRF5) and IRF4 regulate M1 and M2 activation of macrophages, respectively, in peripheral inflammation; but it is unknown whether IRF5/IRF4 are also involved in cerebral inflammatory responses to stroke and whether age-related differences of the IRF5/IRF4 signaling exist in ischemic brain. Here, we investigated the influences of aging on IRF5/IRF4 signaling and post-stroke inflammation in mice. Both young (9-12 weeks) and aged (18 months) male mice were subjected to middle cerebral artery occlusion (MCAO). Morphological and biochemical changes in the ischemic brains and behavior deficits were assessed on 1, 3, and 7 d post-stroke. After MCAO, the aged mice showed smaller infarct sizes but higher neurological deficits and corner test scores than young mice. Young mice had higher levels of IRF4 and CD206 microglia in the ischemic brains, whereas the aged mice expressed more IRF5 and MHCII microglia. After MCAO, serum pro-inflammatory cytokines (TNF-α, iNOS, IL-6) were more prominently up-regulated in aged mice, whereas serum anti-inflammatory cytokines (TGF-β, IL-4, IL-10) were more prominently up-regulated in young mice. Our results demonstrate that aging has a significant influence on stroke outcomes in mice, which is probably mediated by age-specific inflammatory responses.

The effect of hydrophilic titanium surface modification on macrophage inflammatory cytokine gene expression.

PubMed

Hamlet, Stephen; Alfarsi, Mohammed; George, Roy; Ivanovski, Saso

2012-05-01

Chemical modification of microrough titanium dental implants to produce a hydrophilic surface with increased wettability and improved surface energy has been demonstrated clinically to achieve superior bone wound healing and osseointegration compared to that achieved with a microrough titanium surface alone. As the recruitment of the necessary osseoinductive precursors involved in bone wound healing and osseointegration to the wound site is facilitated by the action of cytokines, this study sought to determine the in vitro effect of hydrophilic surface modification on the expression of pro-inflammatory cytokines from adherent macrophages. The surface topography and composition of the titanium surfaces was characterized by scanning electron microscopy and X-ray photoelectron spectroscopy. Macrophage attachment and proliferation was assessed using an MTT assay. The expression of 84 pro-inflammatory cytokines and chemokines by adherent RAW 264.7 cells, a murine leukaemic monocyte cell line, was assessed by PCR array after 24 h culture on either smooth polished, sand-blasted acid-etched (SLA) or hydrophilic-modified SLA (SLActive) titanium surfaces. Following 24 h culture on titanium, surface microroughness activated pro-inflammatory cytokine gene transcription in RAW 264.7 cells. Although there was no significant difference in the degree of cellular attachment or proliferation of RAW 264.7 cells to the different titanium surfaces, by 24 h the hydrophilic surface elicited a gene expression profile with significant down-regulation of the key pro-inflammatory cytokines Tnfα, IL-1α, IL-1β and the chemokine Ccl-2. Down-regulation of the expression of pro-inflammatory cytokine genes may thus modulate the inflammatory response and may facilitate the enhanced bone wound healing and osseointegration observed clinically using implants with a microrough hydrophilic surface. © 2011 John Wiley & Sons A/S.

Chagas disease: modulation of the inflammatory response by acetylcholinesterase in hematological cells and brain tissue.

PubMed

Silva, Aniélen D; Bottari, Nathieli B; do Carmo, Guilherme M; Baldissera, Matheus D; Souza, Carine F; Machado, Vanessa S; Morsch, Vera M; Schetinger, Maria Rosa C; Mendes, Ricardo E; Monteiro, Silvia G; Da Silva, Aleksandro S

2018-01-01

Chagas disease is an acute or chronic illness that causes severe inflammatory response, and consequently, it may activate the inflammatory cholinergic pathway, which is regulated by cholinesterases, including the acetylcholinesterase. This enzyme is responsible for the regulation of acetylcholine levels, an anti-inflammatory molecule linked to the inflammatory response during parasitic diseases. Thus, the aim of this study was to investigate whether Trypanosoma cruzi infection can alter the activity of acetylcholinesterase and acetylcholine levels in mice, and whether these alterations are linked to the inflammatory cholinergic signaling pathway. Twenty-four mice were divided into two groups: uninfected (control group, n = 12) and infected by T. cruzi, Y strain (n = 12). The animals developed acute disease with a peak of parasitemia on day 7 post-infection (PI). Blood, lymphocytes, and brain were analyzed on days 6 and 12 post-infection. In the brain, acetylcholine and nitric oxide levels, myeloperoxidase activity, and histopathology were analyzed. In total blood and brain, acetylcholinesterase activity decreased at both times. On the other hand, acetylcholinesterase activity in lymphocytes increased on day 6 PI compared with the control group. Infection by T. cruzi increased acetylcholine and nitric oxide levels and histopathological damage in the brain of mice associated to increased myeloperoxidase activity. Therefore, an intense inflammatory response in mice with acute Chagas disease in the central nervous system caused an anti-inflammatory response by the activation of the cholinergic inflammatory pathway.

Pulmonary exposure to carbonaceous nanomaterials and sperm quality.

PubMed

Skovmand, Astrid; Jacobsen Lauvås, Anna; Christensen, Preben; Vogel, Ulla; Sørig Hougaard, Karin; Goericke-Pesch, Sandra

2018-01-31

Semen quality parameters are potentially affected by nanomaterials in several ways: Inhaled nanosized particles are potent inducers of pulmonary inflammation, leading to the release of inflammatory mediators. Small amounts of particles may translocate from the lungs into the lung capillaries, enter the systemic circulation and ultimately reach the testes. Both the inflammatory response and the particles may induce oxidative stress which can directly affect spermatogenesis. Furthermore, spermatogenesis may be indirectly affected by changes in the hormonal milieu as systemic inflammation is a potential modulator of endocrine function. The aim of this study was to investigate the effects of pulmonary exposure to carbonaceous nanomaterials on sperm quality parameters in an experimental mouse model. Effects on sperm quality after pulmonary inflammation induced by carbonaceous nanomaterials were investigated by intratracheally instilling sexually mature male NMRI mice with four different carbonaceous nanomaterials dispersed in nanopure water: graphene oxide (18 μg/mouse/i.t.), Flammruss 101, Printex 90 and SRM1650b (0.1 mg/mouse/i.t. each) weekly for seven consecutive weeks. Pulmonary inflammation was determined by differential cell count in bronchoalveolar lavage fluid. Epididymal sperm concentration and motility were measured by computer-assisted sperm analysis. Epididymal sperm viability and morphological abnormalities were assessed manually using Hoechst 33,342/PI flourescent and Spermac staining, respectively. Epididymal sperm were assessed with regard to sperm DNA integrity (damage). Daily sperm production was measured in the testis, and testosterone levels were measured in blood plasma by ELISA. Neutrophil numbers in the bronchoalveolar fluid showed sustained inflammatory response in the nanoparticle-exposed groups one week after the last instillation. No significant changes in epididymal sperm parameters, daily sperm production or plasma testosterone levels were found. Despite the sustained pulmonary inflammatory response, an eight week exposure to graphene oxide, Flammruss 101, Printex 90 and the diesel particle SRM1650b in the present study did not appear to affect semen parameters, daily sperm production or testosterone concentration in male NMRI mice.

Assessment of β-lapachone loaded in lecithin-chitosan nanoparticles for the topical treatment of cutaneous leishmaniasis in L. major infected BALB/c mice.

PubMed

Moreno, Esther; Schwartz, Juana; Larrea, Esther; Conde, Iosune; Font, Maria; Sanmartín, Carmen; Irache, Juan Manuel; Espuelas, Socorro

2015-11-01

Patients affected by cutaneous leishmaniasis need a topical treatment which cures lesions without leaving scars. Lesions are produced not only by the parasite but also by an uncontrolled and persistent inflammatory immune response. In this study, we proposed the loading of β-lapachone (β-LP) in lecithin-chitosan nanoparticles (NP) for targeting the drug to the dermis, where infected macrophages reside, and promote wound healing. Although the loading of β-LP in NP did not influence the drug antileishmanial activity it was critical to achieve important drug accumulation in the dermis and permeation through the skin. When topically applied in Leishmania major infected BALB/c mice, β-LP NP achieved no parasite reduction but they stopped the lesion progression. Immuno-histopathological assays in CL lesions and quantitative mRNA studies in draining lymph nodes confirmed that β-LP exhibited anti-inflammatory activity leading to the down-regulation of IL-1β and COX-2 expression and a decrease of neutrophils infiltrate. Cutaneous leishmaniasis often leaves patients with unsightly scars due to the body's inflammatory response to the infection. The authors in this paper described topical treatment using β-lapachone (β- LP) loaded in lecithin-chitosan nanoparticles (NP) in an animal model. Results confirmed the reduction of inflammatory response without affecting the parasite killing efficacy. These findings would pave way for further clinical testing in the near future. Copyright © 2015 Elsevier Inc. All rights reserved.

Cellular profile of the peritumoral inflammatory infiltrate in squamous cells carcinoma of oral mucosa: Correlation with the expression of Ki67 and histologic grading

PubMed Central

Vieira, Fabricio LD; Vieira, Beatriz J; Guimaraes, Marco AM; Aarestrup, Fernando M

2008-01-01

Background Squamous cells carcinoma is the most important malignant tumor with primary site in the oral cavity and, given the great exposure of mucosa and lips to the etiologic factors of this neoplasm, its incidence is high. Investigation of the prognostic determinants is significant for the expectations of treatment proposal and cure of the patient. The local immune response represented by peritumoral inflammatory infiltrate is a possible prognostic factor. Methods In this study, oral mucosa samples of squamous cells carcinoma were analyzed, separated according to their histological classification as well as the phenotypical profile of the cells comprising the peritumoral inflammatory infiltrate was investigated by immunohistochemical method, in addiction, the cell proliferation index via protein Ki67 expression was determinated. Results The T lymphocytes made up most of this inflammatory infiltrate, and among these cells, there was a predominance of T CD8 lymphocytes relative to the T CD4 lymphocytes. The B lymhocytes were the second most visualized leucocyte cell type followed by macrophages and neutrophils. The immunohistochemical assessment of Ki-67 positive cells revealed a greater expression of this protein in samples of undifferentiated squamous cells carcinoma. Conclusion The results suggest that the cellular immune response is the main defense mechanism in squamous cells carcinoma of oral mucosa, expressed by the large number of T lymphocytes and macrophages, and that the greatest intensity of local response may be associated with the best prognosis. PMID:18764952

Naproxen sodium decreases prostaglandins secretion from cultured human endometrial stromal cells modulating metabolizing enzymes mRNA expression.

PubMed

Carrarelli, Patrizia; Funghi, Lucia; Bruni, Simone; Luisi, Stefano; Arcuri, Felice; Petraglia, Felice

2016-01-01

Dysmenorrhea, defined as painful cramps occurring immediately before or during the menstrual period, is a common symptom of different gynecological diseases. An acute uterine inflammatory response driven by prostaglandins (PGs) is responsible for painful symptoms. Progesterone withdrawal is responsible for activation of cyclooxygenase (COX-2) enzyme and decrease of hydroxyprostaglandin dehydrogenase (HPDG) with consequent increased secretion of PGs secretion, inducing uterine contractility and pain. The most widely used drugs for the treatment of pelvic pain associated with menstrual cycle are non steroidal anti-inflammatory drugs (NSAIDs). The uterine site of action of these drugs is still not defined and the present study evaluated the effect of naproxen sodium in cultured human endometrial stromal cells (HESC) collected from healthy women. PGE2 release was measured by ELISA; COX-2 and HPDG mRNA expression were assessed by qRT-PCR. Naproxen sodium did not affect HESC vitality. Naproxen sodium significantly decreased PGE2 secretion (p < 0.01) and COX-2 mRNA expression (p < 0.01). TNF-α induced PGE2 release was reduced in presence of naproxen sodium (p < 0.05), in association with decreased COX-2 and increased HPDG mRNAs expression. Naproxen sodium decreases endometrial PGE2 release induced by inflammatory stimulus acting on endometrial COX-2 and HPDG expression, suggesting endometrial synthesis of prostaglandins as a possible target for reduction of uterine inflammatory mechanism in dysmenorrhea.

Lactobacillus casei DG and its postbiotic reduce the inflammatory mucosal response: an ex-vivo organ culture model of post-infectious irritable bowel syndrome.

PubMed

Compare, Debora; Rocco, Alba; Coccoli, Pietro; Angrisani, Debora; Sgamato, Costantino; Iovine, Barbara; Salvatore, Umberto; Nardone, Gerardo

2017-04-14

The evidence on the role of gut microbiota in post-infectious irritable bowel syndrome (PI-IBS) is convincing. Lactobacillus spp. positively affect IBS symptoms, although the mechanisms through which probiotics exert their beneficial effects are largely unknown. The aim of the study is to evaluate the role of Lactobacillus casei DG (LC-DG) and its postbiotic (PB) in modulating the inflammatory/immune-response in PI-IBS in an ex-vivo organ culture model. Ex vivo cultures of ileal and colonic mucosa from 10 PI-IBS, diarrhea predominant subtype (D) patients, and 10 healthy controls (HC) were treated with LPS, LC-DG and PB. Interleukin (IL)-1α, IL-6, IL-8 and IL-10 mRNA levels were assessed by real-time PCR and Toll like receptor 4 (TLR-4) protein expression by Western blotting. At baseline, IL-1α, IL-6 and IL-8 mRNA levels as well as TLR-4 protein expression were significantly higher while IL-10 mRNA levels were lower in PI-IBS D than in HC in both ileum and colon. LC-DG and PB significantly reduced the mRNA levels of pro-inflammatory cytokines and TLR-4 while increased that of IL-10 after LPS stimulation. The protective effect was more pronounced for PB than LC-DG treatment. LC-DG and its PB attenuate the inflammatory mucosal response in an ex-vivo organ culture model of PI-IBS D.

Fecal calprotectin in inflammatory bowel disease

PubMed Central

Walsham, Natalie E; Sherwood, Roy A

2016-01-01

Inflammatory bowel disease (IBD) and irritable bowel syndrome share many symptoms. While irritable bowel syndrome is a functional bowel disorder for which no specific treatment is available, the range of effective therapies for IBD is evolving rapidly. Accurate diagnosis of IBD is therefore essential. Clinical assessment, together with various imaging modalities and endoscopy, has been the mainstay of diagnosis for many years. Fecal biomarkers of gastrointestinal inflammation have appeared in the past decade, of which calprotectin, a neutrophil cytosolic protein, has been studied the most. Crohn’s disease and ulcerative colitis are chronic remitting and relapsing diseases, and objective assessment of disease activity and response to treatment are important. This review focuses on the use of fecal calprotectin measurements in the diagnosis and monitoring of patients with IBD. PMID:26869808

Validation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) for the Hand and Foot in a Randomized Placebo-controlled Trial.

PubMed

Glinatsi, Daniel; Bird, Paul; Gandjbakhch, Frederique; Mease, Philip J; Bøyesen, Pernille; Peterfy, Charles G; Conaghan, Philip G; Østergaard, Mikkel

2015-12-01

To assess changes following treatment and the reliability and responsiveness to change of the Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) in a randomized controlled trial. Forty patients with PsA randomized to either placebo or abatacept (ABA) had MRI of either 1 hand (n = 20) or 1 foot (n = 20) at baseline and after 6 months. Images were scored blindly twice by 3 independent readers according to the PsAMRIS (for synovitis, tenosynovitis, periarticular inflammation, bone edema, bone erosion, and bone proliferation). Inflammatory features improved numerically but statistically nonsignificantly in the ABA group but not the placebo group. Baseline intrareader intraclass correlation coefficients (ICC) were good (≥ 0.50) to very good (≥ 0.80) for all features in both hand and foot. Baseline interreader ICC were good (ICC 0.72-0.96) for all features, except periarticular inflammation and bone proliferation in the hand and tenosynovitis in the foot (ICC 0.25-0.44). Intrareader and interreader ICC for change scores varied. Guyatt's responsiveness index (GRI) was high for inflammatory features in the hand and metatarsophalangeal joints (GRI -0.67 to -3.13; bone edema not calculable). Minimal change and low prevalence resulted in low ICC and GRI for bone damage. PsAMRIS showed overall good intrareader agreement in the hand and foot, and inflammatory feature scores were responsive to change, suggesting that PsAMRIS may be a valid tool for MRI assessment of hands and feet in PsA clinical trials.

Respiratory inflammation and infections in high-performance athletes.

PubMed

Gleeson, Maree; Pyne, David B

2016-02-01

Upper respiratory illness is the most common reason for non-injury-related presentation to a sports medicine clinic, accounting for 35-65% of illness presentations. Recurrent or persistent respiratory illness can have a negative impact on health and performance of athletes undertaking high levels of strenuous exercise. The cause of upper respiratory symptoms (URS) in athletes can be uncertain but the majority of cases are related to common respiratory viruses, viral reactivation, allergic responses to aeroallergens and exercise-related trauma to the integrity of respiratory epithelial membranes. Bacterial respiratory infections are uncommon in athletes. Undiagnosed or inappropriately treated asthma and/or allergy are common findings in clinical assessments of elite athletes experiencing recurrent URS. High-performance athletes with recurrent episodes of URS should undergo a thorough clinical assessment to exclude underlying treatable conditions of respiratory inflammation. Identifying athletes at risk of recurrent URS is important in order to prescribe preventative clinical, training and lifestyle strategies. Monitoring secretion rates and falling concentrations of salivary IgA can identify athletes at risk of URS. Therapeutic interventions are limited by the uncertainty of the underlying cause of inflammation. Topical anti-inflammatory sprays can be beneficial for some athletes. Dietary supplementation with bovine colostrum, probiotics and selected antioxidants can reduce the incidence or severity of URS in some athletes. Preliminary studies on athletes prone to URS indicate a genetic predisposition to a pro-inflammatory response and a dysregulated anti-inflammatory cytokine response to intense exercise as a possible mechanism of respiratory inflammation. This review focuses on respiratory infections and inflammation in elite/professional athletes.

Low-level laser therapy (LLLT) reduces inflammatory infiltrate and enhances skeletal muscle repair: Histomorphometric parameters

NASA Astrophysics Data System (ADS)

Paiva-Oliveira, E. L.; Lima, N. C.; Silva, P. H.; Sousa, N. T. A.; Barbosa, F. S.; Orsini, M.; Silva, J. G.

2012-09-01

Low level laser therapy (LLLT) has been suggested as an effective therapeutics in inflammatory processes modulation and tissue repairing. However, there is a lack of studies that analyze the anti-inflammatory effects of the infrared lasers in muscular skeletal injury. The aim of this study was to investigate the effects of low-level laser therapy 904 nm in the repair process of skeletal muscle tissue. Swiss mice were submitted to cryoinjury and divided in test (LLLT-treated) and control groups. Histological sections were stained with hematoxylin-eosin to assess general morphology and inflammatory influx, and Picrossirus to quantify collagen fibers deposition. Our results showed significant reduction in inflammatory infiltrated in irradiated mice after 4 days of treatment compared to control ( p = 0.01). After 8 days, the irradiated group showed high levels at regenerating myofibers with significant statistically differences in relation at control group ( p < 0.01). Collagen deposition was significantly increased in the final stages of regeneration at test group, when compared with control group ( p = 0.05). Our data suggests that LLLT reduces the inflammatory response in the initial stages of injury and accelerates the process of muscular tissue repair.

Micro124-mediated AHR expression regulates the inflammatory response of chronic rhinosinusitis (CRS) with nasal polyps.

PubMed

Liu, C C; Xia, M; Zhang, Y J; Jin, P; Zhao, L; Zhang, J; Li, T; Zhou, X M; Tu, Y Y; Kong, F; Sun, C; Shi, L; Zhao, M Q

2018-06-02

MicroRNAs represent a component of the innate immune responses that can restrain inflammatory signaling, miR124 is an important member of inflammation-associated miRNAs, and abnormal miR124 expression is observed in many inflammatory diseases and immune disorders. However, the role and signaling pathways of miR124 in chronic rhinosinusitis with nasal polyps (CRSwNPs) have not been studied in detail. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is highly conserved in evolution and plays important roles in the inflammatory response process. In our study, we describe the role of miR124 in the inflammatory response of CRS with nasal polyps. We found that the expression of miR124 was decreased in nasal polyps, and negatively correlated with the expression of AHR. MiR124 can inhibit AHR expression by directly target 3' untranslated region (3'-UTR) of AHR. To further investigate the relationship between miR124, AHR and CRS inflammatory response, we transfect HNEpC cells with miR124 mimic, miR124 inhibitors or siRNA of AHR, then all the results showed that miR124 could regulates cellular inflammatory response through negatively regulating AHR expression. This study demonstrated that the regulation of AHR expression by miR124 is critical to the development of inflammatory response in CRSwNPs. Copyright © 2018. Published by Elsevier Inc.

Role of muscarinic receptors in the regulation of immune and inflammatory responses

PubMed Central

Razani-Boroujerdi, Seddigheh; Behl, Muskaan; Hahn, Fletcher F.; Pena-Philippides, Juan Carlos; Hutt, Julie; Sopori, Mohan L.

2008-01-01

Leukocytes contain both nicotinic and muscarinic receptors, and while activation of nicotinic receptors suppresses immune/inflammatory responses, the role of muscarinic receptors in immunity is unclear. We examined the effects of a muscarinic receptor antagonist (atropine) and agonist (oxotremorine), administered chronically through miniosmotic pumps, on immune/inflammatory responses in the rat. Results show that while oxotremorine stimulated, atropine inhibited the antibody and T-cell proliferative responses. Moreover, atropine also suppressed the turpentine-induced leukocytic infiltration and tissue injury, and inhibited chemotaxis of leukocytes toward neutrophil and monocyte/lymphocyte chemoattractants. Thus, activation of nicotinic and muscarinic receptors has opposite effects on the immune/inflammatory responses. PMID:18190972

Childhood maltreatment and inflammatory markers: a systematic review.

PubMed

Coelho, R; Viola, T W; Walss-Bass, C; Brietzke, E; Grassi-Oliveira, R

2014-03-01

Childhood maltreatment (CM) has been associated with several diseases in adult life, including diabetes, obesity and mental disorders. Inflammatory conditions have been postulated as possible mediators of this relationship. The aim was to conduct a systematic review regarding the association between CM and inflammatory markers in adulthood. A literature search of the PubMed, ISI, EMBASE and PsychINFO databases was conducted. The key terms used were as follows: 'Child Maltreatment', 'Childhood Trauma', 'Early Life Stress', 'Psychological Stress', 'Emotional Stress', 'Child Abuse' and 'Child Neglect'. They were cross-referenced separately with the terms: 'C-reactive Protein (CRP)', 'Tumor Necrosis Factor', 'Cytokine', 'Interleukin', 'Inflammatory' and 'Inflammation'. Twenty articles remained in the review after exclusion criteria were applied. Studies showed that a history of CM was associated with increased levels of CRP, fibrinogen and proinflammatory cytokines. Increased levels of circulating CRP in individuals with a history of CM were the most robust finding among the studies. Data about anti-inflammatory mediators are still few and inconsistent. Childhood maltreatment is associated with a chronic inflammatory state independent of clinical comorbidities. However, studies are heterogeneous regarding CM assessment and definition. Important methodological improvements are needed to better understand the potential impact of CM on inflammatory response. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

α7 Nicotinic Agonist AR-R17779 Protects Mice against 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in a Spleen-Dependent Way.

PubMed

Grandi, Andrea; Zini, Irene; Flammini, Lisa; Cantoni, Anna M; Vivo, Valentina; Ballabeni, Vigilio; Barocelli, Elisabetta; Bertoni, Simona

2017-01-01

The existence of a cholinergic anti-inflammatory pathway negatively modulating the inflammatory and immune responses in various clinical conditions and experimental models has long been postulated. In particular, the protective involvement of the vagus nerve and of nicotinic Ach receptors (nAChRs) has been proposed in intestinal inflammation and repeatedly investigated in DSS- and TNBS-induced colitis. However, the role of α 7 nAChRs stimulation is still controversial and the potential contribution of α 4 β 2 nAChRs has never been explored in this experimental condition. Our aims were therefore to pharmacologically investigate the role played by both α 7 and α 4 β 2 nAChRs in the modulation of the local and systemic inflammatory responses activated in TNBS-induced colitis in mice and to assess the involvement of the spleen in nicotinic responses. To this end, TNBS-exposed mice were sub-acutely treated with various subcutaneous doses of highly selective agonists (AR-R17779 and TC-2403) and antagonists (methyllycaconitine and dihydro-β-erythroidine) of α 7 and α 4 β 2 nAChRs, respectively, or with sulfasalazine 50 mg/kg per os and clinical and inflammatory responses were evaluated by means of biochemical, histological and flow cytometry assays. α 4 β 2 ligands evoked weak and contradictory effects, while α 7 nAChR agonist AR-R17779 emerged as the most beneficial treatment, able to attenuate several local markers of colitis severity and to revert the rise in splenic T-cells and in colonic inflammatory cytokines levels induced by haptenization. After splenectomy, AR-R17779 lost its protective effects, demonstrating for the first time that, in TNBS-model of experimental colitis, the anti-inflammatory effect of exogenous α 7 nAChR stimulation is strictly spleen-dependent. Our findings showed that the selective α 7 nAChRs agonist AR-R17779 exerted beneficial effects in a model of intestinal inflammation characterized by activation of the adaptive immune system and that the spleen is essential to mediate this cholinergic protection.

The Food Contaminants Nivalenol and Deoxynivalenol Induce Inflammation in Intestinal Epithelial Cells by Regulating Reactive Oxygen Species Release.

PubMed

Adesso, Simona; Autore, Giuseppina; Quaroni, Andrea; Popolo, Ada; Severino, Lorella; Marzocco, Stefania

2017-12-11

Fusarium mycotoxins are fungal metabolites whose ability to affect cereal grains as multi-contaminants is progressively increasing. The trichothecene mycotoxins nivalenol (NIV) and deoxynivalenol (DON) are often found in almost all agricultural commodities worldwide. They are able to affect animal and human health, including at the intestinal level. In this study, NIV, both alone and in combination with DON, induced inflammation and increased the inflammatory response induced by lipopolysaccharide (LPS) plus Interferon-γ (IFN) in the non-tumorigenic intestinal epithelial cell line (IEC-6). The inflammatory response induced by NIV and DON involves tumor necrosis factor-α (TNF-α) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, nitrotyrosine formation, reactive oxygen species (ROS) release, Nuclear Factor-κB (NF-κB), Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inflammasome activation. The pro-inflammatory effect was strongly induced by NIV and by the mycotoxin mixture, when compared to DON alone. Mechanistic studies indicate a pivotal role for ROS in the observed pro-inflammatory effects induced by mycotoxins. In this study, the interactions between NIV and DON point out the importance of their food co-contamination, further highlighting the risk assessment process that is of growing concern.

Cytotoxic and Inflammatory Potential of Air Samples from Occupational Settings with Exposure to Organic Dust

PubMed Central

Viegas, Susana; Caetano, Liliana Aranha; Korkalainen, Merja; Faria, Tiago; Pacífico, Cátia; Carolino, Elisabete; Quintal Gomes, Anita; Viegas, Carla

2017-01-01

Organic dust and related microbial exposures are the main inducers of several respiratory symptoms. Occupational exposure to organic dust is very common and has been reported in diverse settings. In vitro tests using relevant cell cultures can be very useful for characterizing the toxicity of complex mixtures present in the air of occupational environments such as organic dust. In this study, the cell viability and the inflammatory response, as measured by the production of pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-1 β (IL-1β), were determined in human macrophages derived from THP-1 monocytic cells. These cells were exposed to air samples from five occupational settings known to possess high levels of contamination of organic dust: poultry and swine feed industries, waste sorting, poultry production and slaughterhouses. Additionally, fungi and particle contamination of those settings was studied to better characterize the organic dust composition. All air samples collected from the assessed workplaces caused both cytotoxic and pro-inflammatory effects. The highest responses were observed in the feed industry, particularly in swine feed production. This study emphasizes the importance of measuring the organic dust/mixture effects in occupational settings and suggests that differences in the organic dust content may result in differences in health effects for exposed workers. PMID:29051440

Panax ginseng Improves Functional Recovery after Contusive Spinal Cord Injury by Regulating the Inflammatory Response in Rats: An In Vivo Study

PubMed Central

Kim, Young Ock; Kim, Youngkyung; Lee, Koeun; Na, Sae Won; Hong, Seon Pyo; Valan Arasu, Mariadhas; Yoon, Young Wook; Kim, Junesun

2015-01-01

Spinal cord injury (SCI) results in permanent loss of motor function below the injured site. Neuroinflammatory reaction following SCI can aggravate neural injury and functional impairment. Ginseng is well known to possess anti-inflammatory effects. The present study investigated the neuroprotective effects of Panax ginseng C.A. Mayer (P. ginseng) after SCI. A spinal contusion was made at the T11-12 spinal cord in adult male Sprague-Dawley rats (n = 47) using the NYU impactor. Motor function was assessed using the Basso-Beattie-Bresnahan (BBB) score in P. ginseng (0.1, 0.5, 1, 3, and 5 mg/kg) or vehicle (saline) treated after SCI. We also assessed the protein expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) at the lesion site by western blot and then measured the cavity area using luxol fast blue/cresyl violet staining. P. ginseng treated group in SCI showed a significant improvement in locomotor function after the injury. The protein expression of COX-2 and iNOS at the lesion site and the cavity area were decreased following SCI by P. ginseng treatment. These results suggest that P. ginseng may improve the recovery of motor function after SCI which provides neuroprotection by alleviating posttraumatic inflammatory responses. PMID:26451158

Development of asthmatic inflammation in mice following early-life exposure to ambient environmental particulates and chronic allergen challenge

PubMed Central

Herbert, Cristan; Siegle, Jessica S.; Shadie, Alexander M.; Nikolaysen, Stina; Garthwaite, Linda; Hansbro, Nicole G.; Foster, Paul S.; Kumar, Rakesh K.

2013-01-01

SUMMARY Childhood exposure to environmental particulates increases the risk of development of asthma. The underlying mechanisms might include oxidant injury to airway epithelial cells (AEC). We investigated the ability of ambient environmental particulates to contribute to sensitization via the airways, and thus to the pathogenesis of childhood asthma. To do so, we devised a novel model in which weanling BALB/c mice were exposed to both ambient particulate pollutants and ovalbumin for sensitization via the respiratory tract, followed by chronic inhalational challenge with a low mass concentration of the antigen. We also examined whether these particulates caused oxidant injury and activation of AEC in vitro. Furthermore, we assessed the potential benefit of minimizing oxidative stress to AEC through the period of sensitization and challenge by dietary intervention. We found that characteristic features of asthmatic inflammation developed only in animals that received particulates at the same time as respiratory sensitization, and were then chronically challenged with allergen. However, these animals did not develop airway hyper-responsiveness. Ambient particulates induced epithelial injury in vitro, with evidence of oxidative stress and production of both pro-inflammatory cytokines and Th2-promoting cytokines such as IL-33. Treatment of AEC with an antioxidant in vitro inhibited the pro-inflammatory cytokine response to these particulates. Ambient particulates also induced pro-inflammatory cytokine expression following administration to weanling mice. However, early-life dietary supplementation with antioxidants did not prevent the development of an asthmatic inflammatory response in animals that were exposed to particulates, sensitized and challenged. We conclude that injury to airway epithelium by ambient environmental particulates in early life is capable of promoting the development of an asthmatic inflammatory response in sensitized and antigen-challenged mice. These findings are likely to be relevant to the induction of childhood asthma. PMID:23223614

Key Role of CD36 in Toll-Like Receptor 2 Signaling in Cerebral Ischemia

PubMed Central

Abe, Takato; Shimamura, Munehisa; Jackman, Katherine; Kurinami, Hitomi; Anrather, Josef; Zhou, Ping; Iadecola, Costantino

2010-01-01

Background and Purpose Toll-like receptors (TLRs) and the scavenger receptor CD36 are key molecular sensors for the innate immune response to invading pathogens. However, these receptors may also recognize endogenous “danger signals” generated during brain injury, such as cerebral ischemia, and trigger a maladaptive inflammatory reaction. Indeed, CD36 and TLR2 and 4 are involved in the inflammation and related tissue damage caused by brain ischemia. Because CD36 may act as a coreceptor for TLR2 heterodimers (TLR2/1 or TLR2/6), we tested whether such interaction plays a role in ischemic brain injury. Methods The TLR activators FSL-1 (TLR2/6), Pam3 (TLR2/1), or lipopolysaccharide (TLR4) were injected intracerebroventricularly into wild-type or CD36-null mice, and inflammatory gene expression was assessed in the brain. The effect of TLR activators on the infarct produced by transient middle cerebral artery occlusion was also studied. Results The inflammatory response induced by TLR2/1 activation, but not TLR2/6 or TLR4 activation, was suppressed in CD36-null mice. Similarly, TLR2/1 activation failed to increase infarct volume in CD36-null mice, whereas TLR2/6 or TLR4 activation exacerbated postischemic inflammation and increased infarct volume. In contrast, the systemic inflammatory response evoked by TLR2/6 activation, but not by TLR2/1 activation, was suppressed in CD36-null mice. Conclusions In the brain, TLR2/1 signaling requires CD36. The cooperative signaling of TLR2/1 and CD36 is a critical factor in the inflammatory response and tissue damage evoked by cerebral ischemia. Thus, suppression of CD36-TLR2/1 signaling could be a valuable approach to minimize postischemic inflammation and the attendant brain injury. PMID:20360550

Leptin deficiency-induced obesity exacerbates ultraviolet B radiation-induced cyclooxygenase-2 expression and cell survival signals in ultraviolet B-irradiated mouse skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharma, Som D.; Katiyar, Santosh K., E-mail: skatiyar@uab.ed; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294

Obesity has been implicated in several inflammatory diseases and in different types of cancer. Chronic inflammation induced by exposure to ultraviolet (UV) radiation has been implicated in various skin diseases, including melanoma and nonmelanoma skin cancers. As the relationship between obesity and susceptibility to UV radiation-caused inflammation is not clearly understood, we assessed the role of obesity on UVB-induced inflammation, and mediators of this inflammatory response, using the genetically obese (leptin-deficient) mouse model. Leptin-deficient obese (ob/ob) mice and wild-type counterparts (C57/BL6 mice) were exposed to UVB radiation (120 mJ/cm{sup 2}) on alternate days for 1 month. The mice were thenmore » euthanized and skin samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ELISA and real-time PCR. Here, we report that the levels of inflammatory responses were higher in the UVB-exposed skin of the ob/ob obese mice than those in the UVB-exposed skin of the wild-type non-obese mice. The levels of UVB-induced cyclooxygenase-2 expression, prostaglandin-E{sub 2} production, proinflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser{sup 473}) were higher in the skin of the ob/ob obese mice than the those in skin of their wild-type non-obese counterparts. Compared with the wild-type non-obese mice, the leptin-deficient obese mice also exhibited greater activation of NF-kappaB/p65 and fewer apoptotic cells in the UVB-irradiated skin. Our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVB-induced inflammatory responses and, therefore, obesity may increase susceptibility to UVB-induced inflammation-associated skin diseases, including the risk of skin cancer.« less

Industrial grade 2D molybdenum disulphide (MoS2): an in vitro exploration of the impact on cellular uptake, cytotoxicity, and inflammation

NASA Astrophysics Data System (ADS)

Moore, Caroline; Movia, Dania; Smith, Ronan J.; Hanlon, Damien; Lebre, Filipa; Lavelle, Ed C.; Byrne, Hugh J.; Coleman, Jonathan N.; Volkov, Yuri; McIntyre, Jennifer

2017-06-01

The recent surge in graphene research, since its liquid phase monolayer isolation and characterization in 2004, has led to advancements which are accelerating the exploration of alternative 2D materials such as molybdenum disulphide (MoS2), whose unique physico-chemical properties can be exploited in applications ranging from cutting edge electronic devices to nanomedicine. However, to assess any potential impact on human health and the environment, the need to understand the bio-interaction of MoS2 at a cellular and sub-cellular level is critical. Notably, it is important to assess such potential impacts of materials which are produced by large scale production techniques, rather than research grade materials. The aim of this study was to explore cytotoxicity, cellular uptake and inflammatory responses in established cell-lines that mimic different potential exposure routes (inhalation, A549; ingestion, AGS; monocyte, THP-1) following incubation with MoS2 flakes of varying sizes (50 nm, 117 nm and 177 nm), produced by liquid phase exfoliation. Using high content screening (HCS) and Live/Dead assays, it was established that 1 µg ml-1 (for the three different MoS2 sizes) did not induce toxic effects on any of the cell-lines. Confocal microscopy images revealed a normal cellular morphology in all cases. Transmission electron microscopy (TEM) confirmed the uptake of all MoS2 nanomaterials in all the cell-lines, the MoS2 ultimately locating in single membrane vesicles. At such sub-lethal doses, inflammatory responses are observed, however, associated, at least partially, with the presence of lipopolysaccharide endotoxin in nanomaterial suspensions and surfactant samples. Therefore, the inflammatory response of the cells to the MoS2 or endotoxin contamination was interrogated using a 10-plex ELISA which illustrates cytokine production. The experiments carried out using wild-type and endotoxin hyporesponsive bone marrow derived dendritic cells confirmed that the inflammatory responses result from a combination of endotoxin contamination, the MoS2 nanomaterials themselves, and the stabilizing surfactant.

Inflammatory responses of stromal fibroblasts to inflammatory epithelial cells are involved in the pathogenesis of bovine mastitis.

PubMed

Zhang, Wenyao; Li, Xuezhong; Xu, Tong; Ma, Mengru; Zhang, Yong; Gao, Ming-Qing

2016-11-15

Hypernomic secretion of epithelial cytokines has several effects on stromal cells. The contributions of inflammatory epithelial cells to stromal fibroblasts in bovine mammary glands with mastitis remain poorly understood. Here, we established an inflammatory epithelial cell model of bovine mastitis with gram-negative lipopolysaccharide (LPS) and gram-positive lipoteichoic acid (LTA) bacterial cell wall components. We characterized immune responses of mammary stromal fibroblasts induced by inflammatory epithelial cells. Our results showed that inflammatory epithelial cells affected stromal fibroblast characteristics by increasing inflammatory mediator expression, elevating extracellular matrix protein deposition, decreasing proliferation capacity, and enhancing migration ability. The changes in stromal fibroblast proliferation and migration abilities were mediated by signal molecules, such as WNT signal pathway components. LPS- and LTA-induced inflammatory epithelial cells triggered different immune responses in stromal fibroblasts. Thus, in mastitis, bovine mammary gland stromal fibroblasts were affected by inflammatory epithelial cells and displayed inflammation-specific changes, suggesting that fibroblasts play crucial roles in bovine mastitis. Copyright © 2016 Elsevier Inc. All rights reserved.

Concomitant Exposure to Ovalbumin and Endotoxin Augments Airway Inflammation but Not Airway Hyperresponsiveness in a Murine Model of Asthma

PubMed Central

Mac Sharry, John; Shalaby, Karim H.; Marchica, Cinzia; Farahnak, Soroor; Chieh-Li, Tien; Lapthorne, Susan; Qureshi, Salman T.; Shanahan, Fergus; Martin, James G.

2014-01-01

Varying concentrations of lipopolysaccharide (LPS) in ovalbumin (OVA) may influence the airway response to allergic sensitization and challenge. We assessed the contribution of LPS to allergic airway inflammatory responses following challenge with LPS-rich and LPS-free commercial OVA. BALB/c mice were sensitized with LPS-rich OVA and alum and then underwent challenge with the same OVA (10 µg intranasally) or an LPS-free OVA. Following challenge, bronchoalveolar lavage (BAL), airway responsiveness to methacholine and the lung regulatory T cell population (Treg) were assessed. Both OVA preparations induced BAL eosinophilia but LPS-rich OVA also evoked BAL neutrophilia. LPS-free OVA increased interleukin (IL)-2, IL-4 and IL-5 whereas LPS-rich OVA additionally increased IL-1β, IL-12, IFN-γ, TNF-α and KC. Both OVA-challenged groups developed airway hyperresponsiveness. TLR4-deficient mice challenged with either OVA preparation showed eosinophilia but not neutrophilia and had increased IL-5. Only LPS-rich OVA challenged mice had increased lung Tregs and LPS-rich OVA also induced in vitro Treg differentiation. LPS-rich OVA also induced a Th1 cytokine response in human peripheral blood mononuclear cells.We conclude that LPS-rich OVA evokes mixed Th1, Th2 and innate immune responses through the TLR-4 pathway, whereas LPS-free OVA evokes only a Th2 response. Contaminating LPS is not required for induction of airway hyperresponsiveness but amplifies the Th2 inflammatory response and is a critical mediator of the neutrophil, Th1 and T regulatory cell responses to OVA. PMID:24968337

Immunogenicity of biologics in inflammatory bowel disease

PubMed Central

Vermeire, Séverine; Gils, Ann; Accossato, Paola; Lula, Sadiq; Marren, Amy

2018-01-01

Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract. Treatment options include biologic therapies; however, a proportion of patients lose response to biologics, partly due to the formation of anti-drug antibodies (ADAbs). Concomitant immunosuppressive agents reduce the development of ADAbs. This review article aims to assess the immunogenicity of biologic therapies and their clinical implications. A comprehensive literature search was conducted for articles published January 2009 to August 2015 reporting immunogenicity to adalimumab (ADM), certolizumab pegol (CZP), golimumab, infliximab (IFX), ustekinumab, and vedolizumab in inflammatory bowel disease (IBD). Eligible articles were reviewed and quality assessed by independent reviewers. Overall, 122 publications reporting 114 studies were assessed. ADAbs were reported for all agents, but the percentage of patients developing ADAbs was extremely variable, with the highest (65.3%) being for IFX administration to patients with IBD. ADAb presence was frequently associated with a reduction in primary efficacy and a loss of response, and, for IFX, an increase in adverse events (AEs). Lower serum levels of ADM, CZP and IFX were seen in ADAbs-positive rather than ADAbs-negative patients; pharmacokinetic data were unavailable for other therapies. Little information was available regarding the timing of ADAb development; studies reported their detection from as early as 10–14 days up to months after treatment initiation. Biologic therapies carry an intrinsic risk of immunogenicity, although reported rates of ADAbs vary considerably. The clinical implications of immunogenicity are a concern for effective treatment; further research, particularly into the more recently approved biologics, is required. PMID:29383030

The Acute Exercise-Induced Inflammatory Response: A Comparison of Young-Adult Smokers and Nonsmokers

ERIC Educational Resources Information Center

Kastelein, Tegan E.; Donges, Cheyne E.; Mendham, Amy E.; Duffield, Rob

2017-01-01

Purpose: This study examined postexercise inflammatory and leukocyte responses in smokers and nonsmokers, as well as the effects of cigarette smoking on the acute postexercise inflammatory and leukocyte response in habitual smokers. Method: Eleven recreationally active male smokers and 11 nonsmokers matched for age and aerobic fitness were…

Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia induce distinct host responses.

PubMed

McConnell, Kevin W; McDunn, Jonathan E; Clark, Andrew T; Dunne, W Michael; Dixon, David J; Turnbull, Isaiah R; Dipasco, Peter J; Osberghaus, William F; Sherman, Benjamin; Martin, James R; Walter, Michael J; Cobb, J Perren; Buchman, Timothy G; Hotchkiss, Richard S; Coopersmith, Craig M

2010-01-01

Pathogens that cause pneumonia may be treated in a targeted fashion by antibiotics, but if this therapy fails, then treatment involves only nonspecific supportive measures, independent of the inciting infection. The purpose of this study was to determine whether host response is similar after disparate infections with similar mortalities. Prospective, randomized controlled study. Animal laboratory in a university medical center. Pneumonia was induced in FVB/N mice by either Streptococcus pneumoniae or two different concentrations of Pseudomonas aeruginosa. Plasma and bronchoalveolar lavage fluid from septic animals was assayed by a microarray immunoassay measuring 18 inflammatory mediators at multiple time points. The host response was dependent on the causative organism as well as kinetics of mortality, but the pro-inflammatory and anti-inflammatory responses were independent of inoculum concentration or degree of bacteremia. Pneumonia caused by different concentrations of the same bacteria, Pseudomonas aeruginosa, also yielded distinct inflammatory responses; however, inflammatory mediator expression did not directly track the severity of infection. For all infections, the host response was compartmentalized, with markedly different concentrations of inflammatory mediators in the systemic circulation and the lungs. Hierarchical clustering analysis resulted in the identification of five distinct clusters of the host response to bacterial infection. Principal components analysis correlated pulmonary macrophage inflammatory peptide-2 and interleukin-10 with progression of infection, whereas elevated plasma tumor necrosis factor sr2 and macrophage chemotactic peptide-1 were indicative of fulminant disease with >90% mortality within 48 hrs. Septic mice have distinct local and systemic responses to Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia. Targeting specific host inflammatory responses induced by distinct bacterial infections could represent a potential therapeutic approach in the treatment of sepsis.

Growth and Development Symposium: Inflammation: Role in the etiology and pathophysiology of clinical mastitis in dairy cows.

PubMed

Ballou, M A

2012-05-01

Genetic selection for increased milk production in dairy cattle was not associated with an attenuated inflammatory response. The systemic and local inflammatory responses contribute to altered metabolism, reduced production performance, and increased cull rate of lactating dairy cows with clinical mastitis. More aggressive inflammatory responses were observed during the peripartum period when compared with cows in late lactation after an intramammary challenge with purified lipopolysaccharide. The epidemiology of clinical mastitis indicates that the greatest incidence is observed during the peripartum period; therefore, an enhanced inflammatory response with concomitant suppression in other immune responses may be involved in the etiology and severity of the clinical mastitis observed in peripartum cows. Milk production losses and compositional changes are observed among all mammary quarters from a cow with clinical mastitis, but the responses are more severe and sustained among infected quarters. The infected mammary quarters reflect both the systemic and local reactions, whereas uninfected quarters represent only the systemic response. The systemic effects of the inflammatory response include reduced DMI, hyperthermia, and changes in whole-body nutrient partitioning affecting mammary epithelial substrate availability, whereas local inflammatory effects include energetic requirements of the increased inflammatory leukocyte pool, decreased synthetic capacity of mammary epithelium independent of substrate availability, and paracellular leakage of milk components from the alveolar lumen into the extracellular fluid. Research has focused on improving host immunological defenses, attenuating the inflammatory response, or improving the resolution of the disease state to limit the deleterious effects during clinical mastitis. This paper highlights the role inflammation plays in the etiology and pathophysiology of clinical mastitis as well as potential management strategies to reduce or prevent those losses.

Validation and clinical significance of the Childhood Myositis Assessment Scale for assessment of muscle function in the juvenile idiopathic inflammatory myopathies.

PubMed

Huber, Adam M; Feldman, Brian M; Rennebohm, Robert M; Hicks, Jeanne E; Lindsley, Carol B; Perez, Maria D; Zemel, Lawrence S; Wallace, Carol A; Ballinger, Susan H; Passo, Murray H; Reed, Ann M; Summers, Ronald M; White, Patience H; Katona, Ildy M; Miller, Frederick W; Lachenbruch, Peter A; Rider, Lisa G

2004-05-01

To examine the measurement characteristics of the Childhood Myositis Assessment Scale (CMAS) in children with juvenile idiopathic inflammatory myopathy (juvenile IIM), and to obtain preliminary data on the clinical significance of CMAS scores. One hundred eight children with juvenile IIM were evaluated on 2 occasions, 7-9 months apart, using various measures of physical function, strength, and disease activity. Interrater reliability, construct validity, and responsiveness of the CMAS were examined. The minimum clinically important difference (MID) and CMAS scores corresponding to various degrees of physical disability were estimated. The intraclass correlation coefficient for 26 patients assessed by 2 examiners was 0.89, indicating very good interrater reliability. The CMAS score correlated highly with the Childhood Health Assessment Questionnaire (C-HAQ) score and with findings on manual muscle testing (MMT) (r(s) = -0.73 and 0.73, respectively) and moderately with physician-assessed global disease activity and skin activity, parent-assessed global disease severity, and muscle magnetic resonance imaging (r(s) = -0.44 to -0.61), thereby demonstrating good construct validity. The standardized response mean was 0.81 (95% confidence interval 0.53, 1.09) in patients with at least 0.8 cm improvement on a 10-cm visual analog scale for physician-assessed global disease activity, indicating strong responsiveness. In bivariate regression models predicting physician-assessed global disease activity, MMT remained significant in models containing the CMAS (P = 0.03) while the C-HAQ did not (P = 0.4). Estimates of the MID ranged from 1.5 to 3.0 points on a 0-52-point scale. CMAS scores corresponding to no, mild, mild-to-moderate, and moderate physical disability, respectively, were 48, 45, 39, and 30. The CMAS exhibits good reliability, construct validity, and responsiveness, and is therefore a valid instrument for the assessment of physical function, muscle strength, and endurance in children with juvenile IIM. Preliminary data on MID and corresponding levels of disability should aid in the clinical interpretation of CMAS scores when assessing patients with juvenile IIM.

Mechanisms of lymphocyte migration in autoimmune disease.

PubMed

Norman, M U; Hickey, M J

2005-09-01

The recruitment of leukocytes to inflamed tissues plays an essential role in combating infection and promoting wound healing. However, in autoimmune diseases such as multiple sclerosis and diabetes, leukocytes enter tissues and contribute to inappropriate inflammatory responses, which cause tissue injury and dysfunction. In diseases of this type, lymphocytes play critical roles in initiating and maintaining these aberrant inflammatory responses. The aim of this review is to examine the mechanisms whereby T-lymphocytes enter tissues in autoimmune diseases and to compare these mechanisms between various organs and diseases. An overview of the mechanisms of leukocyte recruitment and the techniques used to study leukocyte trafficking is provided, focusing on the use of intravital microscopy as a tool to assess the functional microvasculature in vivo. We also discuss the series of tissue homing events which allow naïve lymphocytes to first enter lymph nodes and undergo activation, then subsequently to home to the peripheral organ where their cognate antigen is present. Finally, we examine mechanisms of leukocyte recruitment in diseases such as multiple sclerosis, autoimmune diabetes, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and asthma.

Comparative analysis of redox and inflammatory properties of pristine nanomaterials and commonly used semiconductor manufacturing nano-abrasives.

PubMed

Flaherty, Nicole L; Chandrasekaran, Akshaya; del Pilar Sosa Peña, Maria; Roth, Gary A; Brenner, Sara A; Begley, Thomas J; Melendez, J Andrés

2015-12-15

Continued expansion of the nanotechnology industry has necessitated the self-assessment of manufacturing processes, specifically in regards to understanding the health related aspects following exposure to nanomaterials. There exists a growing concern over potential occupational exposure in the semiconductor industry where Al2O3, CeO2 and SiO2 nanoparticles are commonly featured as part of the chemical mechanical planarization (CMP) process. Chronic exposure to toxicants can result not only in acute cytotoxicity but also initiation of a chronic inflammatory state associated with diverse pathologies. In the current investigation, pristine nanoparticles and CMP slurry formulations of Al2O3, SiO2 and CeO2 were employed to assess their ability to induce cytotoxicity, inflammatory responses and reactive oxygen species in a mouse alveolar macrophage cell model. The pristine nanoparticles and slurries were not intrinsically cytotoxic and did not generate free radicals but were found to act as scavengers in the presence of an oxidant stimulant. Al2O3 and SiO2 nanoparticles increased levels of pro-inflammatory cytokines while pristine SiO2 nanoparticles induced generation of F2-Isoprostanes. In co-treatment studies, the pristine nanomaterials modulated the response to the inflammatory stimulant lipopolysaccharide. The studies have established that pristine nanoparticles and slurries do not impact the cells in a similar way indicating that they should not be used as slurry substitutes in toxicity evaluations. Further, we have defined how an alveolar cell line, which would likely be the first challenged upon nanomaterial aerosolization, responds to diverse mixtures of nanomaterials. Moreover, our findings reinforce the importance of using multiple analytic methods to define the redox state of the cell following exposure to commonly used industrial nanomaterials and toxicants. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Reduction in (pro-)inflammatory responses of lung cells exposed in vitro to diesel exhaust treated with a non-catalyzed diesel particle filter

NASA Astrophysics Data System (ADS)

Steiner, Sandro; Czerwinski, Jan; Comte, Pierre; Müller, Loretta L.; Heeb, Norbert V.; Mayer, Andreas; Petri-Fink, Alke; Rothen-Rutishauser, Barbara

2013-12-01

Increasingly stringent regulation of particulate matter emissions from diesel vehicles has led to the widespread use of diesel particle filters (DPFs), the effect of which on exhaust toxicity is so far poorly understood. We exposed a cellular model of the human respiratory epithelium at the air-liquid interface to non-catalyzed wall-flow DPF-filtered diesel exhaust and compared the resulting biological responses to the ones observed upon exposure to unfiltered exhaust. Filtered diesel exhaust acted highly oxidative, even though to a lesser extent than unfiltered exhaust (quantification of total reduced glutathione), and both exhaust types triggered comparable responses to oxidative stress (measurement of heme-oxygenase 1 (HMOX1) and superoxide-dismutase (SOD1) gene expression). Further, diesel exhaust filtration significantly reduced pro-inflammatory responses (measurement of tumor necrosis factor (TNF) and interleukin-8 (IL-8) gene expression and quantification of the secretion of their gene products TNF-α and IL-8). Because inflammatory processes are central to the onset of adverse respiratory health effects caused by diesel exhaust inhalation, our results imply that DPFs may make a valuable contribution to the detoxification of diesel vehicle emissions. The induction of significant oxidative stress by filtered diesel exhaust however, also implies that the non-particulate exhaust components also need to be considered for lung cell risk assessment.

Soy Biodiesel and Petrodiesel Emissions Differ in Size, Chemical Composition and Stimulation of Inflammatory Responses in Cells and Animals

PubMed Central

Fukagawa, Naomi K.; Li, Muyao; Poynter, Matthew E.; Palmer, Brian C.; Parker, Erin; Kasumba, John; Holmén, Britt A.

2013-01-01

Debate about the biological effects of biodiesel exhaust emissions exists due to variation in methods of exhaust generation and biological models used to assess responses. Because studies in cells do not necessarily reflect the integrated response of a whole animal, experiments were conducted in two human cell lines representing bronchial epithelial cells and macrophages and female mice using identical particle suspensions of raw exhaust generated by a Volkswagen light-duty diesel engine using petrodiesel (B0) and a biodiesel blend (B20: 20% soy biodiesel/80% B0 by volume). Tailpipe particle emissions measurement showed B0 generated two times more particle mass, larger ultrafine particle number distribution modes, and particles of more nonpolar organic composition than the B20 fuel. Biological assays (inflammatory mediators, oxidative stress biomarkers) demonstrated that particulate matter (PM) generated by combustion of the two fuels induced different responses in in vitro and in vivo models. Concentrations of inflammatory mediators (Interleukin-6, IL-6; Interferon-gamma-induced Protein 10, IP-10; Granulocyte-stimulating factor, G-CSF) in the medium of B20-treated cells and in bronchoalveolar lavage fluid of mice exposed to B20 were ~20–30% higher than control or B0 PM, suggesting that addition of biodiesel to diesel fuels will reduce PM emissions but not necessarily adverse health outcomes. PMID:24053625

Evaluation of the effect of the degree of acetylation on the inflammatory response to 3D porous chitosan scaffolds.

PubMed

Barbosa, Judite N; Amaral, Isabel F; Aguas, Artur P; Barbosa, Mário A

2010-04-01

The effect of the degree of acetylation (DA) of 3D chitosan (Ch) scaffolds on the inflammatory reaction was investigated. Chitosan porous scaffolds with DAs of 4 and 15% were implanted using a subcutaneous air-pouch model of inflammation. The initial acute inflammatory response was evaluated 24 and 48 h after implantation. To characterize the initial response, the recruitment and adhesion of inflammatory cells to the implant site was studied. The fibrous capsule formation and the infiltration of inflammatory cells within the scaffolds were evaluated for longer implantation times (2 and 4 weeks). Chitosan with DA 15% attracted the highest number of leukocytes to the implant site. High numbers of adherent inflammatory cells were also observed in this material. For longer implantation periods Ch scaffolds with a DA of 15% induced the formation of a thick fibrous capsule and a high infiltration of inflammatory cells within the scaffold. Our results indicate that the biological response to implanted Ch scaffolds was influenced by the DA. Chitosan with a DA of 15% induce a more intense inflammatory response when compared with DA 4% Ch. Because inflammation and healing are interrelated, this result may provide clues for the relative importance of acetyl and amine functional groups in tissue repair and regeneration.

Surgical meshes coated with mesenchymal stem cells provide an anti-inflammatory environment by a M2 macrophage polarization.

PubMed

Blázquez, Rebeca; Sánchez-Margallo, Francisco Miguel; Álvarez, Verónica; Usón, Alejandra; Casado, Javier G

2016-02-01

Surgical meshes are widely used in clinics to reinforce soft tissue's defects, and to give support to prolapsed organs. However, the implantation of surgical meshes is commonly related with an inflammatory response being difficult to eradicate without removing the mesh. Here we hypothesize that the combined use of surgical meshes and mesenchymal stem cells (MSCs) could be a useful tool to reduce the inflammatory reaction secondary to mesh implantation. In vitro determinations of viability, metabolic activity and immunomodulation assays were performed on MSCs-coated meshes. Magnetic resonance imaging, evaluation by laparoscopic optical system and histology were performed for safety assessment. Finally, flow cytometry and qRT-PCR were used to elucidate the mechanism of action of MSCs-coated meshes. Our results demonstrate the feasibility to obtain MSCs-coated surgical meshes and their cryopreservability to be used as an 'off the shelf' product. These biological meshes fulfill the safety aspects as non-adverse effects were observed when compared to controls. Moreover, both in vitro and in vivo studies demonstrated that, local immunomodulation of implanted meshes is mediated by a macrophage polarization towards an anti-inflammatory phenotype. In conclusion, the combined usage of surgical meshes with MSCs fulfills the safety requirements for a future clinical application, providing an anti-inflammatory environment that could reduce the inflammatory processes commonly observed after surgical mesh implantation. Surgical meshes are medical devices widely used in clinics to resolve hernias and organs' prolapses, among other disorders. However, the implantation of surgical meshes is commonly related with an inflammatory response being difficult to eradicate without removing the mesh, causing pain and discomfort in the patient. Previously, the anti-inflammatory, immunomodulatory and pro-regenerative ability of mesenchymal stem cells (MSCs) have been described. To our knowledge, this is the first report where the anti-inflammatory and pro-regenerative ability of MSCs have been successfully applied in combination with surgical meshes, reducing the inflammatory processes commonly observed after mesh implantation. Moreover, our in vitro and in vivo results highlight the safety and efficacy of these bioactive meshes as a 'ready to use' medical product. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics.

PubMed

Shastri, Madhur D; Stewart, Niall; Eapen, Mathew; Peterson, Gregory M; Zaidi, Syed Tabish R; Gueven, Nuri; Sohal, Sukhwinder Singh; Patel, Rahul P

2015-01-01

T-cell-mediated inflammatory cytokines, such as interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-α), play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular-weight heparins (LMWHs), widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin) on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs) of asthmatic subjects to identify the specific components responsible for the effects. PBMCs from asthmatic subjects (consist of ~75% of T-cells) were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-α. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release. Enoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units), were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units), were associated with the stimulatory effect of dalteparin. Enoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two LMWHs arising from different methods of depolymerisation. This study provides a platform for further studies investigating the usefulness of enoxaparin in various inflammatory diseases.

Anti-inflammatory and antinociceptive effects of Chinese medicine SQ gout capsules and its modulation of pro-inflammatory cytokines focusing on gout arthritis.

PubMed

Kodithuwakku, Nandani Darshika; Pan, Min; Zhu, Yi-lin; Zhang, Yan-yan; Feng, Yi-dong; Fang, Wei-rong; Li, Yun-man

2013-12-12

Shuang-Qi gout capsule is a traditional Chinese medicine prescription, which has been used in the treatment of joint pain, inflammation and gout arthritis. This study evaluates anti-inflammatory and antinociceptive effects of Shuang-Qi gout capsule and its modulation of pro-inflammatory cytokines with special reference to gout arthritis. Anti-inflammatory effect of Shuang-Qi gout capsule was investigated bymice tail-flick response, acetic acid induced writhing response, Xylene-induced auricle inflammation and the hind paw volume of the monosodium urate (MSU) crystal induced rats with different time durations. To investigate the effects on gout arthritis, ankle joint of rats induced by MSU crystals and assessed for edema and histopathological changes. In vitro, prepared serum was incubated with urate crystal induced HUVE cells and the release of TNF-α and IL-1β determined by ELISA. Shuang-Qi gout capsule showed significant and dose dependent anti-inflammatory effect via reducing edema and pain, throughout all the models. The high dose of Shuang-Qi gout capsule and Indomethacin significantly attenuated the edema. Histopathological results showed that high and medium dose of Shuang-Qi gout capsule and Indomethacin reduced gouty joint inflammatory features, while the high dose of Shuang-Qi gout capsule showed a better therapeutic effect. High and medium dose of Shuang-Qi gout capsule significantly reduced the release of TNF-α and IL-1β (p<0.05). Shuang-Qi gout capsule can effectively inhibit the inflammation, analgesia, through the modulation of emission of pro-inflammatory cytokines and the curative effect is dose dependent. Conversely, these MSU induced in vivo and in vitro studies of Shuang-Qi gout capsule suggest that, Shuang-Qi gout capsule may be a potential agent for treatment in gouty arthritis. © 2013 Published by Elsevier Ireland Ltd.

Inhibition of Na+/H+ exchanger 1 by cariporide reduces burn-induced intestinal barrier breakdown.

PubMed

Yang, Xuekang; Chen, Ji; Bai, Hua; Tao, Ke; Zhou, Qin; Hou, Hongyi; Hu, Dahai

2013-12-01

Severe burns initiate an inflammatory cascade within the gut, which leads to intestinal mucosal injury. Although Na(+)/H(+) exchanger 1 (NHE1) is recognised as a pivotal player in several inflammatory processes, its role in burn-induced intestinal injury is relatively unknown. We hypothesised that NHE1 might be involved in the increased intestinal permeability and barrier breakdown after severe burns. Thus, we here investigate whether the inhibition of NHE1 has a protective effect on burn-induced intestinal injury. Mice were subjected to a 30% total body surface area (TBSA) full-thickness steam burn. Cariporide was used to assess the function of NHE1 in mice with burn-induced intestinal injury by fluorescence spectrophotometry, Western blotting and enzyme linked immunosorbent assay (ELISA). We found that severe burn increased intestinal permeability, associated with the up-regulation of NHE1 and raised inflammatory cytokine levels. Mice treated with the NHE1 inhibitor cariporide had significantly attenuated burn-induced intestinal permeability and a reduced inflammatory response. NHE1 inhibition also reduced nuclear factor-κB (NF-κB) activation and attenuated p38 mitogen-activated protein kinase (MAPK) phosphorylation. Our study suggests that NHE1 plays an important role in burn-induced intestinal permeability through the regulation of the inflammatory response. Inhibition of NHE1 may be adopted as a potential therapeutic strategy for attenuating intestinal barrier breakdown. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

Medium and Long Chain Fatty Acids Differentially Modulate Apoptosis and Release of Inflammatory Cytokines in Human Liver Cells.

PubMed

Li, Lumin; Wang, Baogui; Yu, Ping; Wen, Xuefang; Gong, Deming; Zeng, Zheling

2016-06-01

Medium chain fatty acids (MCFA) can be more easily absorbed and supply energy more rapidly than long chain fatty acids (LCFA). However, little is known about the inflammatory response by the treatment of MCFA in human liver cells. Thus this study used human liver cells (LO2) to evaluate the effects of MCFA on apoptosis and inflammatory response. Tetrazolim-based colorimetric assay and lactate dehydrogenase assay were used to measure the viability of LO2 cells, isolated spleens and liver cells from BALB/C mice. Inverted fluorescence microscopy and flow cytometry were used to assess the cell apoptosis. Activity of superoxide dismutase and malondialdehyde level were measured to determine the oxidative damage. mRNA or protein levels of classical pro-inflammatory cytokines were analyzed by quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay and western blotting. The results showed that the liver cells treated with the fatty acids at 200 μM for 24 h exhibited good viability. Fatty acids induced inflammatory cytokines at transcriptional and translational levels to a lesser extent than lipopolysaccharide. LCFA (oleic acid) up-regulated tumor necrosis fator-α, monocyte chemoattractant-1 and interleukin-1β while down-regulated IL-6 and IL-8 secretion to a higher extent than MCFA in mRNA and protein levels. These findings suggested that MCFA may induce apoptosis to a less extent and exert more gentle inflammation than LCFA in human liver cells. © 2016 Institute of Food Technologists®

Monocyte Phenotype and Polyfunctionality Are Associated With Elevated Soluble Inflammatory Markers, Cytomegalovirus Infection, and Functional and Cognitive Decline in Elderly Adults

PubMed Central

de Pablo-Bernal, Rebeca Sara; Cañizares, Julio; Rosado, Isaac; Galvá, María Isabel; Alvarez-Ríos, Ana Isabel; Carrillo-Vico, Antonio; Ferrando-Martínez, Sara; Muñoz-Fernández, María Ángeles; Rafii-El-Idrissi Benhnia, Mohammed; Pacheco, Yolanda María; Ramos, Raquel; Leal, Manuel; Ruiz-Mateos, Ezequiel

2016-01-01

Monocytes are mediators of the inflammatory response and include three subsets: classical, intermediate, and nonclassical. Little is known about the phenotypical and functional age-related changes in monocytes and their association with soluble inflammatory biomarkers, cytomegalovirus infection, and functional and mental decline. We assayed the activation ex vivo and the responsiveness to TLR2 and TLR4 agonists in vitro in the three subsets and assessed the intracellular production of IL1-alpha (α), IL1-beta (β), IL-6, IL-8, TNF-α, and IL-10 of elderly adults (median 83 [67–90] years old; n = 20) compared with young controls (median 35 [27–40] years old; n = 20). Ex vivo, the elderly adults showed a higher percentage of classical monocytes that expressed intracellular IL1-α (p = .001), IL1-β (p = .001), IL-6 (p = .002), and IL-8 (p = .007). Similar results were obtained both for the intermediate and nonclassical subsets and in vitro. Polyfunctionality was higher in the elderly adults. The functionality ex vivo was strongly associated with soluble inflammatory markers. The activation phenotype was independently associated with the anti-cytomegalovirus IgG levels and with functional and cognitive decline. These data demonstrate that monocytes are key cell candidates for the source of the high soluble inflammatory levels. Our findings suggest that cytomegalovirus infection might be a driving force in the activation of monocytes and is associated with the functional and cognitive decline. PMID:26286603

Recombinant human erythropoietin reduces plasminogen activator inhibitor and ameliorates pro-inflammatory responses following trauma

PubMed Central

Shiehmorteza, M.; Ahmadi, A.; Abdollahi, M.; Nayebpour, M.; Mohammadi, M.; Hamishehkar, H.; Najafi, A.; Pazoki, M.; Mojtahedzadeh, M.

2011-01-01

Background and the purpose of the study sBesides its hematopoietic effects, erythropoietin (EPO) by mobilization of iron and modulation of some inflammatory cytokines has antioxidant and anti-inflammatory properties. The purpose of this study was to evaluate these effects of erythropoietin and its impact on organ function in traumatized patients. Methods Twenty-six ICU-admitted traumatized patients within 24 hrs after trauma were randomly assigned to the EPO (received EPO, 300 units/Kg/day) and Control (not received EPO) groups. The inflammatory biomarkers including Tumor Necrosis Factor alpha (TNF-α), Interleukin 1 (IL-1), Plasminogen Activator Inhibitor 1 (PAI-1) and Nitrotyrosine were recorded at the admission, 3, 6 and 9 days thereafter. Acute Physiology and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were also recorded. Results Among 12 patients (EPO group) TNF-α level at the day of 9 (P=0.046), and within EPO group at the days of 3 (P=0.026 ameliorate), 6 (P=0.016), and 9 (P=0.052) were significantly lowered. Level of IL-1 and PAI-1 decreased significantly at days of 3, 6 and 9 post intervention. Also there were significant differences between two groups in the SOFA score during three measured time intervals (the first, third and seventh days). Conclusion From the results of this study it seems that injection of erythrocyte stimulating agent is well tolerated and inhibits the inflammatory response and oxidative stress following trauma. PMID:22615653

Similar Metabolic, Innate Immunity, and Adipokine Profiles in Adult and Pediatric Sepsis Versus Systemic Inflammatory Response Syndrome-A Pilot Study.

PubMed

Tavladaki, Theonymfi; Spanaki, Anna Maria; Dimitriou, Helen; Kondili, Efmorfia; Choulaki, Christianna; Georgopoulos, Dimitris; Briassoulis, George

2017-11-01

To examine whether the septic profiles of heat shock protein 72, heat shock protein 90α, resistin, adiponectin, oxygen consumption, CO2 production, energy expenditure, and metabolic pattern, along with illness severity, nutritional, and inflammatory indices, differ between adult and pediatric patients compared with systemic inflammatory response syndrome and healthy controls. To evaluate whether these biomolecules may discriminate sepsis from systemic inflammatory response syndrome in adult and pediatric patients. Prospective cohort study. University ICU and PICU. Seventy-eight adults (sepsis/23; systemic inflammatory response syndrome/23; healthy controls/33), 67 children (sepsis/18; systemic inflammatory response syndrome/23; controls/27), mechanically ventilated. None. Flow cytometry determined mean fluorescence intensity for monocyte or neutrophil heat shock protein expression. Resistin, adiponectin, and extracellular heat shock proteins were measured using enzyme-linked immunosorbent assay; energy expenditure by E-COVX (GE Healthcare). Genomic DNA was extracted with PureLink Genomic DNA kit (Invitrogen, Carlsbad, CA) to detect heat shock protein 72 single nucleotide polymorphisms. Similarly, in adult and pediatric patients, Acute Physiology and Chronic Evaluation-II/Acute Physiology and Pediatric Risk of Mortality-III, Simplified Acute Physiology Score-III, C-reactive protein, lactate, and resistin were higher and myocardial contractility, monocyte heat shock protein 72, oxygen consumption, CO2 production, energy expenditure, metabolic pattern, glucose, and albumin lower in sepsis compared with systemic inflammatory response syndrome or controls (p < 0.05). For discriminating sepsis from systemic inflammatory response syndrome, resistin, extracellular heat shock protein 90α, and lactate achieved a receiver operating characteristic curve greater than 0.80 in children and greater than 0.75 in adults (p < 0.05). In both, adults and children, genotype heat shock protein 72 analysis did not disclose any diagnosis or mortality group differences regarding either rs6457452 or rs1061581 haplotypes. Sepsis presents with similar profiles in adult and pediatric patients, characterized by enhanced inflammatory hormonal response and by repressed innate immunity, metabolism, and myocardial contractility. These features early distinguish sepsis from systemic inflammatory response syndrome across all age groups.

Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages.

PubMed

Moore, Sherri M; Holt, Vivian V; Malpass, Lillie R; Hines, Ian N; Wheeler, Michael D

2015-10-01

The beginning stages of liver damage induced by various etiologies (i.e. high fat diet, alcohol consumption, toxin exposure) are characterized by abnormal accumulation of lipid in liver. Alterations in intracellular lipid transport, storage, and metabolism accompanied by cellular insult within the liver play an important role in the pathogenesis of liver disease, often involving a sustained inflammatory response. The intracellular lipid transporter, fatty acid binding protein 5 (FABP5), is highly expressed in macrophages and may play an important role in the hepatic inflammatory response after endotoxin exposure in mice. This study tested the hypothesis that FABP5 regulates macrophage response to LPS in male C57bl/6 (wild type) and FABP5 knockout mice, both in vitro and in vivo. Treatment with LPS revealed that loss of FABP5 enhances the number of hepatic F4/80(+) macrophages in the liver despite limited liver injury. Conversely, FABP5 knock out mice display higher mRNA levels of anti-inflammatory cytokines IL-10, arginase, YM-1, and Fizz-1 in liver compared to wild type mice. Bone marrow derived macrophages stimulated with inflammatory (LPS and IFN-γ) or anti-inflammatory (IL-4) mediators also showed significantly higher expression of anti-inflammatory/regulatory factors. These findings reveal a regulatory role of FABP5 in the acute inflammatory response to LPS-induced liver injury, which is consistent with the principle finding that FABP5 is a regulator of macrophage phenotype. Specifically, these findings demonstrate that loss of FABP5 promotes a more anti-inflammatory response. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of equine metabolic syndrome on inflammatory responses of horses to intravenous lipopolysaccharide infusion.

PubMed

Tadros, Elizabeth M; Frank, Nicholas; Donnell, Robert L

2013-07-01

To test the hypothesis that inflammatory responses to endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). Animals-6 healthy horses and 6 horses with EMS. Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline data were obtained 30 minutes before each infusion. After infusion, a physical examination was performed hourly for 9 hours and at 15 and 21 hours; a whole blood sample was collected at 30, 60, 90, 120, 180, and 240 minutes for assessment of inflammatory cytokine gene expression. Liver biopsy was performed between 240 and 360 minutes after infusion. Results-Following lipopolysaccharide infusion in healthy horses and horses with EMS, mean rectal temperature, heart rate, and respiratory rate increased, compared with baseline findings, as did whole blood gene expression of interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-α. The magnitude of blood cytokine responses did not differ between groups, but increased expression of IL-6, IL-8, IL-10, and tumor necrosis factor-α persisted for longer periods in EMS-affected horses. Lipopolysaccharide infusion increased liver tissue gene expressions of IL-6 in healthy horses and IL-8 in both healthy and EMS-affected horses, but these gene expressions did not differ between groups. Results supported the hypothesis that EMS affects horses' inflammatory responses to endotoxin by prolonging cytokine expression in circulating leukocytes. These findings are relevant to the association between obesity and laminitis in horses with EMS.

Increased extracellular heat shock protein 90α in severe sepsis and SIRS associated with multiple organ failure and related to acute inflammatory-metabolic stress response in children.

PubMed

Fitrolaki, Michaela-Diana; Dimitriou, Helen; Venihaki, Maria; Katrinaki, Marianna; Ilia, Stavroula; Briassoulis, George

2016-08-01

Mammalian heat-shock-protein (HSP) 90α rapidly responses to environmental insults. We examined the hypothesis that not only serum HSP72 but also HSP90α is increased in the systemic inflammatory response syndrome (SIRS), severe-sepsis (SS), and/or sepsis (S) compared to healthy children (H); we assessed HSP90α relation to (a) multiple organ system failure (MOSF) and (b) inflammatory-metabolic response and severity of illness.A total of 65 children with S, SS, or SIRS and 25 H were included. ELISA was used to evaluate extracellular HSP90α and HSP72, chemiluminescence interleukins (ILs), flow-cytometry neutrophil-CD64 (nCD64)-expression.HSP90α, along with HSP72, were dramatically increased among MOSF patients. Patients in septic groups and SIRS had elevated HSP90α compared to H (P < 0.01). HSP90α was independently related to predicted death rate and severity of illness; positively to HSP72, nCD64, ILs, length of stay, days on ventilator, and fever; negatively to HDL and LDL (P < 0.05). The HSP72 was increased in SS/S and related negatively to HDL and LDL (P < 0.05).Serum HSP90α is markedly elevated in children with severe sepsis and is associated with MOSF. Better than the HSP72, also increased in SS, SIRS, and MOSF, HSP90α is related to the inflammatory stress, fever, outcome endpoints, and predicted mortality and inversely related to the low-LDL/low-HDL stress metabolic pattern.

Neuromuscular and inflammatory responses to handball small-sided games: the effects of physical contact.

PubMed

Dello Iacono, A; Eliakim, A; Padulo, J; Laver, L; Ben-Zaken, S; Meckel, Y

2017-10-01

The aim of this study was to investigate the influence of physical contact on neuromuscular impairments and inflammatory response during handball small-sided games. Using a counterbalanced design, 12 elite male junior handball players were divided into two groups: contact (C-SSG) and no-contact (NC-SSG), performing both contact and no-contact small-sided games, in reverse order on two training sessions separated by 5 days. The methodology and rules were identical for the two SSG regimens, with the only difference being the inclusion or prohibition of upper body use for physical contacts. Upper and lower body neuromuscular performances and blood concentrations of inflammatory cytokine IL-6 were assessed before and immediately after the games. During small-sided games, video analysis was used to establish the physical contact counts. Significant differences were found in most upper and lower limbs muscles kinetic variables and in the physical contact events (all P < 0.001) following the two training regimens. There was an increase in IL-6 after C-SSG and no changes following NC-SSG (P < 0.05 and P = 0.12, respectively). Moreover, a strong correlation was found between the number of physical contacts and IL-6 responses (r = 0.971, P < 0.001) in C-SSG. This study indicates that an inflammatory response and large upper and lower body neuromuscular impairments result from physical contact in elite handball players. These outcomes outline the specific physiological profile of C-SSG that, in turn, might be used by practitioners and coaches as a practical approach to strategically select exercises in athlete's overall training program. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comparison of the prognostic value of pretreatment measurements of systemic inflammatory response in patients undergoing curative resection of clear cell renal cell carcinoma.

PubMed

Lucca, Ilaria; de Martino, Michela; Hofbauer, Sebastian L; Zamani, Nura; Shariat, Shahrokh F; Klatte, Tobias

2015-12-01

Pretreatment measurements of systemic inflammatory response, including the Glasgow prognostic score (GPS), the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), the platelet-to-lymphocyte ratio (PLR) and the prognostic nutritional index (PNI) have been recognized as prognostic factors in clear cell renal cell carcinoma (CCRCC), but there is at present no study that compared these markers. We evaluated the pretreatment GPS, NLR, MLR, PLR and PNI in 430 patients, who underwent surgery for clinically localized CCRCC (pT1-3N0M0). Associations with disease-free survival were assessed with Cox models. Discrimination was measured with the C-index, and a decision curve analysis was used to evaluate the clinical net benefit. On multivariable analyses, all measures of systemic inflammatory response were significant prognostic factors. The increase in discrimination compared with the stage, size, grade and necrosis (SSIGN) score alone was 5.8 % for the GPS, 1.1-1.4 % for the NLR, 2.9-3.4 % for the MLR, 2.0-3.3 % for the PLR and 1.4-3.0 % for the PNI. On the simultaneous multivariable analysis of all candidate measures, the final multivariable model contained the SSIGN score (HR 1.40, P < 0.001), the GPS (HR 2.32, P < 0.001) and the MLR (HR 5.78, P = 0.003) as significant variables. Adding both the GPS and the MLR increased the discrimination of the SSIGN score by 6.2 % and improved the clinical net benefit. In patients with clinically localized CCRCC, the GPS and the MLR appear to be the most relevant prognostic measures of systemic inflammatory response. They may be used as an adjunct for patient counseling, tailoring management and clinical trial design.

Increased extracellular heat shock protein 90α in severe sepsis and SIRS associated with multiple organ failure and related to acute inflammatory-metabolic stress response in children

PubMed Central

Fitrolaki, Michaela-Diana; Dimitriou, Helen; Venihaki, Maria; Katrinaki, Marianna; Ilia, Stavroula; Briassoulis, George

2016-01-01

Abstract Mammalian heat-shock-protein (HSP) 90α rapidly responses to environmental insults. We examined the hypothesis that not only serum HSP72 but also HSP90α is increased in the systemic inflammatory response syndrome (SIRS), severe-sepsis (SS), and/or sepsis (S) compared to healthy children (H); we assessed HSP90α relation to (a) multiple organ system failure (MOSF) and (b) inflammatory-metabolic response and severity of illness. A total of 65 children with S, SS, or SIRS and 25 H were included. ELISA was used to evaluate extracellular HSP90α and HSP72, chemiluminescence interleukins (ILs), flow-cytometry neutrophil-CD64 (nCD64)-expression. HSP90α, along with HSP72, were dramatically increased among MOSF patients. Patients in septic groups and SIRS had elevated HSP90α compared to H (P < 0.01). HSP90α was independently related to predicted death rate and severity of illness; positively to HSP72, nCD64, ILs, length of stay, days on ventilator, and fever; negatively to HDL and LDL (P < 0.05). The HSP72 was increased in SS/S and related negatively to HDL and LDL (P < 0.05). Serum HSP90α is markedly elevated in children with severe sepsis and is associated with MOSF. Better than the HSP72, also increased in SS, SIRS, and MOSF, HSP90α is related to the inflammatory stress, fever, outcome endpoints, and predicted mortality and inversely related to the low-LDL/low-HDL stress metabolic pattern. PMID:27583886

A systematic literature review of US definitions, scoring systems and validity according to the OMERACT filter for tendon lesion in RA and other inflammatory joint diseases.

PubMed

Alcalde, María; D'Agostino, Maria Antonietta; Bruyn, George A W; Möller, Ingrid; Iagnocco, Annamaria; Wakefield, Richard J; Naredo, Esperanza

2012-07-01

To present the published data concerning the US assessment of tendon lesions as well as the US metric properties investigated in inflammatory arthritis. A systematic literature search of PubMed, Embase and the Cochrane Library was performed. Selection criteria were original articles in the English language reporting US, Doppler, tenosynovitis and other tendon lesions in patients with RA and other inflammatory arthritis. Data extraction focused on the definition and quantification of US-detected tenosynovitis and other tendon abnormalities and the metric properties of US according to the OMERACT filter for evaluating the above tendon lesions. Thirty-three of 192 identified articles were included in the review. Most articles were case series (42%) or case-control (33%) studies describing hand and/or foot tenosynovitis in RA patients. The majority of older articles used only B-mode, whereas the most recent studies have incorporated Doppler mode. Definition of tenosynovitis or other tendon lesion was provided in 70% of the evaluated studies. Most of the studies (61%) used a binary score for evaluating tendon abnormalities. Concerning the OMERACT filter, 24 (73%) articles dealt with construct validity. The comparator most commonly used was clinical assessment and MRI. There were few studies assessing criterion validity. Some studies evaluated reliability (36%), responsiveness (21%) and feasibility (12%). US seems a promising tool for evaluating inflammatory tendon lesions. However, further validation is necessary for implementation in clinical practice and trials.

Anti-inflammatory treatment improves high-density lipoprotein function in rheumatoid arthritis

PubMed Central

O'Neill, Francis; Charakida, Marietta; Topham, Eric; McLoughlin, Eve; Patel, Neha; Sutill, Emma; Kay, Christopher W M; D'Aiuto, Francesco; Landmesser, Ulf; Taylor, Peter C; Deanfield, John

2017-01-01

Objective Patients with rheumatoid arthritis (RA) are at increased cardiovascular risk. Recent studies suggest that high-density lipoprotein (HDL) may lose its protective vascular phenotype in inflammatory conditions. However, the effects of common anti-inflammatory treatments on HDL function are not yet known. Methods We compared the function of HDL in 18 patients with RA and 18 matched healthy controls. Subsequently, patients were randomised to (methotrexate+infliximab (M+I) (5 mg/kg)) or methotrexate+placebo (M+P) infusions for 54 weeks. At week 54 and thereafter, all patients received infliximab therapy until completion of the trial (110 weeks), enabling assessment of the impact of 1 year of infliximab therapy in all patients. HDL functional properties were assessed at baseline, 54 weeks and 110 weeks by measuring the impact on endothelial nitric oxide (NO) bioavailability and superoxide production (SO), paraoxonase activity (PON-1) and cholesterol efflux. Results All HDL vascular assays were impaired in patients compared with controls. After 54 weeks, NO in response to HDL was significantly greater in patients who received M+I compared with those who received M+P. Endothelial SO in response to HDL was reduced in both groups, but PON-1 and cholesterol efflux remained unchanged. All vascular measures improved compared with baseline after ≥1 infliximab therapy in the analysis at 110 weeks. No significant trend was noted for cholesterol efflux. Conclusions HDL function can be improved with anti-inflammatory treatment in patients with RA. The M+I combination was superior to the M+P alone, suggesting that the tumour necrosis factor-α pathway may have a role in HDL vascular properties. PMID:27852695

Sulforaphane improves outcomes and slows cerebral ischemic/reperfusion injury via inhibition of NLRP3 inflammasome activation in rats.

PubMed

Yu, Chang; He, Qi; Zheng, Jing; Li, Ling Yu; Hou, Yang Hao; Song, Fang Zhou

2017-04-01

Ischemia/reperfusion (I/R) injury has been correlated with systemic inflammatory response. In addition, NLRP3 has been suggested as a cause in many inflammatory processes. Sulforaphane (SFN) is a naturally occurring isothiocyanate found in cruciferous vegetables, such as broccoli and cabbage. While recent studies have demonstrated that Sulforaphane has protective effects against cerebral ischemia/reperfusion injury, little is known about how those protective effects work. In this study, we focus our investigation on the role and process of Sulforaphane in the inhibition of NLRP3 inflammasome activation, as well as its effect on brain ischemia/reperfusion injury. Adult male Sprague-Dawley rats were injected with Sulforaphane (5 or 10mg/kg) intraperitoneally at the beginning of reperfusion, after a 60min period of occlusion. A neurological score and infarct volume were assessed at 24h after the administration of Sulforaphane. Myeloperoxidase (MPO) activity was measured at 24h to assess neutrophil infiltration in brain tissue. ELISA, RT-PCR and Western blot analyses were used to measure any inflammatory reaction. Sulforaphane treatment significantly reduced infarct volume and improved neurological scores when compared to a vehicle-treated group. Neutrophil infiltration was significantly higher in the vehicle-treated group than in the Sulforaphane treatment group. Sulforaphane treatment inhibits NLRP3 inflammasome activation and the downregulation of cleaved caspase-1, while reducing IL-1β and IL-18 expression. The inhibition of inflammatory response with Sulforaphane treatment improves outcomes after focal cerebral ischemia. This neuroprotective effect is likely exerted by Sulforaphane inhibited NLRP3 inflammasome activation caused by the downregulation of NLRP3, the induction of cleaved caspase-1, and thus the reduction of IL-1β and IL-18. Copyright © 2017 Elsevier B.V. All rights reserved.

Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation.

PubMed

Jin, Rong; Xiao, Adam Y; Chen, Rui; Granger, D Neil; Li, Guohong

2017-12-01

Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. Focal cerebral ischemia was induced in C57BL/6 mice by a 60-minute transient middle cerebral artery occlusion. Animals were treated with anti-CD147 function-blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24 hours after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. CD147 expression was rapidly increased in ischemic brain endothelium after transient middle cerebral artery occlusion. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after transient middle cerebral artery occlusion. The neuroprotective effects were associated with (1) prevented blood-brain barrier damage, (2) decreased intravascular fibrin and platelet deposition, which in turn reduced thrombosis and increased cerebral perfusion, and (3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced NF-κB (nuclear factor κB) activation, MMP-9 (matrix metalloproteinase-9) activity, and PAI-1 (plasminogen activator inhibitor-1) expression in brain microvascular endothelial cells. Inhibition of CD147 ameliorates acute ischemic stroke by reducing thromboinflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thromboinflammatory disorders. © 2017 American Heart Association, Inc.

Effect of steroids on inflammatory markers and clinical parameters in congenital open heart surgery: a randomised controlled trial.

PubMed

Amanullah, Muhammad M; Hamid, Mohammad; Hanif, Hashim M; Muzaffar, Marium; Siddiqui, Maria T; Adhi, Fatima; Ahmad, Khabir; Khan, Shahjahan; Hasan, Zahra

2016-03-01

Cardiopulmonary bypass is associated with systemic inflammatory response. Steroids suppress this response, although the therapeutic evidence remains controversial. We hypothesised that intravenous steroids in children undergoing open-heart surgery would decrease inflammation leading to better early post-operative outcomes. We conducted a randomised controlled trial to evaluate the trends in the levels of immunomodulators and their effects on clinical parameters. To assess the effects of intravenous steroids on early post-operative inflammatory markers and clinical parameters in children undergoing open-heart surgery. A randomised controlled trial involving 152 patients, from one month up to 18 years of age, who underwent open-heart surgery for congenital heart disease from April 2010-2012 was carried out. Patients were randomised and administered either three scheduled intravenous pulse doses of dexamethasone (1 mg/kg) or placebo. Blood samples were drawn at four time intervals and serum levels of inflammatory cytokines - Interleukin-6, 8, 10, 18, and tumour necrosis factor-alpha - were measured. Clinical parameters were also assessed. Blood cytokine levels were compared between the dexamethasone (n=65) and placebo (n=64) groups. Interleukin-6 levels were lower at 6 and 24 hours post-operatively (p<0.001), and Interleukin-10 levels were higher 6 hours post-operatively (p<0.001) in the steroid group. Interleukin-8, 18, and tumour necrosis factor-alpha levels did not differ between the groups at any time intervals. The clinical parameters were similar in both the groups. Dexamethasone caused quantitative suppression of Interleukin-6 and increased Interleukin-10 activation, contributing to reduced immunopathology, but it did not translate into clinical benefit in the short term.

Importance of asparagine on the conformational stability and chemical reactivity of selected anti-inflammatory peptides

NASA Astrophysics Data System (ADS)

Soriano-Correa, Catalina; Barrientos-Salcedo, Carolina; Campos-Fernández, Linda; Alvarado-Salazar, Andres; Esquivel, Rodolfo O.

2015-08-01

Inflammatory response events are initiated by a complex series of molecular reactions that generate chemical intermediaries. The structure and properties of peptides and proteins are determined by the charge distribution of their side chains, which play an essential role in its electronic structure and physicochemical properties, hence on its biological functionality. The aim of this study was to analyze the effect of changing one central amino acid, such as substituting asparagine for aspartic acid, from Cys-Asn-Ser in aqueous solution, by assessing the conformational stability, physicochemical properties, chemical reactivity and their relationship with anti-inflammatory activity; employing quantum-chemical descriptors at the M06-2X/6-311+G(d,p) level. Our results suggest that asparagine plays a more critical role than aspartic acid in the structural stability, physicochemical features, and chemical reactivity of these tripeptides. Substituent groups in the side chain cause significant changes on the conformational stability and chemical reactivity, and consequently on their anti-inflammatory activity.

Effect of maternal exposure to ozone on reproductive outcome and immune, inflammatory, and allergic responses in the offspring

EPA Science Inventory

There is growing concern that exposure to air pollutants during pregnancy affects health outcomes in the offspring due to alterations in the development of immune and other homeostatic processes. To assess the risks of maternal inhalation exposure to ozone (O3), timed pregnant BA...

S-adenosylmethionine lowers the inflammatory response in macrophages associated with changes in DNA methylation

USDA-ARS?s Scientific Manuscript database

S-adenosylmethionine (SAM), the unique methyl donor in DNA methylation, has been shown to lower inflammation. We assessed whether epigenetic mechanisms mediate this effect. Human THP-1 cells were differentiated into macrophages and treated with 0 micromole/L, 500 micromole/L or 1000 micromole/L SAM ...

Treatment of non-steroidal anti-inflammatory drug induced enteropathy.

PubMed Central

Bjarnason, I; Hopkinson, N; Zanelli, G; Prouse, P; Smethurst, P; Gumpel, J M; Levi, A J

1990-01-01

Non-steroidal anti-inflammatory drug induced small intestinal inflammation may have an adverse effect on the joints of patients with rheumatoid arthritis. We therefore assessed small intestinal and joint inflammation in patients with rheumatoid arthritis before and after three to nine months' treatment with sulphasalazine (n = 40) and other second line drugs (n = 20), while keeping the dosage of non-steroidal anti-inflammatory drug at the same level. Sulphasalazine significantly decreased the mean (SD) faecal excretion of 111indium labelled leucocytes from 2.39 (2.22)% to 1.33 (1.13)% (normal less than 1%, p less than 0.01) and improved the joint inflammation as assessed by a variety of parameters. There was no significant correlation between the effects of sulphasalazine treatment on the intestine and the joints. Treatment with other second line drugs had no significant effect on the faecal excretion of 111indium (1.58 (1.04)% and 1.86 (1.51)%, respectively) but improved joint inflammation significantly. The lack of correlation between the intestinal and joint inflammation and their response to treatment suggests that the two are not causally related. PMID:1973396

Apigenin reduce lipoteichoic acid-induced inflammatory response in rat cardiomyoblast cells.

PubMed

Gutiérrez-Venegas, Gloria; González-Rosas, Zeltzin

2017-02-01

Infective endocarditis is caused by Streptococcus sanguinis present in dental plaque, which can induce inflammatory responses in the endocardium. The present study depicts research on the properties of apigenin in embryonic mouse heart cells (H9c2) treated with lipoteichoic acid (LTA) obtained from S. sanguinis. Interleukin-1β and cyclooxygenase (COX)-2 expression were detected by reverse transcriptase polymerase chain reaction. In addition, western blot assays and immuno-fluorescence staining were used to assess translocation of nuclear factor kappa beta (NF-κB), degradation of IκB, as well as activity of the mitogen activated protein kinases: extracellular signal-regulated kinase (ERK)1/2, p38, and c-Jun N-terminal kinase (JNK). Effect of apigenin on cell viability was equally assessed in other experimental series. Our results showed that apigenin blocked activation of ERK, JNK, and p38 in cardiomyocytes treated with LTA in a dose-dependent fashion. Moreover, apigenin showed no cytotoxic effects; it blocked NF-κB translocation and IκB degradation. Our findings suggested that apigenin possessed potential value in the treatment of infectious endocarditis.

Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis.

PubMed

Xu, Danfeng; Lian, Di; Wu, Jing; Liu, Ying; Zhu, Mingjie; Sun, Jiaming; He, Dake; Li, Ling

2017-08-04

Streptococcus pneumoniae meningitis is a serious inflammatory disease of the central nervous system (CNS) and is associated with high morbidity and mortality rates. The inflammatory processes initiated by recognition of bacterial components contribute to apoptosis in the hippocampal dentate gyrus. Brain-derived neurotrophic factor (BDNF) has long been recommended for the treatment of CNS diseases due to its powerful neuro-survival properties, as well as its recently reported anti-inflammatory and anti-apoptotic effects in vitro and in vivo. In this study, we investigated the effects of BDNF-related signaling on the inflammatory response and hippocampal apoptosis in experimental models of pneumococcal meningitis. Pretreatment with exogenous BDNF or the tropomyosin-receptor kinase B (TrkB) inhibitor k252a was performed to assess the activation or inhibition of the BDNF/TrkB-signaling axis prior to intracisternal infection with live S. pneumoniae. At 24 h post-infection, rats were assessed for clinical severity and sacrificed to harvest the brains. Paraffin-embedded brain sections underwent hematoxylin and eosin staining to evaluate pathological severity, and cytokine and chemokine levels in the hippocampus and cortex were evaluated by enzyme-linked immunosorbent assay. Additionally, apoptotic neurons were detected in the hippocampal dentate gyrus by terminal deoxynucleotidyl transferase dUTP-nick-end labeling, key molecules associated with the related signaling pathway were analyzed by real-time polymerase chain reaction and western blot, and the DNA-binding activity of nuclear factor kappa B (NF-κB) was measured by electrophoretic mobility shift assay. Rats administered BDNF exhibited reduced clinical impairment, pathological severity, and hippocampal apoptosis. Furthermore, BDNF pretreatment suppressed the expression of inflammatory factors, including tumor necrosis factor α, interleukin (IL)-1β, and IL-6, and increased the expression of the anti-inflammatory factor IL-10. Moreover, BDNF pretreatment increased TrkB expression, activated downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and inhibited the myeloid differentiation primary response gene 88 (MyD88)/NF-κB-signaling pathway. These data suggested that BDNF administration exerted anti-inflammatory and anti-apoptotic effects on an experimental pneumococcal meningitis model via modulation of MyD88/NF-κB- and PI3K/AKT-signaling pathways. Our results indicated that treatment with exogenous BDNF might constitute a potential therapeutic strategy for the treatment of bacterial meningitis.

Purinergic signaling modulates the cerebral inflammatory response in experimentally infected fish with Streptococcus agalactiae: an attempt to improve the immune response.

PubMed

Souza, Carine F; Baldissera, Matheus D; Bottari, Nathiele B; Moreira, Karen L S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; Santos, Roberto C V; Baldisserotto, Bernardo

2018-06-01

Appropriate control of the immune response is a critical determinant of fish health, and the purinergic cascade has an important role in the immune and inflammatory responses. This cascade regulates the levels of adenosine triphosphate (ATP), adenosine diphosphate, adenosine monophosphate and adenosine (Ado), molecules involved in physiological or pathological events as inflammatory and anti-inflammatory mediators. Thus, the aim of this study was to evaluate whether purinergic signaling, through the activities of nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase, and adenosine deaminase (ADA), is capable of modulating the cerebral immune and inflammatory responses in silver catfish that is experimentally infected with Streptococcus agalactiae. Cerebral NTPDase (with ATP as substrate) and 5'-nucleotidase activities increased, while ADA activity decreased in silver catfish that is experimentally infected with S. agalactiae, compared to the control group. Moreover, the cerebral levels of ATP and Ado increased in infected animals compared to the uninfected control group. Brain histopathology in infected animals revealed inflammatory demyelination (the presence of occasional bubbly collections), increased cellular density in the area near to pia-mater and intercellular edema. Based on this evidence, the modulation of the purinergic cascade by the enzymes NTPDase, 5'-nucleotidase, and ADA exerts an anti-inflammatory profile due to the regulation of ATP and Ado levels. This suggests involvement of purinergic enzymes on streptococcosis pathogenesis, through regulating cerebral ATP and Ado levels, molecules known to participate in physiological or pathological events as inflammatory and anti-inflammatory mediators, respectively. In summary, the modulation of the cerebral purinergic cascade exerts an anti-inflammatory profile in an attempt to reduce inflammatory damage.

Self-esteem levels and cardiovascular and inflammatory responses to acute stress.

PubMed

O'Donnell, Katie; Brydon, Lena; Wright, Caroline E; Steptoe, Andrew

2008-11-01

Acute mental stress tests have helped to clarify the pathways through which psychosocial factors are linked to disease risk. This methodology is now being used to investigate potentially protective psychosocial factors. We investigated whether global self-esteem might buffer cardiovascular and inflammatory responses to acute stress. One hundred and one students completed the Rosenberg Self-Esteem Scale. Heart rate and heart rate variability (HRV) were recorded for 5 min periods at baseline, during two mental stress tasks, (a speech and a color-word task) and 10, 25 and 40 min into a recovery period. Plasma levels of tumor-necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1Ra) were assessed at baseline, immediately post-stress and after 45 min recovery. Repeated measures analysis of variance demonstrated that heart rate levels were lower across all time points in those with high self-esteem, although heart rate reactivity to stress was not related to self-esteem. There were no differences in baseline HRV, TNF-alpha, IL-6 or IL-1Ra. Multiple linear regressions revealed that greater self-esteem was associated with a smaller reduction in heart rate variability during the speech task, but not the color-word task. Greater self-esteem was associated with smaller TNF-alpha and IL-1Ra responses immediately following acute stress and smaller IL-1Ra responses at 45 min post-stress. In conclusion, global self-esteem is associated with lower heart rate and attenuated HRV and inflammatory responses to acute stress. These responses could be processes through which self-esteem protects against the development of disease.

Acetylsalicylic acid supplementation improves protein utilization efficiency while vitamin E supplementation reduces markers of the inflammatory response in weaned pigs challenged with enterotoxigenic E. coli.

PubMed

Kim, Jae Cheol; Mullan, Bruce P; Black, John L; Hewitt, Robert J E; van Barneveld, Robert J; Pluske, John R

2016-01-01

This experiment was conducted to test the hypothesis that vitamin E (Vit E) and acetylsalicylic acid (ASA), a cyclooxygenase-2 (COX-2) inhibitor, will additively reduce the production of the immunosuppressive molecule prostaglandin E 2 (PGE 2 ) and hence reduce inflammatory responses in weaner pigs experimentally infected with an enterotoxigenic strain of E. coli . The experiment was conducted in a research facility with 192 individually-housed male weaner pigs (Landrace × Large White) weighing 6.6 ± 0.04 kg (mean ± SEM). The pigs were experimentally infected with an enterotoxigenic strain of E. coli and were allocated to a 2 × 3 factorial design with the respective factors being without and with 125 ppm ASA and three levels of Vit E supplementation (50, 100 or 200 IU/kg diet, dl -α-tocopheryl acetate). Acetylsalicylic acid supplementation improved average daily gain ( P <  0.05) and tended to improve feed:gain ratio ( P <  0.10) during the first 14 d after weaning. Acetylsalicylic acid supplementation also improved ( P  < 0.001) amino acid utilization efficiency (as assessed by plasma urea level) and tended to decrease ( P  < 0.10) PGE 2 production in the liver without affecting small intestinal histology and tight junction protein mRNA expression in the jejunal epithelium. Vitamin E supplementation greater than 100 IU/kg diet sustained both the plasma Vit E concentration ( P  < 0.001) and plasma haptoglobin content ( P  < 0.001) after weaning. However, there was no additive effects of the combined supplementation of ASA and Vit E on performance, intestinal barrier function and inflammatory responses of weaned pigs. Although ASA and vitamin E improved amino acid utilization efficiency and reduced acute inflammatory responses, ASA and vitamin E did not additively reduce production of PGE 2 and inflammatory responses in weaner pigs experimentally infected with an enterotoxigenic strain of E. coli .

Kefir-isolated bacteria and yeasts inhibit Shigella flexneri invasion and modulate pro-inflammatory response on intestinal epithelial cells.

PubMed

Bolla, P A; Abraham, A G; Pérez, P F; de Los Angeles Serradell, M

2016-02-01

The aim of this work was to evaluate the ability of a kefir-isolated microbial mixture containing three bacterial and two yeast strains (MM) to protect intestinal epithelial cells against Shigella flexneri invasion, as well as to analyse the effect on pro-inflammatory response elicited by this pathogen. A significant decrease in S. flexneri strain 72 invasion was observed on both HT-29 and Caco-2 cells pre-incubated with MM. Pre-incubation with the individual strains Saccharomyces cerevisiae CIDCA 8112 or Lactococcus lactis subsp. lactis CIDCA 8221 also reduced the internalisation of S. flexneri into HT-29 cells although in a lesser extent than MM. Interestingly, Lactobacillus plantarum CIDCA 83114 exerted a protective effect on the invasion of Caco-2 and HT-29 cells by S. flexneri. Regarding the pro-inflammatory response on HT-29 cells, S. flexneri infection induced a significant activation of the expression of interleukin 8 (IL-8), chemokine (C-C motif) ligand 20 (CCL20) and tumour necrosis factor alpha (TNF-α) encoding genes (P<0.05), whereas incubation of cells with MM did not induce the expression of any of the mediators assessed. Interestingly, pre-incubation of HT-29 monolayer with MM produced an inhibition of S. flexneri-induced IL-8, CCL20 and TNF-α mRNA expression. In order to gain insight on the effect of MM (or the individual strains) on this pro-inflammatory response, a series of experiments using a HT-29-NF-κB-hrGFP reporter system were performed. Pre-incubation of HT-29-NF-κB-hrGFP cells with MM significantly dampened Shigella-induced activation. Our results showed that the contribution of yeast strain Kluyveromyces marxianus CIDCA 8154 seems to be crucial in the observed effect. In conclusion, results presented in this study demonstrate that pre-treatment with a microbial mixture containing bacteria and yeasts isolated from kefir, resulted in inhibition of S. flexneri internalisation into human intestinal epithelial cells, along with the inhibition of the signalling via NF-κB that in turn led to the attenuation of the inflammatory response.

PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) independently of its lipid transfer activity

PubMed Central

Deckert, Valérie; Daien, Claire I.; Che, Hélène; Elhmioui, Jamila; Lemaire, Stéphanie; Pais de Barros, Jean-Paul; Desrumaux, Catherine; Combe, Bernard; Hahne, Michael; Lagrost, Laurent; Morel, Jacques

2018-01-01

Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA. PMID:29565987

Hedonic and motivational responses to food reward are unchanged in rats with neuropathic pain

PubMed Central

Okun, Alec; McKinzie, David L.; Witkin, Jeffrey M.; Remeniuk, Bethany; Husein, Omar; Gleason, Scott D.; Oyarzo, Janice; Navratilova, Edita; McElroy, Brian; Cowen, Stephen; Kennedy, Jeffrey D.; Porreca, Frank

2016-01-01

Rewards influence responses to acute painful stimuli, but the relationship of chronic pain to hedonic or motivational aspects of reward is not well understood. Here, we independently evaluated hedonic qualities of sweet or bitter tastants as well as motivation to seek food reward in rats with experimental neuropathic pain induced by L5/6 spinal nerve ligation (SNL). Hedonic response was measured by implantation of intraoral catheters to allow passive delivery of liquid solutions and “liking/disliking” responses were scored according to a facial reactivity scale. SNL rats did not differ from controls in either “liking” or “disliking” reactions to intraoral sucrose or quinine, respectively, at post-surgery day 21, suggesting no differences in perceived hedonic value of sweet or bitter tastants. To assess possible motivational deficits during acute and chronic pain, we employed fixed- and progressive-ratio response paradigms of sucrose pellet presentation in rats with transient inflammatory or chronic neuropathic pain. Assessment of response acquisition and break points under the progressive ratio schedule revealed no differences between sham and SNL rats for up to 120 days post-injury. However, rats with inflammation showed decrements in lever pressing and break points on post-CFA days 1 and 2 that normalized by day 4, consistent with transient ongoing pain. Thus, while acute, ongoing inflammatory pain may transiently reduce reward motivation, we did not detect influences of chronic neuropathic pain on hedonic or motivational responses to food rewards. Adaptations that allow normal reward responding to food regardless of chronic pain may be of evolutionary benefit to promote survival. PMID:27548047

Inflammatory Bowel Disease in Primary Immunodeficiencies.

PubMed

Kelsen, Judith R; Sullivan, Kathleen E

2017-08-01

Inflammatory bowel disease is most often a polygenic disorder with contributions from the intestinal microbiome, defects in barrier function, and dysregulated host responses to microbial stimulation. There is, however, increasing recognition of single gene defects that underlie a subset of patients with inflammatory bowel disease, particularly those with early-onset disease, and this review focuses on the primary immunodeficiencies associated with early-onset inflammatory bowel disease. The advent of next-generation sequencing has led to an improved recognition of single gene defects underlying some cases of inflammatory bowel disease. Among single gene defects, immune response genes are the most frequent category identified. This is also true of common genetic variants associated with inflammatory bowel disease, supporting a pivotal role for host responses in the pathogenesis. This review focuses on practical aspects related to diagnosis and management of children with inflammatory bowel disease who have underlying primary immunodeficiencies.

Novel insights for systemic inflammation in sepsis and hemorrhage.

PubMed

Cai, Bolin; Deitch, Edwin A; Ulloa, Luis

2010-01-01

The inflammatory responses in sepsis and hemorrhage remain a major cause of death. Clinically, it is generally accepted that shock in sepsis or hemorrhage differs in its mechanisms. However, the recognition of inflammatory cytokines as a common lethal pathway has become consent. Proinflammatory cytokines such as tumor necrosis factor (TNF) or high-mobility group box1 (HMGB1) are fanatically released and cause lethal multiorgan dysfunction. Inhibition of these cytokines can prevent the inflammatory responses and organ damage. In seeking potential anti-inflammatory strategies, we reported that ethyl pyruvate and alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonists effectively restrained cytokine production to provide therapeutic benefits in both experimental sepsis and hemorrhage. Here, we review the inflammatory responses and the anti-inflammatory strategies in experimental models of sepsis and hemorrhage, as they may have a consistent inflammatory pathway in spite of their different pathophysiological processes.

Lactobacillus rhamnosus GG and its SpaC pilus adhesin modulate inflammatory responsiveness and TLR-related gene expression in the fetal human gut

PubMed Central

Ganguli, Kriston; Collado, Maria Carmen; Rautava, Jaana; Lu, Lei; Satokari, Reetta; von Ossowski, Ingemar; Reunanen, Justus; de Vos, Willem M.; Palva, Airi; Isolauri, Erika; Salminen, Seppo; Walker, W. Allan; Rautava, Samuli

2015-01-01

Background Bacterial contact in utero modulates fetal and neonatal immune responses. Maternal probiotic supplementation reduces the risk of immune-mediated disease in the infant. We investigated the immunomodulatory properties of live Lactobacillus rhamnosus GG and its SpaC pilus adhesin in human fetal intestinal models. Methods TNF-α mRNA expression was measured by qPCR in a human fetal intestinal organ culture model exposed to live L. rhamnosus GG and proinflammatory stimuli. Binding of recombinant SpaC pilus protein to intestinal epithelial cells was assessed in human fetal intestinal organ culture and the human fetal intestinal epithelial cell line H4 by immunohistochemistry and immunofluorescence, respectively. TLR-related gene expression in fetal ileal organ culture after exposure to recombinant SpaC was assessed by qPCR. Results Live L. rhamnosus GG significantly attenuates pathogen-induced TNF-α mRNA expression in the human fetal gut. Recombinant SpaC protein was found to adhere to the fetal gut and to modulate varying levels of TLR-related gene expression. Conclusion The human fetal gut is responsive to luminal microbes. L. rhamnosus GG significantly attenuates fetal intestinal inflammatory responses to pathogenic bacteria. The L. rhamnosus GG pilus adhesin SpaC binds to immature human intestinal epithelial cells and directly modulates intestinal epithelial cell innate immune gene expression. PMID:25580735

The PI3K/Akt pathway is required for LPS activation of microglial cells.

PubMed

Saponaro, Concetta; Cianciulli, Antonia; Calvello, Rosa; Dragone, Teresa; Iacobazzi, Francesco; Panaro, Maria Antonietta

2012-10-01

Upregulation of inflammatory responses in the brain is associated with a number of neurodegenerative diseases. Microglia are activated in neurodegenerative diseases, producing pro-inflammatory mediators. Critically, lipopolysaccharide (LPS)-induced microglial activation causes dopaminergic neurodegeneration in vitro and in vivo. The signaling mechanisms triggered by LPS to stimulate the release of pro-inflammatory mediators in microglial cells are still incompletely understood. To further explore the mechanisms of LPS-mediated inflammatory response of microglial cells, we studied the role of phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathways known to be activated by toll-like receptor-4 signaling through LPS. In the current study, we report that the activation profile of LPS-induced pAkt activation preceded those of LPS-induced NF-κB activation, suggesting a role for PI3K/Akt in the pathway activation of NF-κB-dependent inflammatory responses of activated microglia. These results, providing the first evidence that PI3K dependent signaling is involved in the inflammatory responses of microglial cells following LPS stimulation, may be useful in preventing inflammatory based neurodegenerative processes.

Anti-inflammatory effect as a mechanism of effectiveness underlying the clinical benefits of pelotherapy in osteoarthritis patients: regulation of the altered inflammatory and stress feedback response

NASA Astrophysics Data System (ADS)

Ortega, E.; Gálvez, I.; Hinchado, M. D.; Guerrero, J.; Martín-Cordero, L.; Torres-Piles, S.

2017-10-01

The purpose of the present investigation was to evaluate whether an anti-inflammatory effect together with an improvement of the regulation of the interaction between the inflammatory and stress responses underlies the clinical benefits of pelotherapy in osteoarthritis (OA) patients. This study evaluated the effects of a 10-day cycle of pelotherapy at the spa centre `El Raposo' (Spain) in a group of 21 OA patients diagnosed with primary knee OA. Clinical assessments included pain intensity using a visual analog scale; pain, stiffness and physical function using the Western Ontario and McMaster Universities Arthritis Index; and health-related quality of life using the EuroQol-5D questionnaire. Serum inflammatory cytokine levels (IL-1β, TNF-α, IL-8, IL-6, IL-10 and TGF-β) were evaluated using the Bio-Plex® Luminex® system. Circulating neuroendocrine-stress biomarkers, such as cortisol and extracellular 72 kDa heat shock protein (eHsp72), were measured by ELISA. After the cycle of mud therapy, OA patients improved the knee flexion angle and OA-related pain, stiffness and physical function, and they reported a better health-related quality of life. Serum concentrations of IL-1β, TNF-α, IL-8, IL-6 and TGF-β, as well as eHsp72, were markedly decreased. Besides, systemic levels of cortisol increased significantly. These results confirm that the clinical benefits of mud therapy may well be mediated, at least in part, by its systemic anti-inflammatory effects and neuroendocrine-immune regulation in OA patients. Thus, mud therapy could be an effective alternative treatment in the management of OA.

Lack of matrix metalloproteinase 3 in mouse models of lung injury ameliorates the pulmonary inflammatory response in female but not in male mice.

PubMed

Puntorieri, Valeria; McCaig, Lynda A; Howlett, Christopher J; Yao, Li-Juan; Lewis, James F; Yamashita, Cory M; Veldhuizen, Ruud A W

2016-09-01

The acute respiratory distress syndrome (ARDS) is a complex pulmonary disorder in which the local release of cytokines and chemokines appears central to the pathophysiology. Based on the known role of matrix metalloproteinase-3 (MMP3) in inflammatory processes, the objective was to examine the role of MMP3 in the pathogenesis of ARDS through the modulation of pulmonary inflammation. Female and male, wild type (MMP3 +/+ ) and knock out (MMP3 -/- ) mice were exposed to two, clinically relevant models of ARDS including (i) lipopolysaccharide (LPS)-induced lung injury, and (ii) hydrochloric acid-induced lung injury. Parameters of lung injury and inflammation were assessed through measurements in lung lavage including total protein content, inflammatory cell influx, and concentrations of mediators such as TNF-α, IL-6, G-CSF, CXCL1, CXCL2, and CCL2. Lung histology and compliance were also evaluated in the LPS model of injury. Following intra-tracheal LPS instillation, all mice developed lung injury, as measured by an increase in lavage neutrophils, and decrease in lung compliance, with no overall effect of genotype observed. Increased concentrations of lavage inflammatory cytokines and chemokines were also observed following LPS injury, however, LPS-instilled female MMP3 -/- mice had lower levels of inflammatory mediators compared to LPS-instilled female MMP3 +/+ mice. This effect of the genotype was not observed in male mice. Similar findings, including the MMP3-related sex differences, were also observed after acid-induced lung injury. MMP3 contributes to the pathogenesis of ARDS, by affecting the pulmonary inflammatory response in female mice in relevant models of lung injury.

Indomethacin promotes survival of new neurons in the adult murine hippocampus accompanied by anti-inflammatory effects following MPTP-induced dopamine depletion.

PubMed

Hain, Elisabeth G; Sparenberg, Maria; Rasińska, Justyna; Klein, Charlotte; Akyüz, Levent; Steiner, Barbara

2018-05-26

Parkinson's disease (PD) is characterized by dopaminergic cell loss and inflammation in the substantia nigra (SN) leading to motor deficits but also to hippocampus-associated non-motor symptoms such as spatial learning and memory deficits. The cognitive decline is correlated with impaired adult hippocampal neurogenesis resulting from dopamine deficit and inflammation, represented in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model of PD. In the inflammatory tissue, cyclooxygenase (COX) is upregulated leading to an ongoing inflammatory process such as prostaglandin-mediated increased cytokine levels. Therefore, inhibition of COX by indomethacin may prevent the inflammatory response and the impairment of adult hippocampal neurogenesis. Wildtype C57Bl/6 and transgenic Nestin-GFP mice were treated with MPTP followed by short-term or long-term indomethacin treatment. Then, aspects of inflammation and neurogenesis were evaluated by cell counts using immunofluorescence and immunohistochemical stainings in the SN and dentate gyrus (DG). Furthermore, hippocampal mRNA expression of neurogenesis-related genes of the Notch, Wnt, and sonic hedgehog signaling pathways and neurogenic factors were assessed, and protein levels of serum cytokines were measured. Indomethacin restored the reduction of the survival rate of new mature neurons and reduced the amount of amoeboid CD68+ cells in the DG after MPTP treatment. Indomethacin downregulated genes of the Wnt and Notch signaling pathways and increased neuroD6 expression. In the SN, indomethacin reduced the pro-inflammatory cellular response without reversing dopaminergic cell loss. Indomethacin has a pro-neurogenic and thereby restorative effect and an anti-inflammatory effect on the cellular level in the DG following MPTP treatment. Therefore, COX inhibitors such as indomethacin may represent a therapeutic option to restore adult neurogenesis in PD.

Development of optical probes for in vivo imaging of polarized macrophages during foreign body reactions.

PubMed

Baker, David W; Zhou, Jun; Tsai, Yi-Ting; Patty, Kaitlen M; Weng, Hong; Tang, Ewin N; Nair, Ashwin; Hu, Wen-Jing; Tang, Liping

2014-07-01

Plasticity of macrophage (MΦ) phenotypes exist in a spectrum from classically activated (M1) cells, to alternatively activated (M2) cells, contributing to both the normal healing of tissues and the pathogenesis of implant failure. Here, folate- and mannose-based optical probes were fabricated to simultaneously determine the degree of MΦ polarization. In vitro tests show the ability of these probes to specifically target M1 and M2 cells. In an in vivo murine model, they were able to distinguish between the M1-dominated inflammatory response to infection and the M2-dominated regenerative response to particle implants. Finally, the probes were used to assess the inflammatory/regenerative properties of biomaterial implants. Our results show that these probes can be used to monitor and quantify the dynamic processes of MΦ polarization and their role in cellular responses in real time. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases.

PubMed

Ananthakrishnan, Ashwin N; Luo, Chengwei; Yajnik, Vijay; Khalili, Hamed; Garber, John J; Stevens, Betsy W; Cleland, Thomas; Xavier, Ramnik J

2017-05-10

The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted a prospective study with Crohn's disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community α-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of the phosphodiesterase type 4 inhibitor roflumilast on early and late allergic response and airway hyperresponsiveness in Aspergillus-fumigatus-sensitized mice.

PubMed

Hoymann, Heinz-Gerd; Wollin, Lutz; Muller, Meike; Korolewitz, Regina; Krug, Norbert; Braun, Armin; Beume, Rolf

2009-01-01

Inhibitory effects of roflumilast on responses characteristic of allergic asthma were investigated in a fungal asthma model in BALB/c mice. Mice were sensitized with Aspergillus antigen (Afu) and exposed to Afu or vehicle, and given roflumilast 1 or 5 mg/kg. Early airway response (EAR) and late airway hyperresponsiveness (AHR) to methacholine were measured via plethysmography. Bronchoalveolar lavage (BAL) was used to assess inflammatory cell count. In Afu-exposed mice, roflumilast dose-dependently reduced the EAR [26% at 1 mg/kg (NS) and 94% at 5 mg/kg (p < 0.01)] and AHR [46% at 1 mg/kg (NS) and 128% at 5 mg/kg (p < 0.05)]. Roflumilast 5 mg/kg reduced neutrophil, eosinophil and lymphocyte counts [87% (p < 0.01), 40% (NS) and 67% (p < 0.01), respectively] in BAL fluid versus controls. In this model, roflumilast inhibited the EAR, suppressed AHR and reduced inflammatory cell infiltration. 2009 S. Karger AG, Basel.

Serum antibody levels correlate with oral fungal cell numbers and influence the patients' response to chronic paracoccidioidomycosis.

PubMed

de Carli, Marina Lara; Cardoso, Beatriz Cristina Bachião; Malaquias, Luiz Cosme Cotta; Nonogaki, Suely; Pereira, Alessandro Antônio Costa; Sperandio, Felipe Fornias; Hanemann, João Adolfo Costa

2015-06-01

Paracoccidioidomycosis (PCM) is a neglected fungal disease that elicits an important granulomatous inflammatory reaction which aims to isolate the fungi and resolve the infection; besides the innate cellular response, the patients' sera may contain different levels of antibodies directed against PCM's pathogenic agent: Paracoccidioides brasiliensis (Pb). The aim of the study was to assess the distinct serum antibody levels of 19 chronic PCM patients and to associate these levels to the granulomatous inflammatory response and presence of fungi in oral lesions caused by Pb. The presence of Pb was detected and counted within oral tissues using immunohistochemistry; antibody levels were classified as negative, low-grade, moderate or high-grade groups. The Kruskal-Wallis and Dunn's test were used to verify possible associations among the groups. Interestingly, lower antibody titres were associated with lesser numbers of Pb, which favours the cellular response over the humoral response to fight PCM. On the other hand, negative serological results were linked to a higher presence of Pb in the tissues, indicating that a deficient humoral response supports the fungal proliferation. The number of Pb was conveniently associated with the level of serum antibodies, showing that the humoral immune response is required, however, not solely responsible to restrain the dissemination of Pb. © 2015 Blackwell Verlag GmbH.

FBXW7 protein has dual-role as tumor suppressor and inflammatory pathway inhibitor | Center for Cancer Research

Cancer.gov

Toll-like receptors (TLRs) are largely responsible for inducing innate immune responses to infection. TLR4 binds lipopolysaccharide (LPS) from Gram-negative bacteria and initiates a signaling pathway to activate inflammatory responses. TLR4 plays a role in diseases such as sepsis and chronic inflammatory disorders. In tumor cells, TLR4 is involved in dampening immune surveillance, and increasing proliferation, inflammatory cytokine production, and invasive migration. Determining how TLR4 expression and signaling is regulated may enable these adverse conditions to be better managed.

Evaluation of the Tobacco Heating System 2.2. Part 7: Systems toxicological assessment of a mentholated version revealed reduced cellular and molecular exposure effects compared with mentholated and non-mentholated cigarette smoke.

PubMed

Kogel, Ulrike; Titz, Bjoern; Schlage, Walter K; Nury, Catherine; Martin, Florian; Oviedo, Alberto; Lebrun, Stefan; Elamin, Ashraf; Guedj, Emmanuel; Trivedi, Keyur; Ivanov, Nikolai V; Vanscheeuwijck, Patrick; Peitsch, Manuel C; Hoeng, Julia

2016-11-30

Modified risk tobacco products (MRTPs) are being developed with the aim of reducing smoking-related health risks. The Tobacco Heating System 2.2 (THS2.2) is a candidate MRTP that uses the heat-not-burn principle. Here, systems toxicology approaches were engaged to assess the respiratory effects of mentholated THS2.2 (THS2.2M) in a 90-day rat inhalation study (OECD test guideline 413). The standard endpoints were complemented by transcriptomics and quantitative proteomics analyses of respiratory nasal epithelium and lung tissue and by lipidomics analysis of lung tissue. The adaptive response of the respiratory nasal epithelium to conventional cigarette smoke (CS) included squamous cell metaplasia and an inflammatory response, with high correspondence between the molecular and histopathological results. In contrast to CS exposure, the adaptive tissue and molecular changes to THS2.2M aerosol exposure were much weaker and were limited mostly to the highest THS2.2M concentration in female rats. In the lung, CS exposure induced an inflammatory response, triggered cellular stress responses, and affected sphingolipid metabolism. These responses were not observed or were much lower after THS2.2M aerosol exposure. Overall, this system toxicology analysis complements and reconfirms the results from classical toxicological endpoints and further suggests potentially reduced health risks of THS2.2M. Copyright © 2016. Published by Elsevier Inc.

Oxidative stress in Nipah virus-infected human small airway epithelial cells.

PubMed

Escaffre, Olivier; Halliday, Hailey; Borisevich, Viktoriya; Casola, Antonella; Rockx, Barry

2015-10-01

Nipah virus (NiV) is a zoonotic emerging pathogen that can cause severe and often fatal respiratory disease in humans. The pathogenesis of NiV infection of the human respiratory tract remains unknown. Reactive oxygen species (ROS) produced by airway epithelial cells in response to viral infections contribute to lung injury by inducing inflammation and oxidative stress; however, the role of ROS in NiV-induced respiratory disease is unknown. To investigate whether NiV induces oxidative stress in human respiratory epithelial cells, we used oxidative stress markers and monitored antioxidant gene expression. We also used ROS scavengers to assess their role in immune response modulation. Oxidative stress was confirmed in infected cells and correlated with the reduction in antioxidant enzyme gene expression. Infected cells treated by ROS scavengers resulted in a significant decrease of the (F2)-8-isoprostane marker, inflammatory responses and virus replication. In conclusion, ROS are induced during NiV infection in human respiratory epithelium and contribute to the inflammatory response. Understanding how oxidative stress contributes to NiV pathogenesis is crucial for therapeutic development.

Acute pancreatitis at the beginning of the 21st century: The state of the art

PubMed Central

Tonsi, Alfredo F; Bacchion, Matilde; Crippa, Stefano; Malleo, Giuseppe; Bassi, Claudio

2009-01-01

Acute pancreatitis is an acute inflammatory disease of the pancreas which can lead to a systemic inflammatory response syndrome with significant morbidity and mortality in 20% of patients. Gallstones and alcohol consumption are the most frequent causes of pancreatitis in adults. The treatment of mild acute pancreatitis is conservative and supportive; however severe episodes characterized by necrosis of the pancreatic tissue may require surgical intervention. Advanced understanding of the pathology, and increased interest in assessment of disease severity are the cornerstones of future management strategies of this complex and heterogeneous disease in the 21st century. PMID:19554647

Sphingosine kinase inhibition alleviates endothelial permeability induced by thrombin and activated neutrophils.

PubMed

Itagaki, Kiyoshi; Zhang, Qin; Hauser, Carl J

2010-04-01

Inflammation and microvascular thrombosis are interrelated causes of acute lung injury in the systemic inflammatory response syndrome. Neutrophils (polymorphonuclear neutrophil [PMN]) and endothelial cells (EC) activated by systemic inflammatory response syndrome interact to increase pulmonary vascular permeability, but the interactions between PMN and EC are difficult to study. Recently, we reported that sphingosine 1-phosphate is a second messenger eliciting store-operated calcium entry (SOCE) in response to inflammatory agonists in both PMN and EC. Store-operated calcium entry is therefore a target mechanism for the therapeutic modulation of inflammatory PMN-EC interactions. Here, we isolated, modeled, and studied the effects of pharmacologic SOCE inhibition using real-time systems to monitor EC permeability after exposure to activated PMN. We created systems to continuously assess permeability of human pulmonary artery endothelial cells and human microvascular endothelial cells from lung. Endothelial cells show increased permeability after challenge by activated PMN. Such permeability increases can be attenuated by exposure of the cocultures to sphingosine kinase (SK) inhibitors (SKI-2, N,N-dimethylsphingosine [DMS]) or Ca2+ entry inhibitors (Gd3+, MRS-1845). Human microvascular endothelial cells from lung pretreated with SKI-2 or DMS showed decreased permeability when later exposed to activated PMN. Likewise, when PMNs were activated with thapsigargin (TG) in the presence of SKI-2, DMS, Gd, or MRS-1845, their ability to cause EC permeability subsequently was reduced. SKI-2 also inhibited the activation of human pulmonary artery ECs by thrombin. These studies will provide a firm mechanistic foundation for understanding how systemic SOCE inhibition may be used to prevent acute lung injury in vivo.

FOXP3+ T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration

PubMed Central

Castiglioni, Alessandra; Basso, Veronica; Vezzoli, Michela; Monno, Antonella; Almada, Albert E.; Mondino, Anna; Wagers, Amy J.; Manfredi, Angelo A.; Rovere-Querini, Patrizia

2015-01-01

Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue. PMID:26039259

A metabolomics and mouse models approach to study inflammatory and immune responses to radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fornace, Albert J.; Li, Henghong

2013-12-02

The three-year project entitled "A Metabolomics and Mouse Models Approach to Study Inflammatory and Immune Responses to Radiation" was initiated in September 2009. The overall objectives of this project were to investigate the acute and persistent effects of low dose radiation on T cell lymphocyte function and physiology, as well the contributions of these cells to radiation-induced inflammatory responses. Inflammation after ionizing radiation (IR), even at low doses, may impact a variety of disease processes, including infectious disease, cardiovascular disease, cancer, and other potentially inflammatory disorders. There were three overall specific aims: 1. To investigate acute and persistent effects ofmore » low dose radiation on T cell subsets and function; 2. A genetic approach with mouse models to investigate p38 MAPK pathways that are involved in radiation-induced inflammatory signaling; 3. To investigate the effect of radiation quality on the inflammatory response. We have completed the work proposed in these aims.« less

Inflammatory Mechanisms Linking Periodontal Diseases to Cardiovascular Diseases

PubMed Central

Schenkein, Harvey A.; Loos, Bruno G.

2015-01-01

Aims In this paper, inflammatory mechanisms that link periodontal diseases to cardiovascular diseases (CVD) are reviewed. Materials and Methods and Results This paper is a literature review. Studies in the literature implicate a number of possible mechanisms that could be responsible for increased inflammatory responses in atheromatous lesions due to periodontal infections. These include increased systemic levels of inflammatory mediators stimulated by bacteria and their products at sites distant from the oral cavity, elevated thrombotic and hemostatic markers that promote a prothrombotic state and inflammation, cross-reactive systemic antibodies that promote inflammation and interact with the atheroma, promotion of dyslipidemia with consequent increases in proinflammatory lipid classes and subclasses, and common genetic susceptibility factors present in both disease leading to increased inflammatory responses. Conclusions Such mechanisms may be thought to act in concert to increase systemic inflammation in periodontal disease and to promote or exacerbate atherogenesis. However, proof that the increase in systemic inflammation attributable to periodontitis impacts inflammatory responses during atheroma development, thrombotic events, or myocardial infarction or stroke is lacking. PMID:23627334

Redox signaling in acute pancreatitis

PubMed Central

Pérez, Salvador; Pereda, Javier; Sabater, Luis; Sastre, Juan

2015-01-01

Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF–VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis. PMID:25778551

Inflammatory responses of stromal fibroblasts to inflammatory epithelial cells are involved in the pathogenesis of bovine mastitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Wenyao; Li, Xuezhong; Xu, Tong

Hypernomic secretion of epithelial cytokines has several effects on stromal cells. The contributions of inflammatory epithelial cells to stromal fibroblasts in bovine mammary glands with mastitis remain poorly understood. Here, we established an inflammatory epithelial cell model of bovine mastitis with gram-negative lipopolysaccharide (LPS) and gram-positive lipoteichoic acid (LTA) bacterial cell wall components. We characterized immune responses of mammary stromal fibroblasts induced by inflammatory epithelial cells. Our results showed that inflammatory epithelial cells affected stromal fibroblast characteristics by increasing inflammatory mediator expression, elevating extracellular matrix protein deposition, decreasing proliferation capacity, and enhancing migration ability. The changes in stromal fibroblast proliferationmore » and migration abilities were mediated by signal molecules, such as WNT signal pathway components. LPS- and LTA-induced inflammatory epithelial cells triggered different immune responses in stromal fibroblasts. Thus, in mastitis, bovine mammary gland stromal fibroblasts were affected by inflammatory epithelial cells and displayed inflammation-specific changes, suggesting that fibroblasts play crucial roles in bovine mastitis. - Highlights: • Inflammatory BMEs affect the properties of BMFs during mastitis. • BMEs inhibited the proliferation and promoted the migration of BMFs. • BMEs enhanced secretion of inflammatory mediators and deposition of ECM in BMFs. • Changes of the properties of BMFs were mediated by specific signal molecules.« less

Ultrasound imaging for the rheumatologist XXX. Sonographic assessment of the painful knee.

PubMed

Meenagh, G; Filippucci, E; Delle Sedie, A; Iagnocco, A; Scirè, C A; Riente, L; Montecucco, C; Valesini, G; Bombardieri, S; Grassi, W

2010-01-01

The knee joint is a frequent focus of attention for rheumatologists when assessing patients presenting to a clinic and may represent underlying intra-articular inflammatory pathology or involvement of the surrounding soft tissues. This study describes the correlation between clinical and ultrasound findings in patients presenting with a variety of rheumatic disorders and knee pain. US imaging provides for a sensitive and detailed identification of different intra- and peri-articular pathology responsible for knee pain.

Transient downregulation of microRNA-206 protects alkali burn injury in mouse cornea by regulating connexin 43

PubMed Central

Li, Xiaoyan; Zhou, Huanfen; Tang, Weiqiang; Guo, Qing; Zhang, Yan

2015-01-01

Purpose: Chemical burn in cornea may cause permanent visual problem or complete blindness. In the present study, we investigated the role of microRNA 206 (miR-206) in relieving chemical burn in mouse cornea. Method: An alkali burn model was established in C57BL/6 mice to induce chemical corneal injury. Within 72 hours, the transient inflammatory responses in alkali-treated corneas were measured by opacity and corneal neovascularization (CNV) levels, and the gene expression profile of miR-206 was measured by quantitative real-time PCR (qPCR). Inhibitory oligonucleotides of miR-206, miR-206-I, were intrastromally injected into alkali-burned corneas. The possible protective effects of down-regulating miR-206 were assessed by both in vivo measurements of inflammatory responses and in vitro histochemical examinations of corneal epithelium sections. The possible binding of miR-206 on its molecular target, connexin43 (Cx43), was assessed by luciferase reporter (LR) and western blot (WB) assays. Cx43 was silenced by siRNA to examine its effect on regulating miR-206 modulation in alkali-burned cornea. Results: Opacity and CNV levels, along with gene expression of miR-206, were all transiently elevated within 72 hours of alkali-burned mouse cornea. Intrastromal injection of miR-206-I into alkali-burned cornea down-regulated miR-206 and ameliorated inflammatory responses both in vivo and in vitro. LR and WB assays confirmed that Cx43 was directly targeted by miR-206 in mouse cornea. Genetic silencing of Cx43 reversed the protective effect of miR-206 down-regulation in alkali-burned cornea. Conclusion: miR-206, associated with Cx43, is a novel molecular modulator in alkali burn in mouse cornea. PMID:26045777

Trichuris suis ova in relapsing-remitting multiple sclerosis and clinically isolated syndrome (TRIOMS): study protocol for a randomized controlled trial.

PubMed

Rosche, Berit; Wernecke, Klaus-Dieter; Ohlraun, Stephanie; Dörr, Jan-Markus; Paul, Friedemann

2013-04-25

Trichuris suis ova is a probiotic treatment based on the hygiene hypothesis. It has been demonstrated as safe and effective in autoimmune inflammatory bowel diseases and clinical trials indicate that helminth infections also have an immunomodulatory effect in multiple sclerosis.We hypothesize that administering 2,500 Trichuris suis ova eggs orally every two weeks for 12 months is--due to its immunomodulatory and anti-inflammatory effect--significantly more effective than oral placebo in preventing new T2 and Gd+ lesions, as quantified by cerebral MRI and clinical examination, in relapsing-remitting multiple sclerosis and clinically isolated syndrome. Fifty patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome with clinical activity, not undergoing any standard therapies, will be randomized 1:1 to Trichuris suis ova 2,500 eggs every two weeks or matching placebo. The safety, tolerability and effect on disease activity and in vivo mechanisms of action of Trichuris suis ova in MS will be assessed by neurological, laboratory and immunological exams and magnetic resonance imaging throughout the 12-month treatment period and over a follow-up period of 6 months. Various immunological analyses will be used to assess the overall patient immune response prior to and at varying time points following treatment with Trichuris suis ova. We anticipate that Trichuris suis ova will be well tolerated and more effective than the placebo in preventing new T2 and Gd+ lesions, as quantified by MRI. We also expect the Th1/Th17 proinflammatory response to shift towards the more anti-inflammatory Th2 response. This study has important clinical implications and will involve extensive research on the immunology of helminth therapy. ClinicalTrials.gov: NCT01413243.

Calpain 3 and CaMKIIβ signaling are required to induce HSP70 necessary for adaptive muscle growth after atrophy

PubMed Central

Kramerova, Irina; Torres, Jorge A; Eskin, Ascia; Nelson, Stanley F; Spencer, Melissa J

2018-01-01

Abstract Mutations in CAPN3 cause autosomal recessive limb girdle muscular dystrophy 2A. Calpain 3 (CAPN3) is a calcium dependent protease residing in the myofibrillar, cytosolic and triad fractions of skeletal muscle. At the triad, it colocalizes with calcium calmodulin kinase IIβ (CaMKIIβ). CAPN3 knock out mice (C3KO) show reduced triad integrity and blunted CaMKIIβ signaling, which correlates with impaired transcriptional activation of myofibrillar and oxidative metabolism genes in response to running exercise. These data suggest a role for CAPN3 and CaMKIIβ in gene regulation that takes place during adaptation to endurance exercise. To assess whether CAPN3- CaMKIIβ signaling influences skeletal muscle remodeling in other contexts, we subjected C3KO and wild type mice to hindlimb unloading and reloading and assessed CaMKIIβ signaling and gene expression by RNA-sequencing. After induced atrophy followed by 4 days of reloading, both CaMKIIβ activation and expression of inflammatory and cellular stress genes were increased. C3KO muscles failed to activate CaMKIIβ signaling, did not activate the same pattern of gene expression and demonstrated impaired growth at 4 days of reloading. Moreover, C3KO muscles failed to activate inducible HSP70, which was previously shown to be indispensible for the inflammatory response needed to promote muscle recovery. Likewise, C3KO showed diminished immune cell infiltration and decreased expression of pro-myogenic genes. These data support a role for CaMKIIβ signaling in induction of HSP70 and promotion of the inflammatory response during muscle growth and remodeling that occurs after atrophy, suggesting that CaMKIIβ regulates remodeling in multiple contexts: endurance exercise and growth after atrophy. PMID:29528394

Phytol-based novel adjuvants in vaccine formulation: 2. Assessment of efficacy in the induction of protective immune responses to lethal bacterial infections in mice.

PubMed

Lim, So-Yon; Bauermeister, Adam; Kjonaas, Richard A; Ghosh, Swapan K

2006-10-23

Adjuvants are known to significantly enhance vaccine efficacy. However, commercial adjuvants often have limited use because of toxicity in humans. The objective of this study was to determine the comparative effectiveness of a diterpene alcohol, phytol and its hydrogenated derivative PHIS-01, relative to incomplete Freund's adjuvant (IFA), a commonly used adjuvant in augmenting protective immunity in mice against E. coli and S. aureus, and in terms of inflammatory cytokines. Vaccines, consisting of heat-attenuated E. coli or S. aureus and either of the two phytol-based adjuvants or IFA, were tested in female BALB/c mice. The vaccines were administered intraperitoneally at 10-day intervals. The efficacy of the phytol and PHIS-01, as compared to IFA, was assessed by ELISA in terms of anti-bacterial antibody and inflammatory cytokines. We also examined the ability of the vaccines to induce specific protective immunity by challenging mice with different doses of live bacteria. IFA, phytol, and PHIS-01 were equally efficient in evoking anti-E. coli antibody response and in providing protective immunity against live E. coli challenges. In contrast, the antibody response to S. aureus was significant when PHIS-01 was used as the adjuvant. However, in terms of the ability to induce protective immunity, phytol was most effective against S. aureus. Moreover, during challenges with live E. coli and S. aureus immune mice produced much less IL-6, the mediators of fatal septic shock syndromes. Our results show that vaccine formulations containing phytol and PHIS-01 as adjuvants confer a robust and protective immunity against both Gram-negative and Gram-positive bacteria without inducing adverse inflammatory cytokine due to IL-6.

Effects of surface finishing conditions on the biocompatibility of a nickel-chromium dental casting alloy.

PubMed

McGinley, Emma Louise; Coleman, David C; Moran, Gary P; Fleming, Garry J P

2011-07-01

To assess the effects of surface finishing condition (polished or alumina particle air abraded) on the biocompatibility of direct and indirect exposure to a nickel-chromium (Ni-Cr) d.Sign®10 dental casting alloy on oral keratinocytes. Biocompatibility was performed by assessing cellular viability and morphology, metabolic activity, cellular toxicity and presence of inflammatory cytokine markers. Discs of d.Sign®10 were cast, alumina particle air abraded and half were polished before surface roughness was determined by profilometry. Biocompatibility was assessed by placing the discs directly or indirectly (with immersion solutions) into contact with TR146 monolayers. Metal ion release was determined by ICP-MS. Cell viability was assessed by trypan blue dye exclusion, metabolic activity by XTT and cellular toxicity by LDH. Inflammatory cytokine analysis was performed using sandwich ELISAs. The mean polished Ra value was significantly reduced (P<0.001) compared with the alumina particle air abraded discs but metal ion release was significantly increased for the polished discs. Significant reductions in cell density of polished compared with alumina particle air abraded discs was observed following direct or indirect exposure. A significant reduction in metabolic activity, increase in cellular toxicity and an increase in the presence of inflammatory cytokine markers was highlighted for the polished relative to the alumina particle air abraded discs at 24h. Finishing condition of the Ni-Cr dental alloy investigated has important clinical implications. The approach of employing cell density and morphology, metabolic activity, cellular toxicity levels and inflammatory marker responses to TR146 epithelial cells combined with ICP-MS afforded the authors an increased insight into the complex processes dental alloys undergo in the oral environment. Copyright © 2011 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition.

PubMed

Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana; Koudelka, Adolf; Rudolph, Tanja K; Woodcock, Steven R; Freeman, Bruce A; Kubala, Lukas; Pekarova, Michaela

2016-11-01

Inflammatory-mediated pathological processes in the endothelium arise as a consequence of the dysregulation of vascular homeostasis. Of particular importance are mediators produced by stimulated monocytes/macrophages inducing activation of endothelial cells (ECs). This is manifested by excessive soluble pro-inflammatory mediator production and cell surface adhesion molecule expression. Nitro-fatty acids are endogenous products of metabolic and inflammatory reactions that display immuno-regulatory potential and may represent a novel therapeutic strategy to treat inflammatory diseases. The purpose of our study was to characterize the effects of nitro-oleic acid (OA-NO2) on inflammatory responses and the endothelial-mesenchymal transition (EndMT) in ECs that is a consequence of the altered healing phase of the immune response. The effect of OA-NO2 on inflammatory responses and EndMT was determined in murine macrophages and murine and human ECs using Western blotting, ELISA, immunostaining, and functional assays. OA-NO2 limited the activation of macrophages and ECs by reducing pro-inflammatory cytokine production and adhesion molecule expression through its modulation of STAT, MAPK and NF-κB-regulated signaling. OA-NO2 also decreased transforming growth factor-β-stimulated EndMT and pro-fibrotic phenotype of ECs. These effects are related to the downregulation of Smad2/3. The study shows the pleiotropic effect of OA-NO2 on regulating EC-macrophage interactions during the immune response and suggests a role for OA-NO2 in the regulation of vascular endothelial immune and fibrotic responses arising during chronic inflammation. These findings propose the OA-NO2 may be useful as a novel therapeutic agent for treatment of cardiovascular disorders associated with dysregulation of the endothelial immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

Thermoresponsive Polymers with Lower Critical Solution Temperature- or Upper Critical Solution Temperature-Type Phase Behaviour Do Not Induce Toxicity to Human Endothelial Cells.

PubMed

Ji, Yuejia; Zhu, Mengxiang; Gong, Yu; Tang, Haoyu; Li, Juan; Cao, Yi

2017-01-01

Thermoresponsive polymers have gained extensive attention as biomedical materials especially for targeted drug delivery systems. We have recently developed water-soluble polypeptide-based thermoresponsive polymers that exhibit lower critical solution temperature (LCST)- or upper critical solution temperature (UCST)-type phase behaviours. In this study, the toxicity of these polymers to human umbilical vein endothelial cells (HUVECs) was investigated to assess the safety and biocompatibility. Up to 100 μg/ml, thermoresponsive polymers did not induce cytotoxicity to HUVECs, showing as unaltered mitochondrial viability assessed as cell counting kit-8 (CCK-8) assay and membrane integrity assessed as lactate dehydrogenase (LDH) assay. Inflammatory response, assessed as the release of chemokine-soluble monocyte chemotactic protein 1 (sMCP-1) and interleukin-8 (IL-8) as well as cytokine IL-6, was not significantly affected by the polymers. In addition, 1 μM thapsigargin (TG), an endoplasmic reticulum (ER) stress inducer, significantly decreased mitochondrial viability, but did not affect membrane integrity or inflammatory response. The presence of thermoresponsive polymers with LCST-type phase behaviour did not further affect the effects of TG. In conclusion, the thermoresponsive polymers used in this study are not toxic to endothelial cells and therefore could be further considered as safe materials for biomedical applications. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Inflammatory mediators of cognitive impairment in bipolar disorder

PubMed Central

Bauer, Isabelle E.; Pascoe, Michaela C.; Wollenhaupt-Aguiar, Bianca; Kapczinski, Flavio; Soares, Jair C.

2014-01-01

Objectives Recent studies have pointed to neuroinflammation, oxidative stress and neurotrophic factors as key mediators in the pathophysiology of mood disorders. Little is however known about the cascade of biological episodes underlying the cognitive deficits observed during the acute and euthymic phases of bipolar disorder (BD). The aim of this review is to assess the potential association between cognitive impairment and biomarkers of inflammation, oxidative stress and neurotrophic activity in BD. Methods Scopus (all databases), Pubmed and Ovid Medline were systematically searched with no language or year restrictions, up to November 2013, for human studies that collected both inflammatory markers and cognitive data in BD. Selected search terms were bipolar disorder, depression, mania, psychosis, inflammatory, cognitive and neurotrophic. Results Ten human studies satisfied the criteria for consideration. The findings showed that high levels of peripheral inflammatory-cytokine, oxidative stress and reduced brain derived neurotrophic factor (BDNF) levels were associated with poor cognitive performance. The BDNF val66met polymorphism is a potential vulnerability factor for cognitive impairment in BD. Conclusions Current data provide preliminary evidence of a link between the cognitive decline observed in BD and mechanisms of neuroinflammation and neuroprotection. The identification of BD specific inflammatory markers and polymorphisms in inflammatory response genes may be of assistance for therapeutic intervention. PMID:24862657

FBXW7 protein has dual-role as tumor suppressor and inflammatory pathway inhibitor | Center for Cancer Research

Cancer.gov

Toll-like receptors (TLRs) are largely responsible for inducing innate immune responses to infection. TLR4 binds lipopolysaccharide (LPS) from Gram-negative bacteria and initiates a signaling pathway to activate inflammatory responses. TLR4 plays a role in diseases such as sepsis and chronic inflammatory disorders. In tumor cells, TLR4 is involved in dampening immune

Systemic Corticosteroid Responses in Children with Severe Asthma: Phenotypic and Endotypic Features.

PubMed

Fitzpatrick, Anne M; Stephenson, Susan T; Brown, Milton R; Nguyen, Khristopher; Douglas, Shaneka; Brown, Lou Ann S

Severe asthma in children is a heterogeneous disorder associated with variable responses to corticosteroid treatment. Criterion standards for corticosteroid responsiveness assessment in children are lacking. This study sought to characterize systemic corticosteroid responses in children with severe asthma after treatment with intramuscular triamcinolone and to identify phenotypic and molecular predictors of an intramuscular triamcinolone response. Asthma-related quality of life, exhaled nitric oxide, blood eosinophils, lung function, and inflammatory cytokine and chemokine mRNA gene expression in peripheral blood mononuclear cells were assessed in 56 children with severe asthma at baseline and 14 days after intramuscular triamcinolone injection. The Asthma Control Questionnaire was used to classify children with severe asthma into corticosteroid response groups. Three groups of children with severe asthma were identified: controlled severe asthma, children who achieved control after triamcinolone, and children who did not achieve control. At baseline, these groups were phenotypically similar. After triamcinolone, discordance between symptoms, lung function, exhaled nitric oxide, and blood eosinophils was noted. Clinical phenotypic predictors were of limited utility in predicting the triamcinolone response, whereas systemic mRNA expression of inflammatory cytokines and chemokines related to IL-2, IL-10, and TNF signaling pathways, namely, AIMP1, CCR2, IL10RB, and IL5, strongly differentiated children who failed to achieve control with triamcinolone administration. Systemic corticosteroid responsiveness in children with severe asthma is heterogeneous. Alternative prediction models that include molecular endotypic as well as clinical phenotypic features are needed to identify which children derive the most clinical benefit from systemic corticosteroid step-up therapy given the potential side effects. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Predictors of Clinical Response and Remission at One year among a Multicenter Cohort of Patients with Inflammatory Bowel Disease Treated with Vedolizumab

PubMed Central

Allegretti, Jessica R.; Barnes, Edward L.; Stevens, Betsey; Storm, Margaret; Ananthakrishnan, Ashwin; Yajnik, Vijay; Korzenik, Joshua

2017-01-01

Background Vedolizumab (VDZ) has demonstrated long term efficacy in Crohn’s disease (CD) and ulcerative colitis (UC) in phase III trials. Aims Our aim was to evaluate the efficacy of VDZ at week 54 in inflammatory bowel disease (IBD) in a multicenter cohort of patients. Methods Adult patients completing induction therapy with VDZ were eligible for this study. Clinical response and remission was assessed using the Harvey Bradshaw index (HBI) for CD, the simple clinical colitis activity index (SCCAI) for UC and physician assessment. Results Among 136 total patients (96 CD and 40 UC), 76 (56%) demonstrated clinical response or remission at week 54. In univariate analysis, for patients with CD concomitant initiation of immunomodulator therapy (2.71, 95% CI 1.11 – 6.57), the addition of an immunomodulator (OR 11.49, 3.16 – 41.75) and CRP <3 (4.92, 95% CI 1.99 – 12.15) were associated with increased odds of clinical response or remission at week 54. For UC patients hospitalization after VDZ induction was associated with decreased odds of response or remission at week 54 ( OR 0.22, 95%CI 0.05–0.88). On multivariate analysis in CD, addition of an immunomodulator (OR 8.33, 95% CI 2.15–32.26) remained significant predictors of clinical response or remission at week 54. Conclusions Among a multicenter cohort of patients with IBD demonstrating primary response to VDZ, the addition of combination therapy with an immunomodulator is a significant predictor of clinical response or remission at week 54 in patients with CD. PMID:28357697

From the Cover: Interplay Between IFN-γ and IL-6 Impacts the Inflammatory Response and Expression of Interferon-Regulated Genes in Environmental-Induced Autoimmunity.

PubMed

Cauvi, David M; Cauvi, Gabrielle; Toomey, Christopher B; Jacquinet, Eric; Pollard, Kenneth Michael

2017-07-01

IFN-γ has been found to be robustly important to disease pathogenesis in both idiopathic and induced models of murine lupus. In transgenic mice, over production of IFN-γ in the skin results in an inflammatory response and autoimmunity. This suggests that localized exposure to environmental factors that induce autoimmunity may be associated with expression of an IFN-γ-dependent inflammatory response. Using murine mercury-induced autoimmunity (mHgIA), the severity of inflammation and proinflammatory cytokine expression, including the cellular source of IFN-γ, were assessed at the site of subcutaneous exposure and in secondary lymphoid organs. Exposure induced a localized chronic inflammation comprising both innate and adaptive immune cells but only CD8+ T and NK cells were reduced in the absence of IFN-γ. IFN-γ+ cells began to appear as early as day 1 and comprised both resident (γδ T) and infiltrating cells (CD8+ T, NKT, CD11c+). The requirements for inflammation were examined in mice deficient in genes required (Ifng, Il6) or not required (Casp1) for mHgIA. None of these genes were essential for induction of inflammation, however IFN-γ and IL-6 were required for exacerbation of other proinflammatory cytokines. Additionally, lack of IFN-γ or IL-6 impacted expression of genes regulated by either IFN-γ or type I IFN. Significantly, both IFN-γ and IL-6 were required for increased expression of IRF-1 which regulates IFN stimulated genes and is required for mHgIA. Thus IRF-1 may be at the nexus of the interplay between IFN-γ and IL-6 in exacerbating a xenobiotic-induced inflammatory response, regulation of interferon responsive genes and autoimmunity. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frank, Evan A.; Birch, M. Eileen; Yadav, Jagjit S., E-mail: Jagjit.Yadav@uc.edu

Carbon nanotubes (CNTs) are rapidly emerging as high-priority occupational toxicants. CNT powders contain fibrous particles that aerosolize readily in places of manufacture and handling, posing an inhalation risk for workers. Studies using animal models indicate that lung exposure to CNTs causes prolonged inflammatory responses and diffuse alveolar injury. The mechanisms governing CNT-induced lung inflammation are not fully understood but have been suggested to involve alveolar macrophages (AMs). In the current study, we sought to systematically assess the effector role of AMs in vivo in the induction of lung inflammatory responses to CNT exposures and investigate their cell type-specific mechanisms. Multi-wallmore » CNTs characterized for various physicochemical attributes were used as the CNT type. Using an AM-specific depletion and repopulation approach in a mouse model, we unambiguously demonstrated that AMs are major effector cells necessary for the in vivo elaboration of CNT-induced lung inflammation. We further investigated in vitro AM responses and identified molecular targets which proved critical to pro-inflammatory responses in this model, namely MyD88 as well as MAPKs and Ca{sup 2} {sup +}/CamKII. We further demonstrated that MyD88 inhibition in donor AMs abrogated their capacity to reconstitute CNT-induced inflammation when adoptively transferred into AM-depleted mice. Taken together, this is the first in vivo demonstration that AMs act as critical effector cell types in CNT-induced lung inflammation and that MyD88 is required for this in vivo effector function. AMs and their cell type-specific mechanisms may therefore represent potential targets for future therapeutic intervention of CNT-related lung injury. - Highlights: • Demonstrated in vivo effector role of alveolar macrophages (AMs) in CNT toxicity • MyD88, MAPKs, and Ca{sup 2} {sup +}/CamKII are required for AM inflammatory responses in vitro. • MyD88 signaling is required for in vivo effector function of AMs. • MyD88 may be a potential target for intervention in CNT lung exposures.« less

High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia.

PubMed

Baufeld, Caroline; Osterloh, Anja; Prokop, Stefan; Miller, Kelly R; Heppner, Frank L

2016-09-01

Diets high in fat (HFD) are known to cause an immune response in the periphery as well as the central nervous system. In peripheral adipose tissue, this immune response is primarily mediated by macrophages that are recruited to the tissue. Similarly, reactivity of microglia, the innate immune cells of the brain, has been shown to occur in the hypothalamus of mice fed a high-fat diet. To characterize the nature of the microglial response to diets high in fat in a temporal fashion, we studied the phenotypic spectrum of hypothalamic microglia of mice fed high-fat diet for 3 days and 8 weeks by assessing their tissue reaction and inflammatory signature. While we observed a significant increase in Iba1+ myeloid cells and a reaction of GFAP+ astrocytes in the hypothalamus after 8 weeks of HFD feeding, we found the hypothalamic myeloid cell reaction to be limited to endogenous microglia and not mediated by infiltrating myeloid cells. Moreover, obese humans were found to present with signs of hypothalamic gliosis and exacerbated microglia dystrophy, suggesting a targeted microglia response to diet in humans as well. Notably, the glial reaction occurring in the mouse hypothalamus was not accompanied by an increase in pro-inflammatory cytokines, but rather by an anti-inflammatory reaction. Gene expression analyses of isolated microglia not only confirmed this observation, but also revealed a downregulation of microglia genes important for sensing signals in the microenvironment. Finally, we demonstrate that long-term exposure of microglia to HFD in vivo does not impair the cell's ability to respond to additional stimuli, like lipopolysaccharide. Taken together, our findings support the notion that microglia react to diets high in fat in a region-specific manner in rodents as well as in humans; however, this response changes over time as it is not exclusively pro-inflammatory nor does exposure to HFD prime microglia in the hypothalamus.

Halothane reduces the early lipopolysaccharide-induced lung inflammation in mechanically ventilated rats.

PubMed

Giraud, O; Seince, P F; Rolland, C; Leçon-Malas, V; Desmonts, J M; Aubier, M; Dehoux, M

2000-12-01

Several studies suggest that anesthetics modulate the immune response. The aim of this study was to investigate the effect of halothane and thiopental on the lung inflammatory response. Rats submitted or not to intratracheal (IT) instillation of lipopolysaccharides (LPS) were anesthetized with either halothane (0. 5, 1, or 1.5%) or thiopental (60 mg. kg(-1)) and mechanically ventilated for 4 h. Control rats were treated or not by LPS without anesthesia. Lung inflammation was assessed by total and differential cell counts in bronchoalveolar lavage fluids (BALF) and by cytokine measurements (tumor necrosis factor-alpha [TNF-alpha], interleukin-6 [IL-6], macrophage inflammatory protein-2 [MIP-2], and monocyte chemoattractant protein-1 [MCP-1]) in BALF and lung homogenates. In the absence of LPS treatment, neither halothane nor thiopental modified the moderate inflammatory response induced by tracheotomy or mechanical ventilation. Cell recruitment and cytokine concentrations were increased in all groups receiving IT LPS. However, in halothane-anesthetized rats (halothane > or = 1%), but not in thiopental-anesthetized rats, the LPS-induced lung inflammation was altered in a dose-dependent manner. Indeed, when using 1% halothane, polymorphonuclear leukocyte (PMN) recruitment was decreased by 55% (p < 0.001) and TNF-alpha, IL-6, and MIP-2 concentrations in BALF and lung homogenates were decreased by more than 60% (p < 0.001) whereas total protein and MCP-1 concentrations remained unchanged. The decrease of MIP-2 (observed at the protein and messenger RNA [mRNA] level) was strongly correlated to the decrease of PMN recruitment (r = 0.73, p < 0.05). This halothane-reduced lung inflammatory response was transient and was reversed 20 h after the end of the anesthesia. Our study shows that halothane > or = 1%, delivered during 4 h by mechanical ventilation, but not mechanical ventilation per se, alters the early LPS-induced lung inflammation in the rat, suggesting a specific effect of halothane on this response.

Nutraceuticals of anti-inflammatory activity as complementary therapy for rheumatoid arthritis.

PubMed

Al-Okbi, Sahar Y

2014-09-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by elevated oxidative stress and inflammatory biomarkers. The severe side effects of drug used during such disease necessitate the search for new and safe approaches. Food is a rich source of antioxidants and anti-inflammatory bioactive constituents including phenolic compounds, polyunsaturated fatty acids, phytosterols, toccopherols, and carotenoids. We have a series of publications dealing with the anti-inflammatory activity of different food extracts (as nutraceuticals) in experimental animals (acute and chronic inflammation model) and in clinical study (RA patients). Fish oil, primrose oil, extracts of black cumin, fenugreek, liquorice, coriander, tomato, carrot, sweet potato, broccoli, green tea, rosemary, hazelnut, walnut, wheat germ, and date in addition to the probiotic Bifidobacterium bifidum were the nutraceuticals studied. During these studies, changes in inflammatory biomarkers (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), seromucoids, fibrinogen, tumor necrosis factor-α (TNF-α), prostaglandin E2), oxidative stress (malondialdehyde), antioxidant status (total antioxidant capacity, vitamin C, vitamin E, retinol, β-carotene), the level of copper (Cu) and zinc (Zn) and colonic microflora in response to the administration of nutraceuticals have been assessed. Results of these studies showed that the majority of nutraceuticals studied possess beneficial effect toward chronic inflammatory diseases, which might be due to the presence of one or more of the above-mentioned phytochemicals. Anti-inflammatory and antioxidant nutraceuticals may serve as complementary medicine for the management of RA. © The Author(s) 2012.

Shift Work in Rats Results in Increased Inflammatory Response after Lipopolysaccharide Administration: A Role for Food Consumption.

PubMed

Guerrero-Vargas, Natalí N; Guzmán-Ruiz, Mara; Fuentes, Rebeca; García, Joselyn; Salgado-Delgado, Roberto; Basualdo, María del Carmen; Escobar, Carolina; Markus, Regina P; Buijs, Ruud M

2015-08-01

The suprachiasmatic nucleus (SCN) drives circadian rhythms in behavioral and physiological variables, including the inflammatory response. Shift work is known to disturb circadian rhythms and is associated with increased susceptibility to develop disease. In rodents, circadian disruption due to shifted light schedules (jet lag) induced increased innate immune responses. To gain more insight into the influence of circadian disruption on the immune response, we characterized the inflammatory response in a model of rodent shift work and demonstrated that circadian disruption affected the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. Since food consumption is a main disturbing element in the shift work schedule, we also evaluated the inflammatory response to LPS in a group of rats that had no access to food during their working hours. Our results demonstrated that the shift work schedule decreased basal TNF-α levels in the liver but not in the circulation. Despite this, we observed that shift work induced increased cytokine response after LPS stimulation in comparison to control rats. Also, Kupffer cells (liver macrophages) isolated from shift work rats produced more TNF-α in response to in vitro LPS stimulation, suggesting important effects of circadian desynchronization on the functionality of this cell type. Importantly, the effects of shift work on the inflammatory response to LPS were prevented when food was not available during the working schedule. Together, these results show that dissociating behavior and food intake from the synchronizing drive of the SCN severely disturbs the immune response. © 2015 The Author(s).

The role of the JAK2-STAT3 pathway in pro-inflammatory responses of EMF-stimulated N9 microglial cells

PubMed Central

2010-01-01

Background In several neuropathological conditions, microglia can become overactivated and cause neurotoxicity by initiating neuronal damage in response to pro-inflammatory stimuli. Our previous studies have shown that exposure to electromagnetic fields (EMF) activates cultured microglia to produce tumor necrosis factor (TNF)-α and nitric oxide (NO) through signal transduction involving the activator of transcription STAT3. Here, we investigated the role of STAT3 signaling in EMF-induced microglial activation and pro-inflammatory responses in more detail than the previous study. Methods N9 microglial cells were treated with EMF exposure or a sham treatment, with or without pretreatment with an inhibitor (Pyridone 6, P6) of the Janus family of tyrosine kinases (JAK). The activation state of microglia was assessed via immunoreaction using the microglial marker CD11b. Levels of inducible nitric oxide synthase (iNOS), TNF-α and NO were measured using real-time reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and the nitrate reductase method. Activation of JAKs and STAT3 proteins was evaluated by western blotting for specific tyrosine phosphorylation. The ability of STAT3 to bind to DNA was detected with an electrophoresis mobility shift assay (EMSA). Results EMF was found to significantly induce phosphorylation of JAK2 and STAT3, and DNA-binding ability of STAT3 in N9 microglia. In addition, EMF dramatically increased the expression of CD11b, TNF-α and iNOS, and the production of NO. P6 strongly suppressed the phosphorylation of JAK2 and STAT3 and diminished STAT3 activity in EMF-stimulated microglia. Interestingly, expression of CD11b as well as gene expression and production of TNF-α and iNOS were suppressed by P6 at 12 h, but not at 3 h, after EMF exposure. Conclusions EMF exposure directly triggers initial activation of microglia and produces a significant pro-inflammatory response. Our findings confirm that the JAK2-STAT3 pathway may not mediate this initial microglial activation but does promote pro-inflammatory responses in EMF-stimulated microglial cells. Thus, the JAK2-STAT3 pathway might be a therapeutic target for reducing pro-inflammatory responses in EMF-activated microglia. PMID:20828402

Protective antifungal activity of essential oils extracted from Buddleja perfoliata and Pelargonium graveolens against fungi isolated from stored grains.

PubMed

Juárez, Z N; Bach, H; Sánchez-Arreola, E; Bach, H; Hernández, L R

2016-05-01

The chemical composition and antifungal activity of essential oils extracted from Buddleja perfoliata and Pelargonium graveolens were analysed to assess their efficacy as a potential alternative to synthetic chemical fungicides to protect stored grain. Essential oils were obtained by hydrodistillation, while GC-MS were used to characterize the components of theses oils. The main components identified from the essential oil of B. perfoliata were cubenol, eudesmol, germacrene D-4-ol and cis-verbenol; whereas (-)-aristolene, β-citronellol and geraniol, were identified in P. graveolens. These essential oils were tested against a panel of fungal strains isolated from stored grains. Toxicity of the essential oils was assessed using two models represented by human-derived macrophages and the brine shrimp assay. Moreover, inflammatory response of the oils was assessed by measuring secretion of the pro-inflammatory cytokines IL-6 and TNF-α using a human-derived macrophage cell line. Results show potent antifungal activity against a collection of fungi, with minimal inhibitory concentrations ranging from 0·3 to 50 μg ml(-1) for both plants. A moderated cytotoxicity was observed, but no inflammatory responses. These oils can be used as an alternative for synthetic chemical fungicides used to protect stored grains. Synthetic chemical fungicides are used to protect stored grains, but their broad use raises concerns about effects on the environment and human health. The impact of the present report is that the use of essential oils is an eco-friendly alternative for fungal control in postharvest grains with a low impact to the environment. © 2016 The Society for Applied Microbiology.

Attenuation of warm ischemia-reperfusion injury in the liver by bucillamine through decreased neutrophil activation and Bax/Bcl-2 modulation.

PubMed

Junnarkar, Sameer P; Tapuria, Niteen; Mani, Alireza; Dijk, Sas; Fuller, Barry; Seifalian, Alexander M; Davidson, Brian R

2010-12-01

Liver transplantation and resection surgery involve a period of ischemia and reperfusion to the liver, which initiates an inflammatory cascade resulting in liver and remote organ injury. Bucillamine is a low molecular weight thiol antioxidant that is capable of rapidly entering cells. We hypothesized that bucillamine acts by replenishing glutathione levels, thus reducing neutrophil activation, modulating Bax/Bcl-2 expression, and subsequently, attenuating the effects of warm ischemia-reperfusion injury (IRI) in the liver. The effect of bucillamine was studied in a rat model of liver IRI with 45 min of partial (70%) liver ischemia and 3 h of reperfusion. Liver injury was assessed by measuring serum transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and liver histology. Oxidative stress was quantified by measuring F(2) isoprostane and glutathione levels. Leukocyte adhesion was assessed by intravital microscopy, and inflammatory cytokine response was assessed by measuring serum cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels. Bax and Bcl-2 expression was measured by reverse transcription-polymerase chain reaction. The model produced significant liver injury with elevated transaminases and an acute inflammatory response. Bucillamine reduced the liver injury, as indicated by reduced AST (932 ± 200.8 vs 2072.5 ± 511.79, P < 0.05). Bucillamine reduced Bax expression, serum CINC-1 levels, and neutrophil adhesion, and upregulated Bcl-2. However, bucillamine did not affect tissue glutathione levels nor the levels of oxidative stress, as measured by plasma and hepatic F(2) isoprostane levels. Bucillamine reduces warm ischemia-reperfusion in the liver by inhibiting neutrophil activation and modulating Bax/Bcl-2 expression. © 2010 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Predicting the severity of systemic inflammatory response syndrome (SIRS)-associated coagulopathy with hemostatic molecular markers and vascular endothelial injury markers.

PubMed

Iba, Toshiaki; Gando, Satoshi; Murata, Atsuo; Kushimoto, Shigeki; Saitoh, Daizoh; Eguchi, Yutaka; Ohtomo, Yasuhiro; Okamoto, Kohji; Koseki, Kazuhide; Mayumi, Toshihiko; Ikeda, Toshiaki; Ishhikura, Hiroyasu; Ueyama, Masashi; Ogura, Yuji; Endo, Shigeatsu; Shimazaki, Shuji

2007-11-01

The changes in biomarkers of coagulation or fibrinolysis, anticoagulation, inflammation, and endothelial damage occur in patients with systemic inflammatory response syndrome (SIRS). The purpose of this study is to assess the prognostic value of these markers in patients with SIRS-associated hypercoagulopathy. Sixty-six SIRS patients with a platelet count less than 15.0 x 10(4)/mm3 in three university hospital intensive care units were enrolled in this prospective, comparative study. Blood samples were obtained on day 0 and day 2. Twelve hemostatic, inflammatory, and vascular endothelial indices were measured and the data were compared between the severe group (patients with a total maximum Sequential Organ Failure Assessment score of 10 or more and nonsurvivors; n = 25) and the less-severe group (Sequential Organ Failure Assessment score <10; n = 41). Significant changes between the groups were observed in platelet count, fibrin or fibrinogen degradation products, interleukin-6, soluble thrombomodulin, antithrombin (AT) activity, and protein C activity, both on day 0 and on day 2. In contrast, the d-dimer, soluble fibrin, plasmin-[alpha]2-antiplasmin complex, and E-selectin levels were higher in the severe group only on day 2. No significant difference was seen regarding the thrombin-AT complex and total plasminogen activator inhibitor on both days. A comparison of the areas under the receiver operating characteristic curve revealed the AT activity to be the best predictor of a progression of organ dysfunction. The changes in some hemostatic molecular markers and vascular endothelial markers were conspicuous in patients with organ dysfunction. The AT activity is considered to be the most useful predictor of organ dysfunction.

Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes

PubMed Central

Gillette, Devyn D.; Curry, Heather M.; Cremer, Thomas; Ravneberg, David; Fatehchand, Kavin; Shah, Prexy A.; Wewers, Mark D.; Schlesinger, Larry S.; Butchar, Jonathan P.; Tridandapani, Susheela; Gavrilin, Mikhail A.

2014-01-01

Background: Human monocyte inflammatory responses differ between virulent and attenuated Francisella infection. Results: A mixed infection model showed that the virulent F. tularensis Schu S4 can attenuate inflammatory cytokine responses to the less virulent F. novicida in human monocytes. Conclusion: F. tularensis dampens inflammatory response by an active process. Significance: This suppression may contribute to enhanced pathogenicity of F. tularensis. Francisella tularensis is a Gram-negative facultative bacterium that can cause the disease tularemia, even upon exposure to low numbers of bacteria. One critical characteristic of Francisella is its ability to dampen or subvert the host immune response. Previous work has shown that monocytes infected with highly virulent F. tularensis subsp. tularensis strain Schu S4 responded with a general pattern of quantitatively reduced pro-inflammatory signaling pathway genes and cytokine production in comparison to those infected with the less virulent related F. novicida. However, it has been unclear whether the virulent Schu S4 was merely evading or actively suppressing monocyte responses. By using mixed infection assays with F. tularensis and F. novicida, we show that F. tularensis actively suppresses monocyte pro-inflammatory responses. Additional experiments show that this suppression occurs in a dose-dependent manner and is dependent upon the viability of F. tularensis. Importantly, F. tularensis was able to suppress pro-inflammatory responses to earlier infections with F. novicida. These results lend support that F. tularensis actively dampens human monocyte responses and this likely contributes to its enhanced pathogenicity. PMID:24783062

Dietary Allium hookeri reduces inflammatory response and increases expression of intestinal tight junctions proteins in LPS-induced young broiler chickens

USDA-ARS?s Scientific Manuscript database

We undertook a study to assess the effects of Allium hookeri (AH) root and fermented root on inflammation and intestinal integrity of lipopolysaccharide (LPS)-challenged chickens. Birds were assigned to six groups (n = 25 birds/treatment) and fed with basal diets or basal diets supplemented with AH ...

Mononuclear cell secretome protects from experimental autoimmune myocarditis

PubMed Central

Hoetzenecker, Konrad; Zimmermann, Matthias; Hoetzenecker, Wolfram; Schweiger, Thomas; Kollmann, Dagmar; Mildner, Michael; Hegedus, Balazs; Mitterbauer, Andreas; Hacker, Stefan; Birner, Peter; Gabriel, Christian; Gyöngyösi, Mariann; Blyszczuk, Przemyslaw; Eriksson, Urs; Ankersmit, Hendrik Jan

2015-01-01

Aims Supernatants of serum-free cultured mononuclear cells (MNC) contain a mix of immunomodulating factors (secretome), which have been shown to attenuate detrimental inflammatory responses following myocardial ischaemia. Inflammatory dilated cardiomyopathy (iDCM) is a common cause of heart failure in young patients. Experimental autoimmune myocarditis (EAM) is a CD4+ T cell-dependent model, which mirrors important pathogenic aspects of iDCM. The aim of this study was to determine the influence of MNC secretome on myocardial inflammation in the EAM model. Methods and results BALB/c mice were immunized twice with an alpha myosin heavy chain peptide together with Complete Freund adjuvant. Supernatants from mouse mononuclear cells were collected, dialysed, and injected i.p. at Day 0, Day 7, or Day 14, respectively. Myocarditis severity, T cell responses, and autoantibody formation were assessed at Day 21. The impact of MNC secretome on CD4+ T cell function and viability was evaluated using in vitro proliferation and cell viability assays. A single high-dose application of MNC secretome, injected at Day 14 after the first immunization, effectively attenuated myocardial inflammation. Mechanistically, MNC secretome induced caspase-8-dependent apoptosis in autoreactive CD4+ T cells. Conclusion MNC secretome abrogated myocardial inflammation in a CD4+ T cell-dependent animal model of autoimmune myocarditis. This anti-inflammatory effect of MNC secretome suggests a novel and simple potential treatment concept for inflammatory heart diseases. PMID:23321350

Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice.

PubMed

Sina, Christian; Lipinski, Simone; Gavrilova, Olga; Aden, Konrad; Rehman, Ateequr; Till, Andreas; Rittger, Andrea; Podschun, Rainer; Meyer-Hoffert, Ulf; Haesler, Robert; Midtling, Emilie; Pütsep, Katrin; McGuckin, Michael A; Schreiber, Stefan; Saftig, Paul; Rosenstiel, Philip

2013-04-01

Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk(-/-) ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk(-/-) mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. Using Ctsk(-/-) mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk(-/-) mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk(-/-) mice ameliorates the severity of intestinal inflammation. These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.

Histologic Inflammatory Response to Transvaginal Polypropylene Mesh: A Systematic Review.

PubMed

Thomas, Dominique; Demetres, Michelle; Anger, Jennifer T; Chughtai, Bilal

2018-01-01

To evaluate the inflammatory response following transvaginal implantation of polypropylene (PP) mesh. A comprehensive literature search was performed in the following databases from inception in April 2017: Ovid MEDLINE, Ovid EMBASE, and The Cochrane Library (Wiley). The studies retrieved were screened for eligibility against predefined inclusion and exclusion criteria. Twenty-three articles were included in this review. Following the implantation of PP mesh, there are immediate and local inflammatory responses. PP mesh elicits an inflammatory response that decreases over time; however, no studies documented a complete resolution. Further studies are needed to determine if there is a complete resolution of inflammation or if it persists. Copyright © 2017 Elsevier Inc. All rights reserved.

Lymphocyte function following radioiodine therapy in patients with thyroid carcinoma.

PubMed

Barsegian, V; Müller, S P; Horn, P A; Bockisch, A; Lindemann, M

2011-01-01

Since the nuclear disaster in Fukushima has raised great concern about the danger of radioactivity, we here addressed the question if the therapeutic use of iodine 131, the most frequently applied radionuclide, was harmful to immune function in patients. It was our aim to define for the first time in a clinical setting how radioiodine therapy alters anti-microbial immune responses. In 21 patients with thyroid carcinoma anti-microbial lymphocyte responses were assessed by lymphocyte transformation test and ELISpot - measuring lymphocyte proliferation and on a single cell level production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) - prior to therapy, at day 1 and day 7 post therapy. Proliferative lymphocyte responses and interferon-γ production after in vitro stimulation with microbial antigens were significantly (p < 0.05) increased at day 1 vs. pre therapy, and returned to pre therapy levels at day 7. On the contrary, at day 1 interleukin-10 production was significantly (p < 0.05) reduced. Thus, we observed a short-term increase in pro-inflammatory immune responses. However, T lymphocyte responses were in the range of healthy controls at all three time points. Thyroid carcinoma patients receiving radioiodine therapy do not display any sign of immunosuppression.

Stress-dependent changes in neuroinflammatory markers observed after common laboratory stressors are not seen following acute social defeat of the Sprague Dawley rat.

PubMed

Hueston, Cara M; Barnum, Christopher J; Eberle, Jaime A; Ferraioli, Frank J; Buck, Hollin M; Deak, Terrence

2011-08-03

Exposure to acute stress has been shown to increase the expression of pro-inflammatory cytokines in brain, blood and peripheral organs. However, the nature of the inflammatory response evoked by acute stress varies depending on the stressor used and species examined. The goal of the following series of studies was to characterize the consequences of social defeat in the Sprague Dawley (SD) rat using three different social defeat paradigms. In Experiments 1 and 2, adult male SD rats were exposed to a typical acute resident-intruder paradigm of social defeat (60 min) by placement into the home cage of a larger, aggressive Long Evans rat and brain tissue was collected at multiple time points for analysis of IL-1β protein and gene expression changes in the PVN, BNST and adrenal glands. In subsequent experiments, rats were exposed to once daily social defeat for 7 or 21 days (Experiment 3) or housed continuously with an aggressive partner (separated by a partition) for 7 days (Experiment 4) to assess the impact of chronic social stress on inflammatory measures. Despite the fact that social defeat produced a comparable corticosterone response as other stressors (restraint, forced swim and footshock; Experiment 5), acute social defeat did not affect inflammatory measures. A small but reliable increase in IL-1 gene expression was observed immediately after the 7th exposure to social defeat, while other inflammatory measures were unaffected. In contrast, restraint, forced swim and footshock all significantly increased IL-1 gene expression in the PVN; other inflammatory factors (IL-6, cox-2) were unaffected in this structure. These findings provide a comprehensive evaluation of stress-dependent inflammatory changes in the SD rat, raising intriguing questions regarding the features of the stress challenge that may be predictive of stress-dependent neuroinflammation. Copyright © 2011 Elsevier Inc. All rights reserved.

Acute phase protein haptoglobin as inflammatory marker in serum and synovial fluid in an equine model of arthritis.

PubMed

Barrachina, Laura; Remacha, Ana Rosa; Soler, Lourdes; García, Natalia; Romero, Antonio; Vázquez, Francisco José; Vitoria, Arantza; Álava, María Ángeles; Lamprave, Fermín; Rodellar, Clementina

2016-12-01

Acute phase proteins are useful inflammatory markers in horses. Haptoglobin (Hp) serum level is increased in horses undergoing different inflammatory processes, including arthritis. However, Hp concentration has not been assessed in inflammatory synovial fluid (SF). The aim of the present study was to investigate the Hp response in serum and SF in horses undergoing experimentally induced arthritis. For this purpose, serum and SF samples were collected from 12 animals before amphotericin B-induced arthritis was created (T0, healthy) and 15days after the lesion induction (T1, joint inflammation) and Hp was determined by single radial immunodiffusion. The Hp increase between T0 and T1 was significant in both serum and SF, and serum Hp concentration at T0 was significantly higher than in SF, but significant differences were not found at T1, indicating a higher Hp increase in SF. A significant positive correlation for Hp concentration between serum and SF samples was found. These results highlight the potential usefulness of Hp as inflammatory marker in horses, showing for the first time the increase of Hp in SF from joint inflammation in the horse. Copyright © 2016 Elsevier B.V. All rights reserved.

Anti-inflammatory effects of Melatonin: a mechanistic review.

PubMed

Nabavi, Seyed Mohammad; Nabavi, Seyed Fazel; Sureda, Antoni; Xiao, Janbo; Dehpour, Ahmad Reza; Shirooie, Samira; Silva, Ana Sanches; Baldi, Alessandra; Khan, Haroon; Daglia, Maria

2018-06-14

N-acetyl-5-methoxy-tryptamine (melatonin) is a natural substance produced both by plants, as a secondary metabolite, and animals, by the pineal gland and other tissues. In humans, melatonin participates in numerous functions including the regulation of mood, sleep, reproduction, promotion of immunomodulation, antioxidant defense and as an anti-inflammatory agent. The anti-inflammatory activity of melatonin could yield beneficial effects on intake, particularly against the chronic inflammation which underlies many chronic diseases. This review aims to provide an assessment of the literature data on the anti-inflammatory activity of melatonin, with a particular focus on the mechanisms responsible for this behavior. We can conclude that many in vitro studies and in vivo studies in experimental animal model systems show that melatonin exerts anti-inflammatory activity in a number of chronic diseases which affect different organs in different circumstances. Clinical trials, however, often fail to reach positive results and are thus far inconclusive. Thus, in the future, long-term well-designed investigations on melatonin-rich foods or melatonin food supplements could provide valuable information towards public health recommendations on melatonin, taking into account both the nature of the compound and the optimal dose, for protection from long-term inflammation linked to chronic diseases.

Bilobalide, a unique constituent of Ginkgo biloba, inhibits inflammatory pain in rats.

PubMed

Goldie, Michelle; Dolan, Sharron

2013-08-01

Standardized Ginkgo biloba extract EGb 761 has been shown to inhibit inflammatory hyperalgesia in rats; however, the mechanism of action is not known. This study set out to investigate the anti-inflammatory and analgesic potential of bilobalide, a unique G. biloba constituent, in three well-characterized models of acute inflammatory pain. The effect of oral, intraplantar or intrathecal administration of bilobalide or drug-vehicle (0.25% agar; 10% ethanol in H2O) on responses to noxious thermal and mechanical stimulation of the hindpaw, and paw oedema were assessed in adult male Wistar rats before and after intradermal hindpaw injection of carrageenan (3%; 50 μl) or capsaicin (10 μg; 50 μl) or after hindpaw incision (n=6-8/group). Oral administration of bilobalide (10-30 mg/kg) significantly inhibited thermal hyperalgesia in response to carrageenan, capsaicin and paw incision, independent of dose, with an efficacy similar to that of diclofenac. In the carrageenan model, mechanical hypersensitivity and paw oedema were also significantly reduced after treatment with bilobalide (10-30 mg/kg). Intrathecal administration of bilobalide (0.5-1 μg) inhibited carrageenan-induced thermal hyperalgesia, but had no effect on mechanical hypersensitivity or paw oedema (application≥2 μg induced adverse effects, precluding testing of higher doses). Intraplantar administration of bilobalide (30-100 μg) had no effect. These data show that bilobalide is a potent anti-inflammatory and antihyperalgesic agent, the therapeutic effects of which are mediated in part through a central site of action, and may account for the therapeutic action of the whole extract G. biloba.

LPS-induced inflammatory response triggers cell cycle reactivation in murine neuronal cells through retinoblastoma proteins induction.

PubMed

D'Angelo, Barbara; Astarita, Carlo; Boffo, Silvia; Massaro-Giordano, Mina; Antonella Ianuzzi, Carmelina; Caporaso, Antonella; Macaluso, Marcella; Giordano, Antonio

2017-01-01

Cell cycle reactivation in adult neurons is an early hallmark of neurodegeneration. The lipopolysaccharide (LPS) is a well-known pro-inflammatory factor that provokes neuronal cell death via glial cells activation. The retinoblastoma (RB) family includes RB1/p105, retinoblastoma-like 1 (RBL1/p107), and retinoblastoma-like 2 (Rb2/p130). Several studies have indicated that RB proteins exhibit tumor suppressor activities, and play a central role in cell cycle regulation. In this study, we assessed LPS-mediated inflammatory effect on cell cycle reactivation and apoptosis of neuronally differentiated cells. Also, we investigated whether the LPS-mediated inflammatory response can influence the function and expression of RB proteins. Our results showed that LPS challenges triggered cell cycle reactivation of differentiated neuronal cells, indicated by an accumulation of cells in S and G2/M phase. Furthermore, we found that LPS treatment also induced apoptotic death of neurons. Interestingly, we observed that LPS-mediated inflammatory effect on cell cycle re-entry and apoptosis was concomitant with the aberrant expression of RBL1/p107 and RB1/p105. To the best of our knowledge, our study is the first to indicate a role of LPS in inducing cell cycle re-entry and/or apoptosis of differentiated neuronal cells, perhaps through mechanisms altering the expression of specific members of RB family proteins. This study provides novel information on the biology of post-mitotic neurons and could help in identifying novel therapeutic targets to prevent de novo cell cycle reactivation and/or apoptosis of neurons undergoing neurodegenerative processes.

Anti-inflammatory effects of Boletus edulis polysaccharide on asthma pathology.

PubMed

Wu, Songquan; Wang, Guangli; Yang, Ruhui; Cui, Yubao

2016-01-01

Asthma is a chronic airway disease common around the world. The burden of this disease could be reduced with new and effective treatments. Here, the efficacy of a polysaccharide extract from the Boletus edulis (BEP) mushroom, which has demonstrated anti-inflammatory properties, was tested in a mouse model of asthma. Five groups of BaLB/C mice were developed; one group served as a control and did not have asthma induction. The other four groups of mice were sensitized by ovalbumin challenge. FinePointe™ RC animal airway resistance and pulmonary compliance was used to assess airway function in asthma models. Three of the 4 model groups received treatments: one received pravastatin, one received dexamethasone, and one received BEP. Histopathology of lung tissues was performed using H&E and AB-PAS staining. Levels of cytokines IL-4 and IFN-g were detected using ELISA, qRT-PCR, and Western blotting. Cyclophilin A was measured by Western blot, and flow cytometry was used to determine the proportion of CD4 + CD25 + FOXP3 + Treg cells. BEP treatment resulted in improvements in lung pathology, IL-4 level (P<0.05), and IFN-γ level (P<0.05) similar to traditional dexamethasone treatment. Further, the proportion of anti-inflammatory CD4 + CD25 + FOXP3 + Treg cells significantly increased (P<0.05) compared to untreated asthma models, and expression of cyclophilin A significantly decreased (P<0.05). Thus, Boletus edulis polysaccharide reduces pro-inflammatory responses and increases anti-inflammatory responses in mouse models of asthma, suggesting this may be a novel treatment method.

Anti-inflammatory effects of Boletus edulis polysaccharide on asthma pathology

PubMed Central

Wu, Songquan; Wang, Guangli; Yang, Ruhui; Cui, Yubao

2016-01-01

Asthma is a chronic airway disease common around the world. The burden of this disease could be reduced with new and effective treatments. Here, the efficacy of a polysaccharide extract from the Boletus edulis (BEP) mushroom, which has demonstrated anti-inflammatory properties, was tested in a mouse model of asthma. Five groups of BaLB/C mice were developed; one group served as a control and did not have asthma induction. The other four groups of mice were sensitized by ovalbumin challenge. FinePointe™ RC animal airway resistance and pulmonary compliance was used to assess airway function in asthma models. Three of the 4 model groups received treatments: one received pravastatin, one received dexamethasone, and one received BEP. Histopathology of lung tissues was performed using H&E and AB-PAS staining. Levels of cytokines IL-4 and IFN-g were detected using ELISA, qRT-PCR, and Western blotting. Cyclophilin A was measured by Western blot, and flow cytometry was used to determine the proportion of CD4+CD25+FOXP3+ Treg cells. BEP treatment resulted in improvements in lung pathology, IL-4 level (P<0.05), and IFN-γ level (P<0.05) similar to traditional dexamethasone treatment. Further, the proportion of anti-inflammatory CD4+CD25+FOXP3+ Treg cells significantly increased (P<0.05) compared to untreated asthma models, and expression of cyclophilin A significantly decreased (P<0.05). Thus, Boletus edulis polysaccharide reduces pro-inflammatory responses and increases anti-inflammatory responses in mouse models of asthma, suggesting this may be a novel treatment method. PMID:27830033

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagib, Marwa M.; Tadros, Mariane G., E-mail: mirogeogo@yahoo.com; ELSayed, Moushira I.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) driven through altered immune responses with production of proinflammatory cytokines. Many therapies are used, but side effects and loss of response limit long-term effectiveness. New therapeutic strategies are thus needed for patients who don't respond to current treatments. Recently, there is suggested involvement of the proinflammatory hormone angiotensin II in inflammatory bowel disease. The aim of this study was to investigate the possible role of olmesartan medoxomil (OLM-M), an angiotensin II receptor blocker in ameliorating ulcerative colitis. Colitis was induced in male Wistar rats by administration of 5% dextran sodiummore » sulphate (DSS) in drinking water for 5 days. OLM-M (1, 3 and 10 mg/kg) was administered orally during 21 days prior to the induction of colitis, and for 5 days after. Sulfasalazine (500 mg/kg) was used as reference drug. All animals were tested for changes in colon length, disease activity index (DAI) and microscopic damage. Colon tissue concentration/activity of tumor necrosis alpha (TNF-α), myeloperoxidase (MPO), prostaglandin E2 (PGE2), reduced glutathione (GSH) and malondialdehyde (MDA) were assessed. Results showed that the OLM-M dose-dependently ameliorated the colonic histopathological and biochemical injuries, an effect that is comparable or even better than that of the standard sulfasalazine. These results suggest that olmesartan medoxomil may be effective in the treatment of UC through its anti-inflammatory and antioxidant effects. - Highlights: • Olmesartan medoximil reduced dextran sodium sulphate- induced colitis. • Mechanism involved anti-inflammatory and antioxidant effects dose- dependently. • It suppressed malondialdehyde and restored reduced glutathione levels. • It reduced inflammatory markers levels and histological changes.« less

Sirt1 restrains lung inflammasome activation in a murine model of sepsis.

PubMed

Gao, Rong; Ma, Zhongsen; Hu, Yuxin; Chen, Jiao; Shetty, Sreerama; Fu, Jian

2015-04-15

Excessive inflammation is a major cause of organ damage during sepsis. The elderly are highly susceptible to sepsis-induced organ injury. Sirt1 expression is reduced during aging. In the present study, we investigated the role of Sirt1, a histone deacetylase, in controlling inflammatory responses in a murine sepsis model induced by cecal ligation and puncture (CLP). We examined lung inflammatory signaling in inducible Sirt1 knockout (Sirt1(-/-)) mice and wild-type littermates (Sirt1(+/+)) after CLP. Our results demonstrated that Sirt1 deficiency led to severe lung inflammatory injury. To further investigate molecular mechanisms of Sirt1 regulation of lung inflammatory responses in sepsis, we conducted a series of experiments to assess lung inflammasome activation after CLP. We detected increased lung inflammatory signaling including NF-κB, signal transducer and activator of transcription 3, and ERK1/2 activation in Sirt1(-/-) mice after CLP. Furthermore, inflammasome activity was increased in Sirt1(-/-) mice after CLP, as demonstrated by increased IL-1β and caspase-7 cleavage and activation. Aggravated inflammasome activation in Sirt1(-/-) mice was associated with the increased production of lung proinflammatory mediators, including ICAM-1 and high-mobility group box 1, and further disruption of tight junctions and adherens junctions, as demonstrated by dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression, which was associated with the upregulation of matrix metallopeptidase 9 expression. In summary, our results suggest that Sirt1 suppresses acute lung inflammation during sepsis by controlling inflammasome activation pathway. Copyright © 2015 the American Physiological Society.

Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype

PubMed Central

Mathey, Emily K; Park, Susanna B; Hughes, Richard A C; Pollard, John D; Armati, Patricia J; Barnett, Michael H; Taylor, Bruce V; Dyck, P James B; Kiernan, Matthew C; Lin, Cindy S-Y

2015-01-01

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP. PMID:25677463

The role of adipokines in the rapid antidepressant effects of ketamine.

PubMed

Machado-Vieira, R; Gold, P W; Luckenbaugh, D A; Ballard, E D; Richards, E M; Henter, I D; De Sousa, R T; Niciu, M J; Yuan, P; Zarate, C A

2017-01-01

We previously found that body mass index (BMI) strongly predicted response to ketamine. Adipokines have a key role in metabolism (including BMI). They directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders. Here, we sought to examine the role of three key adipokines-adiponectin, resistin and leptin-as potential predictors of response to ketamine or as possible transducers of its therapeutic effects. Eighty treatment-resistant subjects who met DSM-IV criteria for either major depressive disorder (MDD) or bipolar disorder I/II and who were currently experiencing a major depressive episode received a single ketamine infusion (0.5 mg kg -1 for 40 min). Plasma adipokine levels were measured at three time points (pre-infusion baseline, 230 min post infusion and day 1 post infusion). Overall improvement and response were assessed using percent change from baseline on the Montgomery-Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. Lower baseline levels of adiponectin significantly predicted ketamine's antidepressant efficacy, suggesting an adverse metabolic state. Because adiponectin significantly improves insulin sensitivity and has potent anti-inflammatory effects, this finding suggests that specific systemic abnormalities might predict positive response to ketamine. A ketamine-induced decrease in resistin was also observed; because resistin is a potent pro-inflammatory compound, this decrease suggests that ketamine's anti-inflammatory effects may be transduced, in part, by its impact on resistin. Overall, the findings suggest that adipokines may either predict response to ketamine or have a role in its possible therapeutic effects.

Anesthesiologists at work: an increase in pro-inflammatory and Th2 cytokine production, and alterations in proliferative immune responses.

PubMed

Beilin, B; Greenfeld, K; Abiri, N; Yardeni, I Z; Bessler, H; Ben-Eliyahu, S

2006-11-01

Anesthesiologists are a population at high risk of alcohol and drug abuse, depression, suicide, and psychiatric hospitalization. The impact of their working milieu on specific immune indices has scarcely been studied, and it is assumed that immune perturbations may contribute to some of the above risks. This study took advantage of an unplanned, 3-month long strike of anesthesiologists, and explored its relations to specific immune measures. We assessed induced cytokine production and lymphocytes proliferative responses in blood samples taken from 10 anesthesiologists just before the strike and at its end, after a long period of markedly reduced workload. The results indicated that the proliferative responses to phytohemagglutinin (PHA) and concanavalin A (Con A) were significantly lower at the end of the strike. At this time point, we observed a significant decrease in the production of interleukin-6 (IL-6), IL-10 and IL1ra levels, and a significant increase in IL-2 production. A strong trend towards a decline in tumor necrosis factor-alpha (TNF-alpha) levels was evident, while levels of IL-1beta were unchanged. These findings suggest that the working conditions of anesthesiologists are associated with specific immune alterations, including a shift towards a Th2 cytokines' dominance, and an elevated pro-inflammatory cytokine response. A reduced Th1 profile has been related to increased susceptibility to infections, and high pro-inflammatory cytokine levels were recently proposed as etiological factors in cardiovascular diseases and in depression.

Eosinophil Activities Modulate the Immune/Inflammatory Character of Allergic Respiratory Responses in Mice

PubMed Central

Jacobsen, Elizabeth A.; LeSuer, William E.; Willetts, Lian; Zellner, Katie R.; Mazzolini, Kirea; Antonios, Nathalie; Beck, Brandon; Protheroe, Cheryl; Ochkur, Sergei I.; Colbert, Dana; Lacy, Paige; Moqbel, Redwan; Appleton, Judith; Lee, Nancy A.; Lee, James J.

2014-01-01

Background The importance and specific role(s) of eosinophils in modulating the immune/inflammatory phenotype of allergic pulmonary disease remain to be defined. Established animals models assessing the role(s) of eosinophils as contributors and/or causative agents of disease have relied on congenitally deficient mice where the developmental consequences of eosinophil depletion are unknown. Methods We developed a novel conditional eosinophil-deficient strain of mice (iPHIL) through a gene knock-in strategy inserting the human diphtheria toxin (DT) receptor (DTR) into the endogenous eosinophil peroxidase genomic locus. Results Expression of DTR rendered resistant mouse eosinophil progenitors sensitive to DT without affecting any other cell types. The presence of eosinophils was shown to be unnecessary during the sensitization phase of either ovalbumin (OVA) or house dust mite (HDM) acute asthma models. However, eosinophil ablation during airway challenge led to a predominantly neutrophilic phenotype (>15% neutrophils) accompanied by allergen-induced histopathologies and airway hyperresponsiveness in response to methacholine indistinguishable from eosinophilic wild type mice. Moreover, the iPHIL neutrophilic airway phenotype was shown to be a steroid-resistant allergic respiratory variant that was reversible upon restoration of peripheral eosinophils. Conclusions Eosinophil contributions to allergic immune/inflammatory responses appear to be limited to the airway challenge and not the sensitization phase of allergen provocation models. The reversible steroid-resistant character of the iPHIL neutrophilic airway variant suggests underappreciated mechanisms by which eosinophils shape the character of allergic respiratory responses. PMID:24266710

Toxicological Implications and Inflammatory Response in Human Lymphocytes Challenged with Oxytetracycline

PubMed Central

Di Cerbo, A.; Palatucci, A. T.; Rubino, V.; Centenaro, S.; Giovazzino, A.; Fraccaroli, E.; Cortese, L.; Ruggiero, G.; Guidetti, G.; Canello, S.

2015-01-01

ABSTRACT Antibiotics are widely used in zoo technical and veterinary practices as feed supplementation to ensure wellness of farmed animals and livestock. Several evidences have been suggesting both the toxic role for tetracyclines, particularly for oxytetracycline (OTC). This potential toxicity appears of great relevance for human nutrition and for domestic animals. This study aimed to extend the evaluation of such toxicity. The biologic impact of the drug was assessed by evaluating the proinflammatory effect of OTC and their bone residues on cytokine secretion by in vitro human peripheral blood lymphocytes. Our results showed that both OTC and OTC‐bone residues significantly induced the T lymphocyte and non‐T cell secretion of interferon (IFN)‐γ, as cytokine involved in inflammatory responses in humans as well as in animals. These results may suggest a possible implication for new potential human and animal health risks depending on the entry of tetracyclines in the food‐processing chain. PMID:26537863

C-reactive protein as a marker of periodontal disease.

PubMed

Kanaparthy, Rosaiah; Kanaparthy, Aruna; Mahendra, Muktishree

2012-01-01

Periodontal subgingival pathogens affect local and systemic immune and inflammatory response and cause the release of cytokines; this results in periodontal destruction and initiation of an acute phase systemic inflammatory response characterized by the release of C-reactive proteins (CRP). This study set out to evaluate the serum concentration of CRP that can be used as a marker of periodontal disease as well as a risk indicator for cardiovascular disease. Based on their periodontal status, 45 patients were divided into three groups. The following clinical parameters were recorded: plaque index, gingival index, bleeding index, probing pocket depth, and clinical attachment levels. Scoring was done on six tooth surfaces for all teeth. For the CRP assessment, blood samples were collected from subjects at the time of clinical examination. The results indicated an increase in serum CRP levels in patients with generalized aggressive periodontitis and chronic periodontitis as compared to controls.

Analysis of inflammatory cytokines in human blood, breath condensate, and urine using a multiplex immunoassay platform

EPA Science Inventory

A change in the expression of cytokines in human biological media indicates an inflammatory response to external stressors and reflects an early step along the adverse outcome pathway (AOP) for various health endpoints. To characterize and interpret this inflammatory response, m...

Regulation of Survival by IKKe in Inflammatory Breast Cancer Involves EpCAM

DTIC Science & Technology

2016-02-01

responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms . Blood. 2010;115(25):5232-40. 29. Duncan JS, Whittle MC, Nakamura K...responses and normalizes inflammatory cytokines in murine myeloprolifer - ative neoplasms . Blood. 2010;115(25):5232–5240. 34. Aref AR, et al. Screening

Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages

PubMed Central

Padmore, Trudy; Stark, Carahline; Turkevich, Leonid A.; Champion, Julie A.

2017-01-01

Background In the lung, macrophages attempt to engulf inhaled high aspect ratio pathogenic materials, secreting inflammatory molecules in the process. The inability of macrophages to remove these materials leads to chronic inflammation and disease. How the biophysical and biochemical mechanisms of these effects are influenced by fiber length remains undetermined. This study evaluates the role of fiber length on phagocytosis and molecular inflammatory responses to non-cytotoxic fibers, enabling development of quantitative length-based models. Methods Murine alveolar macrophages were exposed to long and short populations of JM-100 glass fibers, produced by successive sedimentation and repeated crushing, respectively. Interactions between fibers and macrophages were observed using time-lapse video microscopy, and quantified by flow cytometry. Inflammatory biomolecules (TNF-α, IL-1 α, COX-2, PGE2) were measured. Results Uptake of short fibers occurred more readily than for long, but long fibers were more potent stimulators of inflammatory molecules. Stimulation resulted in dose-dependent secretion of inflammatory biomolecules but no cytotoxicity or strong ROS production. Linear cytokine dose-response curves evaluated with length-dependent potency models, using measured fiber length distributions, resulted in identification of critical fiber lengths that cause frustrated phagocytosis and increased inflammatory biomolecule production. Conclusion Short fibers played a minor role in the inflammatory response compared to long fibers. The critical lengths at which frustrated phagocytosis occurs can be quantified by fitting dose-response curves to fiber distribution data. PMID:27784615

Lavandula angustifolia Mill. Essential Oil Exerts Antibacterial and Anti-Inflammatory Effect in Macrophage Mediated Immune Response to Staphylococcus aureus.

PubMed

Giovannini, D; Gismondi, A; Basso, A; Canuti, L; Braglia, R; Canini, A; Mariani, F; Cappelli, G

2016-01-01

Different studies described the antibacterial properties of Lavandula angustifolia (Mill.) essential oil and its anti-inflammatory effects. Besides, no data exist on its ability to activate human macrophages during the innate response against Staphylococcus aureus. The discovery of promising regulators of macrophage-mediated inflammatory response, without side effects, could be useful for the prevention of, or as therapeutic remedy for, various inflammation-mediated diseases. This study investigated, by transcriptional analysis, how a L. angustifolia essential oil treatment influences the macrophage response to Staphylococcus aureus infection. The results showed that the treatment increases the phagocytic rate and stimulates the containment of intracellular bacterial replication by macrophages. Our data showed that this stimulation is coupled with expression of genes involved in reactive oxygen species production (i.e., CYBB and NCF4). Moreover, the essential oil treatment balanced the inflammatory signaling induced by S. aureus by repressing the principal pro-inflammatory cytokines and their receptors and inducing the heme oxygenase-1 gene transcription. These data showed that the L. angustifolia essential oil can stimulate the human innate macrophage response to a bacterium which is responsible for one of the most important nosocomial infection and might suggest the potential development of this plant extract as an anti-inflammatory and immune regulatory coadjutant drug.

Maternal Microbe-Specific Modulation of Inflammatory Response in Extremely Low-Gestational-Age Newborns

PubMed Central

Fichorova, Raina N.; Onderdonk, Andrew B.; Yamamoto, Hidemi; Delaney, Mary L.; DuBois, Andrea M.; Allred, Elizabeth; Leviton, Alan

2011-01-01

The fetal response to intrauterine inflammatory stimuli appears to contribute to the onset of preterm labor as well as fetal injury, especially affecting newborns of extremely low gestational age. To investigate the role of placental colonization by specific groups of microorganisms in the development of inflammatory responses present at birth, we analyzed 25 protein biomarkers in dry blood spots obtained from 527 newborns delivered by Caesarean section in the 23rd to 27th gestation weeks. Bacteria were detected in placentas and characterized by culture techniques. Odds ratios for having protein concentrations in the top quartile for gestation age for individual and groups of microorganisms were calculated. Mixed bacterial vaginosis (BV) organisms were associated with a proinflammatory pattern similar to those of infectious facultative anaerobes. Prevotella and Gardnerella species, anaerobic streptococci, peptostreptococci, and genital mycoplasmas each appeared to be associated with a different pattern of elevated blood levels of inflammation-related proteins. Lactobacillus was associated with low odds of an inflammatory response. This study provides evidence that microorganisms colonizing the placenta provoke distinctive newborn inflammatory responses and that Lactobacillus may suppress these responses. PMID:21264056

Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

PubMed

Chen, Xiong; Cai, Xueding; Le, Rongrong; Zhang, Man; Gu, Xuemei; Shen, Feixia; Hong, Guangliang; Chen, Zimiao

2018-02-05

Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries. Copyright © 2017. Published by Elsevier Inc.

Dyadic confirmatory factor analysis of the inflammatory bowel disease family responsibility questionnaire.

PubMed

Greenley, Rachel Neff; Reed-Knight, Bonney; Blount, Ronald L; Wilson, Helen W

2013-09-01

Evaluate the factor structure of youth and maternal involvement ratings on the Inflammatory Bowel Disease Family Responsibility Questionnaire, a measure of family allocation of condition management responsibilities in pediatric inflammatory bowel disease. Participants included 251 youth aged 11-18 years with inflammatory bowel disease and their mothers. Item-level descriptive analyses, subscale internal consistency estimates, and confirmatory factor analyses of youth and maternal involvement were conducted using a dyadic data-analytic approach. Results supported the validity of 4 conceptually derived subscales including general health maintenance, social aspects, condition management tasks, and nutrition domains. Additionally, results indicated adequate support for the factor structure of a 21-item youth involvement measure and strong support for a 16-item maternal involvement measure. Additional empirical support for the validity of the Inflammatory Bowel Disease Family Responsibility Questionnaire was provided. Future research to replicate current findings and to examine the measure's clinical utility is warranted.

Immunopathological Patterns from EAE and Theiler’s Virus Infection: Is Multiple Sclerosis a Homogenous 1-stage or Heterogenous 2-stage Disease?

PubMed Central

Martinez, Nicholas E.; Sato, Fumitaka; Omura, Seiichi; Minagar, Alireza; Alexander, J. Steven; Tsunoda, Ikuo

2012-01-01

Multiple sclerosis (MS) is a disease which can present in different clinical courses. The most common form of MS is the relapsing-remitting (RR) course, which in many cases evolves into secondary progressive (SP) disease. Autoimmune models such as experimental autoimmune encephalomyelitis (EAE) have been developed to represent the various clinical forms of MS. These models along with clinico-pathological evidence obtained from MS patients have allowed us to propose ‘1-stage’ and ‘2-stage’ disease theories to explain the transition in the clinical course of MS from RR to SP. Relapses in MS are associated with pro-inflammatory T helper (Th) 1/Th17 immune responses, while remissions are associated with anti-inflammatory Th2/regulatory T (Treg) immune responses. Based on the ‘1-stage disease’ theory, the transition from RR to SP disease occurs when the inflammatory immune response overwhelms the anti-inflammatory immune response. The ‘2-stage disease’ theory proposes that the transition from RR to SP-MS occurs when the Th2 response or some other responses overwhelm the inflammatory response resulting in the sustained production of anti-myelin antibodies, which cause continuing demyelination, neurodegeneration, and axonal loss. The Theiler’s virus model is also a 2-stage disease, where axonal degeneration precedes demyelination during the first stage, followed by inflammatory demyelination during the second stage. PMID:22633747

A multiscale modeling approach to inflammation: A case study in human endotoxemia

NASA Astrophysics Data System (ADS)

Scheff, Jeremy D.; Mavroudis, Panteleimon D.; Foteinou, Panagiota T.; An, Gary; Calvano, Steve E.; Doyle, John; Dick, Thomas E.; Lowry, Stephen F.; Vodovotz, Yoram; Androulakis, Ioannis P.

2013-07-01

Inflammation is a critical component in the body's response to injury. A dysregulated inflammatory response, in which either the injury is not repaired or the inflammatory response does not appropriately self-regulate and end, is associated with a wide range of inflammatory diseases such as sepsis. Clinical management of sepsis is a significant problem, but progress in this area has been slow. This may be due to the inherent nonlinearities and complexities in the interacting multiscale pathways that are activated in response to systemic inflammation, motivating the application of systems biology techniques to better understand the inflammatory response. Here, we review our past work on a multiscale modeling approach applied to human endotoxemia, a model of systemic inflammation, consisting of a system of compartmentalized differential equations operating at different time scales and through a discrete model linking inflammatory mediators with changing patterns in the beating of the heart, which has been correlated with outcome and severity of inflammatory disease despite unclear mechanistic underpinnings. Working towards unraveling the relationship between inflammation and heart rate variability (HRV) may enable greater understanding of clinical observations as well as novel therapeutic targets.

Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation.

PubMed

Pariollaud, Marie; Gibbs, Julie E; Hopwood, Thomas W; Brown, Sheila; Begley, Nicola; Vonslow, Ryan; Poolman, Toryn; Guo, Baoqiang; Saer, Ben; Jones, D Heulyn; Tellam, James P; Bresciani, Stefano; Tomkinson, Nicholas Co; Wojno-Picon, Justyna; Cooper, Anthony Wj; Daniels, Dion A; Trump, Ryan P; Grant, Daniel; Zuercher, William; Willson, Timothy M; MacDonald, Andrew S; Bolognese, Brian; Podolin, Patricia L; Sanchez, Yolanda; Loudon, Andrew Si; Ray, David W

2018-06-01

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBβ alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

PubMed Central

2017-01-01

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity. PMID:28154473

Chronic stress enhances progression of periodontitis via α1-adrenergic signaling: a potential target for periodontal disease therapy.

PubMed

Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan

2014-10-17

This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the α1-adrenergic receptor (α1-AR) and β2-adrenergic receptor (β2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of α1-AR and β2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1β, IL-6 and IL-8 were detected after pretreatment with the α1/β2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, α1-AR and β2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of α1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of α1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1β, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an α1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.

Glycogen synthase kinase-3β (GSK3β) inhibition suppresses the inflammatory response to Francisella infection and protects against tularemia in mice

PubMed Central

Zhang, Ping; Katz, Jenny; Michalek, Suzanne M.

2011-01-01

Francisella tularensis, the causative agent of tularemia, is currently considered a category A bioterrorism agent due to its high virulence. Infection with F. tularensis results in an inflammatory response that plays an important role in the pathogenesis of the disease; however, the cellular mechanisms regulating this response are poorly understood. Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. In this study, we investigated the effect of GSK3β inhibition in regulating F. tularensis LVS-induced inflammatory responses. F. tularensis LVS infection of murine peritoneal macrophages induced a TLR2 dependent phosphorylation of GSK3β. Inhibition of GSK3β resulted in a significant decrease in the production of pro-inflammatory cytokine IL-6, IL-12p40 and TNF-α, as well as a significant increase in the production of the anti-inflammatory cytokine IL-10. GSK3β regulated the F. tularensis LVS-induced cytokine response by differentially affecting the activation of transcription factors NF-κB and CREB. Inhibition of GSK3β by lithium in vivo suppressed the inflammatory response in mice infected with F. tularensis LVS and conferred a survival advantage. In addition, we show that the production of IFN-γ contributed to the development of tularemia and to the fatal outcome of the infected animals, depending on the timing and the relative level of the IFN-γ produced. IFN-γ potentiated F. tularensis LVS-induced cytokine production by increasing GSK3β activity and the nuclear translocation of NF-κB. Taken together, these results demonstrate a regulatory function of GSK3β in modulating inflammatory responses that can be detrimental to the host during an F. tularensis LVS infection, and suggest that inhibition of GSK3β may represent a novel therapeutic approach in the treatment of tularemia. PMID:18929413

Inflammatory peeling skin syndrome caused a novel mutation in CDSN.

PubMed

Telem, Dana Fuchs; Israeli, Shirli; Sarig, Ofer; Sprecher, Eli

2012-04-01

Generalized peeling skin syndrome (PSS) is a rare autosomal recessive dermatosis manifesting with continuous exfoliation of the stratum corneum. The inflammatory (type B) subtype of PSS was recently found to be caused by deleterious mutations in the CDSN gene encoding corneodesmosin, a major component of desmosomal junctions in the uppermost layers of the epidermis. In the present study, we assessed a 10-month-old baby, who presented with generalized superficial peeling of the skin. Using PCR amplification and direct sequencing, we identified the third PSS-associated mutation in CDSN, a homozygous 4 bp duplication in the second exon of the gene (c.164_167dup GCCT; p.Thr57ProfsX6). These data further support the notion that corneodesmosin deficiency impairs cell-cell adhesion in the upper epidermis, paving the way for an abnormal inflammatory response due to epidermal barrier disruption.

Bioactive Extract from Moringa oleifera Inhibits the Pro-inflammatory Mediators in Lipopolysaccharide Stimulated Macrophages

PubMed Central

Fard, Masoumeh Tangestani; Arulselvan, Palanisamy; Karthivashan, Govindarajan; Adam, Siti Khadijah; Fakurazi, Sharida

2015-01-01

Introduction: Inflammation is a well-known physiological response to protect the body against infection and restore tissue injury. Nevertheless, the chronic inflammation can trigger various inflammatory associated diseases/disorder. Moringa oleifera is a widely grown plant in most tropical countries and it has been recognized traditionally for several medicinal benefits. Objectives: The objective of this study was to investigate the anti-inflammatory properties of M. oleifera extract on lipopolysaccharide (LPS) - stimulated macrophages. Materials and Methods: The anti-inflammatory effect of M. oleifera hydroethanolic bioactive leaves extracts was evaluated by assessing the inhibition of nitric oxide (NO) production during Griess reaction and the expression of pro-inflammatory mediators in macrophages. Results: Interestingly, we found that M. oleifera hydroethanolic bioactive leaves extract significantly inhibited the secretion of NO production and other inflammatory markers such as prostaglandin E2, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β. Meanwhile, the bioactive extract has induced the production of IL-10 in a dose-dependent manner. In addition, M. oleifera hydroethanolic bioactive leaves extract effectively suppressed the protein expression of inflammatory markers inducible NO synthase, cyclooxygenase-2, and nuclear factor kappa-light-chain-enhancer of activated B-cells p65 in LPS-induced RAW264.7 macrophages in a dose-dependent manner. Conclusion: These findings support the traditional use of M. oleifera plant as an effective treatment for inflammation associated diseases/disorders. SUMMARY Hydroethanolic extracts of Moringa oleifera effectively inhibit the NO production in LPS induced inflammatory model.M. oleifera crude extracts successfully modulate the production of pro-inflammatory mediators in LPS stimulated macrophages.M. oleifera extracts suppressed the expression of inflammatory mediators in LPS stimulated macrophages. PMID:27013794

Inflammatory Mechanisms and Oxidative Stress as Key Factors Responsible for Progression of Neurodegeneration: Role of Brain Innate Immune System.

PubMed

Leszek, Jerzy; Barreto, George E; Gąsiorowski, Kazimierz; Koutsouraki, Euphrosyni; Ávila-Rodrigues, Marco; Aliev, Gjumrakch

2016-01-01

Chronic inflammation is characterized by longstanding microglial activation followed by sustained release of inflammatory mediators, which aid in enhanced nitrosative and oxidative stress. The sustained release of inflammatory mediators propels the inflammatory cycle by increased microglial activation, promoting their proliferation and thus stimulating enhanced release of inflammatory factors. Elevated levels of several cytokines and chronic neuroinflammation have been associated with many neurodegenerative disorders of central nervous system like age-related macular degeneration, Alzheimer disease, multiple sclerosis, Parkinson's disease, Huntington' disease, and tauopathies. This review highlights the basic mechanisms of neuroinflammation, the characteristics of neurodegenerative diseases, and the main immunologic responses in CNS neurodegenerative disorders. A comprehensive outline for the crucial role of microglia in neuroinflammation and neurodegeneration and the role of Toll-like receptor signalling in coexistence of inflammatory mechanisms and oxidative stress as major factors responsible for progression of neurodegeneration have also been presented.

Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia

PubMed Central

Torgrimson-Ojerio, Britta; Ross, Rebecca L.; Dieckman, Nathaniel F.; Avery, Stephanie; Bennett, Robert M.; Jones, Kim D.; Guarino, Anthony J.; Wood, Lisa J.

2014-01-01

Exercise intolerance, as evidenced by a worsening of pain, fatigue, and stiffness after novel exertion, is a key feature of fibromyalgia (FM). In this pilot study, we investigate whether; insufficient muscle repair processes and impaired anti-inflammatory mechanisms result in an exaggerated pro-inflammatory cytokine response to exhaustive exercise, and consequently a worsening of muscle pain, stiffness and fatigue in the days post-exercise. We measured changes in muscle pain and tenderness, fatigue, stiffness, and serum levels of neuroendocrine and inflammatory cytokine markers in 20 women with FM and 16 healthy controls (HCs) before and after exhaustive treadmill exercise. Compared to HCs, FM participants failed to mount the expected anti-inflammatory response to exercise and experienced a worsening of symptoms post-exercise. However, changes in post-exertional symptoms were not mediated by post-exertional changes in pro-inflammatory cytokine levels. Implications of these findings are discussed. PMID:25457842

Harnessing and Modulating Inflammation in Strategies for Bone Regeneration

PubMed Central

Mountziaris, Paschalia M.; Spicer, Patrick P.; Kasper, F. Kurtis

2011-01-01

Inflammation is an immediate response that plays a critical role in healing after fracture or injury to bone. However, in certain clinical contexts, such as in inflammatory diseases or in response to the implantation of a biomedical device, the inflammatory response may become chronic and result in destructive catabolic effects on the bone tissue. Since our previous review 3 years ago, which identified inflammatory signals critical for bone regeneration and described the inhibitory effects of anti-inflammatory agents on bone healing, a multitude of studies have been published exploring various aspects of this emerging field. In this review, we distinguish between regenerative and damaging inflammatory processes in bone, update our discussion of the effects of anti-inflammatory agents on bone healing, summarize recent in vitro and in vivo studies demonstrating how inflammation can be modulated to stimulate bone regeneration, and identify key future directions in the field. PMID:21615330

Unilateral renal ischaemia in rats induces a rapid secretion of inflammatory markers to renal lymph and increased capillary permeability

PubMed Central

Bivol, Liliana Monica; Iversen, Bjarne Magnus; Hultström, Michael; Wallace, Paal William; Reed, Rolf Kåre

2015-01-01

Key points Transient reduction in renal blood flow results in inflammation and is a primary cause of acute kidney injury, thereby representing a major clinical problem.It is not known whether the inflammatory reaction is local only or part of a systemic response.We accessed the renal microenvironment through isolation of lymph and were in this way able to investigate whether the inflammatory reaction is local or systemic.Transient ischaemia followed by reperfusion resulted in a rapid production of inflammatory mediators locally in the renal interstitium.We moreover showed that the injury response affected the glomerular as well as the non‐glomerular barrier and resulted in a reduced size and charge selectivity of the glomerular capillaries. Abstract A better understanding of the inflammatory process associated with renal ischaemia–reperfusion (IR) injury may be clinically important. In this study we examined the role of the kidney in production of inflammatory mediators by analysing renal lymph after 30 min unilateral occlusion of renal artery followed by 120 min reperfusion, as well as the effect of IR on size selectivity for proteins in both glomerular and peritubular capillaries. All measured mediators increased dramatically in renal hilar lymph, plasma and renal cortical tissue samples and returned to control levels after 120 min reperfusion. The responses were differentiated; interleukin‐1β, monocyte chemoattractant protein‐1 and leptin were markedly increased in plasma before reperfusion, reflecting an extrarenal response possibly induced by afferent renal nerve activity from the ischaemic kidney. Tumour necrosis factor‐α  was the only mediator showing elevated lymph‐to‐plasma ratio following 30 min reperfusion, indicating that most cytokines were released directly into the bloodstream. The IR‐induced rise in cytokine levels was paralleled by a significant increase in high molecular weight plasma proteins in both lymph and urine. The latter was shown as a 14‐ to 166‐fold increase in glomerular sieving coefficient of plasma proteins assessed by a novel proteomic approach, and indicated a temporarily reduced size selectivity of both glomerular and peritubular capillaries. Collectively, our data suggest that cytokines from the ischaemic kidney explain most of the rise in plasma concentration, and that the locally produced substances enter the systemic circulation through transport directly to plasma and not via the interstitium to lymph. PMID:26584508

Cytokine responses induced by diesel exhaust particles are suppressed by PAR-2 silencing and antioxidant treatment, and driven by polar and non-polar soluble constituents.

PubMed

Bach, Nicolai; Bølling, Anette Kocbach; Brinchmann, Bendik C; Totlandsdal, Annike I; Skuland, Tonje; Holme, Jørn A; Låg, Marit; Schwarze, Per E; Øvrevik, Johan

2015-10-14

Adsorbed soluble organics seem to be the main drivers of inflammatory responses induced by diesel exhaust particles (DEP). The specific compounds contributing to this process and the cellular mechanisms behind DEP-induced inflammation are not well known. We have assessed pro-inflammatory effects of DEP and various soluble DEP fractions, in human bronchial epithelial cells (BEAS-2B). DEP increased the expression of interleukin (IL)-6 and CXCL8. Silencing of the aryl hydrocarbon receptor (AhR) by siRNA or pretreatment with AhR-antagonists did not attenuate DEP-induced IL-6 and CXCL8 responses. However, the halogenated aromatic hydrocarbon (HAH)-selective AhR antagonist CH223191 caused a considerable reduction in DEP-induced CYP1A1 expression indicating that this response may be due to dioxin or dioxin-like constituents in DEP. Knock-down of protease activated receptor (PAR)-2 attenuated IL-6 responses without affecting CXCL8. Antioxidants did not affect IL-6 expression after 4h DEP-exposure and only partly reduced CXCL8 expression. However, after 24h exposure antioxidant treatment partly suppressed IL-6 protein release and completely blocked CXCL8 release. Furthermore, a heptane-soluble (non-polar) extract of DEP induced both IL-6 and CXCL8 release, whereas a PBS-soluble (highly polar) extract induced only IL-6. Thus, pro-inflammatory responses in DEP-exposed epithelial cells appear to be the result of both reactive oxygen species and receptor signaling, mediated through combinatorial effects between both non-polar and polar constituents adhered to the particle surface. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Hyperoxic exposure of immature mice increases the inflammatory response to subsequent rhinovirus infection: Association with danger signals

PubMed Central

Cui, Tracy X.; Maheshwer, Bhargavi; Hong, Jun Y.; Goldsmith, Adam M.; Bentley, J. Kelley; Popova, Antonia P.

2016-01-01

Infants with a history of prematurity and bronchopulmonary dysplasia (BPD) have a high risk of asthma and viral-induced exacerbations later in life. We hypothesized that hyperoxic exposure, a predisposing factor to BPD, modulates the innate immune response, producing an exaggerated pro-inflammatory reaction to viral infection. Two-to-3 day-old C57BL/6J mice were exposed to air or 75% oxygen for 14 days. Mice were infected intranasally with rhinovirus (RV) immediately after O2 exposure. Lung mRNA and protein expression, histology, dendritic cells (DCs) and airways responsiveness were assessed 1-12 days after infection. Tracheal aspirates from premature human infants were collected for mRNA detection. Hyperoxia increased lung IL-12 expression which persisted up to 12 days post-exposure. Hyperoxia-exposed RV-infected mice showed further increases in IL-12 and increased expression of IFN-γ, TNF-α, CCL2, CCL3 and CCL4, as well as increased airway inflammation and responsiveness. In RV-infected, air-exposed mice the response was not significant. Induced IL-12 expression in hyperoxia-exposed, RV-infected mice was associated with increased IL-12-producing CD103+ lung DCs. Hyperoxia also increased expression of Clec9a, a CD103+ DC-specific damaged cell-recognition molecule. Hyperoxia increased levels of ATP metabolites and expression of adenosine receptor A1, further evidence of cell damage and related signaling. In human preterm infants, tracheal aspirate Clec9a expression positively correlated with the level of prematurity. Hyperoxic exposure increases the activation of CD103+, Clec9a+ DCs, leading to increased inflammation and airway hyperresponsiveness upon RV infection. In premature infants, danger signal-induced DC activation may promote pro-inflammatory airway responses, thereby increasing respiratory morbidity. PMID:27183577

Age-related differences in pulmonary inflammatory responses to JP-8 jet fuel aerosol inhalation.

PubMed

Wang, S; Young, R S; Witten, M L

2001-02-01

Our previous studies have demonstrated that JP-8 jet fuel aerosol inhalation induced lung injury and dysfunction. To further examine JP-8 jet fuel-induced inflammatory mechanisms, a total of 40 male C57BL/6 mice (young, 3.5 months; adult, 12 months; half in each age group) were randomly assigned to the exposure or control groups. Mice were nose-only exposed to room air or atmospheres of 1000 mg/m3 JP-8 jet fuel for 1 h/day for 7 days. Lung injury was assessed by pulmonary mechanics, respiratory permeability, lavaged cell profile, and chemical mediators in bronchoalveolar lavage fluid (BALF). The young and adult mice exposed to JP-8 jet fuel had similar values with regards to increased lung dynamic compliance, lung permeability, BALF cell count, and decreased PGE2. However, there were several different responses between the young-versus-adult mice with respect to BALF cell differential, TNF-alpha, and 8-iso-PGF2,, levels after exposure to JP-8 jet fuel. These data suggest that JP-8 jet fuel may have different inflammatory mechanisms leading to lung injury and dysfunction in the younger-versus-adult mice.

Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine.

PubMed

McILwain, R Britt; Timpa, Joseph G; Kurundkar, Ashish R; Holt, David W; Kelly, David R; Hartman, Yolanda E; Neel, Mary Lauren; Karnatak, Rajendra K; Schelonka, Robert L; Anantharamaiah, G M; Killingsworth, Cheryl R; Maheshwari, Akhil

2010-01-01

Extracorporeal membrane oxygenation (ECMO) is a life-saving support system used in neonates and young children with severe cardiorespiratory failure. Although ECMO has reduced mortality in these critically ill patients, almost all patients treated with ECMO develop a systemic inflammatory response syndrome (SIRS) characterized by a 'cytokine storm', leukocyte activation, and multisystem organ dysfunction. We used a neonatal porcine model of ECMO to investigate whether rising plasma concentrations of inflammatory cytokines during ECMO reflect de novo synthesis of these mediators in inflamed tissues, and therefore, can be used to assess the severity of ECMO-related SIRS. Previously healthy piglets (3-week-old) were subjected to venoarterial ECMO for up to 8 h. SIRS was assessed by histopathological analysis, measurement of neutrophil activation (flow cytometry), plasma cytokine concentrations (enzyme immunoassays), and tissue expression of inflammatory genes (PCR/western blots). Mast cell degranulation was investigated by measurement of plasma tryptase activity. Porcine neonatal ECMO was associated with systemic inflammatory changes similar to those seen in human neonates. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) concentrations rose rapidly during the first 2 h of ECMO, faster than the tissue expression of these cytokines. ECMO was associated with increased plasma mast cell tryptase activity, indicating that increased plasma concentrations of inflammatory cytokines during ECMO may result from mast cell degranulation and associated release of preformed cytokines stored in mast cells. TNF-alpha and IL-8 concentrations rose faster in plasma than in the peripheral tissues during ECMO, indicating that rising plasma levels of these cytokines immediately after the initiation of ECMO may not reflect increasing tissue synthesis of these cytokines. Mobilization of preformed cellular stores of inflammatory cytokines such as in mucosal mast cells may have an important pathophysiological role in ECMO-related SIRS.

Corrosion and mechanical performance of AZ91 exposed to simulated inflammatory conditions.

PubMed

Brooks, Emily K; Der, Stephanie; Ehrensberger, Mark T

2016-03-01

Magnesium (Mg) and its alloys, including Mg-9%Al-1%Zn (AZ91), are biodegradable metals with potential use as temporary orthopedic implants. Invasive orthopedic procedures can provoke an inflammatory response that produces hydrogen peroxide (H2O2) and an acidic environment near the implant. This study assessed the influence of inflammation on both the corrosion and mechanical properties of AZ91. The AZ91 samples in the inflammatory protocol were immersed for three days in a complex biologically relevant electrolyte (AMEM culture media) that contained serum proteins (FBS), 150 mM of H2O2, and was titrated to a pH of 5. The control protocol immersed AZ91 samples in the same biologically relevant electrolyte (AMEM & FBS) but without H2O2 and the acid titration. After 3 days all samples were switched into fresh AMEM & FBS for an additional 3-day immersion. During the initial immersion, inflammatory protocol samples showed increased corrosion rate determined by mass loss testing, increased Mg and Al ion released to solution, and a completely corroded surface morphology as compared to the control protocol. Although corrosion in both protocols slowed once the test electrolyte solution was replaced at 3 days, the samples originally exposed to the simulated inflammatory conditions continued to display enhanced corrosion rates as compared to the control protocol. These lingering effects may indicate the initial inflammatory corrosion processes modified components of the surface oxide and corrosion film or initiated aggressive localized processes that subsequently left the interface more vulnerable to continued enhanced corrosion. The electrochemical properties of the interfaces were also evaluated by EIS, which found that the corrosion characteristics of the AZ91 samples were potentially influenced by the role of intermediate adsorption layer processes. The increased corrosion observed for the inflammatory protocol did not affect the flexural mechanical properties of the AZ91 at any time point assessed. Copyright © 2015 Elsevier B.V. All rights reserved.

Underlying chronic inflammation alters the profile and mechanisms of acute neutrophil recruitment.

PubMed

Ma, Bin; Whiteford, James R; Nourshargh, Sussan; Woodfin, Abigail

2016-11-01

Chronically inflamed tissues show altered characteristics that include persistent populations of inflammatory leukocytes and remodelling of the vascular network. As the majority of studies on leukocyte recruitment have been carried out in normal healthy tissues, the impact of underlying chronic inflammation on ongoing leukocyte recruitment is largely unknown. Here, we investigate the profile and mechanisms of acute inflammatory responses in chronically inflamed and angiogenic tissues, and consider the implications for chronic inflammatory disorders. We have developed a novel model of chronic ischaemia of the mouse cremaster muscle that is characterized by a persistent population of monocyte-derived cells (MDCs), and capillary angiogenesis. These tissues also show elevated acute neutrophil recruitment in response to locally administered inflammatory stimuli. We determined that Gr1 low MDCs, which are widely considered to have anti-inflammatory and reparative functions, amplified acute inflammatory reactions via the generation of additional proinflammatory signals, changing both the profile and magnitude of the tissue response. Similar vascular and inflammatory responses, including activation of MDCs by transient ischaemia-reperfusion, were observed in mouse hindlimbs subjected to chronic ischaemia. This response demonstrates the relevance of the findings to peripheral arterial disease, in which patients experience transient exercise-induced ischaemia known as claudication.These findings demonstrate that chronically inflamed tissues show an altered profile and altered mechanisms of acute inflammatory responses, and identify tissue-resident MDCs as potential therapeutic targets. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Central activation of the cholinergic anti-inflammatory pathway reduces surgical inflammation in experimental post-operative ileus

PubMed Central

The, FO; Cailotto, C; van der Vliet, J; de Jonge, WJ; Bennink, RJ; Buijs, RM; Boeckxstaens, GE

2011-01-01

BACKGROUND AND PURPOSE Electrical stimulation of the vagus nerve reduces intestinal inflammation following mechanical handling, thereby shortening post-operative ileus in mice. Previous studies in a sepsis model showed that this cholinergic anti-inflammatory pathway can be activated pharmacologically by central administration of semapimod, an inhibitor of p38 mitogen-activated protein kinase. We therefore evaluated the effect of intracerebroventricular (i.c.v.) semapimod on intestinal inflammation and post-operative ileus in mice. EXPERIMENTAL APPROACH Mice underwent a laparotomy or intestinal manipulation 1 h after i.c.v. pre-treatment with semapimod (1 µg·kg−1) or saline. Drugs were administered through a cannula placed in the left lateral ventricle 1 week prior to experimentation. Twenty-four hours after surgery, gastric emptying was measured using scintigraphy, and the degree of intestinal inflammation was assessed. Finally, activation of brain regions was assessed using quantitative immunohistochemistry for c-fos. KEY RESULTS Intestinal manipulation induced inflammation of the manipulated intestine and significantly delayed gastric emptying, 24 h after surgery in saline-treated animals. Semapimod significantly reduced this inflammation and improved gastric emptying. Vagotomy enhanced the inflammatory response induced by intestinal manipulation and abolished the anti-inflammatory effect of semapimod. Semapimod but not saline induced a significant increase in c-fos expression in the paraventricular nucleus, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve. CONCLUSIONS AND IMPLICATIONS Our findings show that i.c.v. semapimod reduces manipulation-induced intestinal inflammation and prevented post-operative ileus. This anti-inflammatory effect depends on central activation of the vagus nerve. PMID:21371006

Luteinized unruptured follicle syndrome increased by inactive disease and selective cyclooxygenase 2 inhibitors in women with inflammatory arthropathies.

PubMed

Micu, Mihaela C; Micu, Romeo; Ostensen, Monika

2011-09-01

Administration of nonsteroidal antiinflammatory drugs (NSAIDs) may impair fertility. The occurrence of the luteinized unruptured follicle (LUF) syndrome was assessed in women with inflammatory arthropathies exposed to NSAIDs and compared to that in nonexposed women. Fourteen patients with inflammatory rheumatic disease, 29 women with noninflammatory musculoskeletal conditions, and 449 women not exposed to NSAIDs were studied by intravaginal ultrasound monitoring for follicular development and ovulation in 1 or more menstrual cycles. Disease activity was assessed in inflammatory rheumatic disease. In 59 monitored cycles of patients with continuous NSAID exposure, 35.6% of LUF syndromes occurred compared to 3.4% of LUF syndromes in untreated women (P < 0.001). Etoricoxib was responsible for 75% of LUF syndromes in patients exposed continuously, whereas diclofenac generated 15% of LUF syndromes. An ibuprofen dosage of 1,600 mg/day did not induce LUF syndrome either at continuous periovulatory or discontinuous exposure. Interestingly, the frequency of LUF syndrome was 46.2% in patients with inactive inflammatory disease compared to 15% in patients with active disease (P = 0.023). Etoricoxib generated LUF syndrome in 94.2% of the cases with inactive disease versus 28.6% in patients with active disease (P = 0.003). NSAIDs increased the risk of the LUF syndrome, particularly in patients with inactive disease. The selective cyclooxygenase 2 (COX-2) inhibitor etoricoxib was a more potent inductor of LUF syndrome than nonselective COX inhibitors. Continuous periovulatory exposure to NSAIDs should be avoided when planning a pregnancy in patients with rheumatic diseases. Copyright © 2011 by the American College of Rheumatology.

Capsular Polysaccharide is a Main Component of Mycoplasma ovipneumoniae in the Pathogen-Induced Toll-Like Receptor-Mediated Inflammatory Responses in Sheep Airway Epithelial Cells

PubMed Central

Jiang, Zhongjia; Song, Fuyang; Li, Yanan; Xue, Di; Deng, Guangcun; Li, Min

2017-01-01

Mycoplasma ovipneumoniae (M. ovipneumoniae) is characterized as an etiological agent of primary atypical pneumonia that specifically infects sheep and goat. In an attempt to better understand the pathogen-host interaction between the invading M. ovipneumoniae and airway epithelial cells, we investigated the host inflammatory responses against capsular polysaccharide (designated as CPS) of M. ovipneumoniae using sheep bronchial epithelial cells cultured in an air-liquid interface (ALI) model. Results showed that CPS derived from M. ovipneumoniae could activate toll-like receptor- (TLR-) mediated inflammatory responses, along with an elevated expression of nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factor 3 (IRF3) as well as various inflammatory-associated mediators, representatively including proinflammatory cytokines, such as IL1β, TNFα, and IL8, and anti-inflammatory cytokines such as IL10 and TGFβ of TLR signaling cascade. Mechanistically, the CPS-induced inflammation was TLR initiated and was mediated by activations of both MyD88-dependent and MyD88-independent signaling pathways. Of importance, a blockage of CPS with specific antibody led a significant reduction of M. ovipneumoniae-induced inflammatory responses in sheep bronchial epithelial cells. These results suggested that CPS is a key virulent component of M. ovipneumoniae, which may play a crucial role in the inflammatory response induced by M. ovipneumoniae infections. PMID:28553017

Sex Differences in the Association between Stressor-Evoked Interleukin-6 Reactivity and C-Reactive Protein

PubMed Central

Lockwood, Kimberly G.; Marsland, Anna L.; Cohen, Sheldon; Gianaros, Peter J.

2016-01-01

Individuals differ consistently in the magnitude of their inflammatory responses to acute stressors, with females often showing larger responses than males. While the clinical significance of these individual differences remains unclear, it may be that greater inflammatory responses relate to increased systemic inflammation and thereby risk for chronic inflammatory disease. Here, we examined whether acute stressor-evoked interleukin (IL)-6 responses associate with resting levels of C-reactive protein (CRP), a marker of systemic inflammation, and whether this association differs by sex. Subjects were 57 healthy midlife adults (30–51 years; 33% female; 68% white). Blood was drawn before and 30-min after two mental stress tasks: a multisource interference task and a Stroop color word task. Hierarchical regressions controlling for age, sex, race, and BMI tested whether stressor-evoked IL-6 responses were associated with resting CRP and whether this association differed by sex. Results indicated that sex and stressor-evoked IL-6 responses interacted to predict CRP (ΔR2 = .08, B = −1.33, β = −.39, p = .02). In males, larger stressor-evoked IL-6 responses associated with higher CRP, whereas in females, stressor-evoked IL-6 responses showed a non-significant negative association with CRP. These findings indicate that inflammatory responses to acute stressors associate with resting levels of CRP; however, this association differs by sex. Previous literature suggests that there are sex differences in stressor-evoked IL-6 responses, but this is the first study to show sex differences in the relationship between acute inflammatory responses and systemic inflammation. The contribution of these sex differences to inflammatory disease risk warrants further investigation. PMID:27377561

Inflammation responses in patients with pulmonary tuberculosis in an intensive care unit

PubMed Central

Liu, Qiu-Yue; Han, Fen; Pan, Li-Ping; Jia, Hong-Yan; Li, Qi; Zhang, Zong-De

2018-01-01

Pulmonary tuberculosis caused by Mycobacterium tuberculosis remains a global problem. Inflammatory responses are the primary characteristics of patients with pulmonary tuberculosis in intensive care units (ICU). The aim of the present study was to investigate the clinical importance of inflammatory cells and factors for patients with pulmonary tuberculosis in ICU. A total of 124 patients with pulmonary tuberculosis in ICU were recruited for the present study. The inflammatory responses in patients with pulmonary tuberculosis in ICU were examined by changes in inflammatory cells and factors in the serum. The results indicated that serum levels of lymphocytes, plasma cells, granulocytes and monocytes were increased in patients with pulmonary tuberculosis in ICU compared with healthy controls. The serum levels of inflammatory factors interleukin (IL)-1, IL-6, IL-10, IL-12, and IL-4 were upregulated in patients with pulmonary tuberculosis in ICU. Lower plasma concentrations of IL-2, IL-15 and interferon-γ were detected in patients with pulmonary tuberculosis compared with healthy controls. It was demonstrated that high mobility group box-1 protein expression levels were higher in the serum of patients with pulmonary tuberculosis compared with healthy controls. Notably, an imbalance of T-helper cell (Th)1/Th2 cytokines was observed in patients with pulmonary tuberculosis. Pulmonary tuberculosis caused by M. tuberculosis also upregulated expression of matrix metalloproteinase (MMP)-1 and MMP-9 in hPMCs. In conclusion, these outcomes demonstrated that inflammatory responses and inflammatory factors are associated with the progression of pulmonary tuberculosis, suggesting that inhibition of inflammatory responses and inflammatory factors may be beneficial for the treatment of patients with pulmonary tuberculosis in ICU. PMID:29456674

Induced Pluripotent Stem Cell‐Derived Endothelial Cells Overexpressing Interleukin‐8 Receptors A/B and/or C‐C Chemokine Receptors 2/5 Inhibit Vascular Injury Response

PubMed Central

Giordano, Samantha; Zhao, Xiangmin; Chen, Yiu‐Fai; Litovsky, Silvio H.; Hage, Fadi G.; Townes, Tim M.; Sun, Chiao‐Wang; Wu, Li‐Chen; Oparil, Suzanne

2017-01-01

Abstract Recruitment of neutrophils and monocytes/macrophages to the site of vascular injury is mediated by binding of chemoattractants to interleukin (IL) 8 receptors RA and RB (IL8RA/B) C‐C chemokine receptors (CCR) 2 and 5 expressed on neutrophil and monocyte/macrophage membranes. Endothelial cells (ECs) derived from rat‐induced pluripotent stem cells (RiPS) were transduced with adenovirus containing cDNA of IL8RA/B and/or CCR2/5. We hypothesized that RiPS‐ECs overexpressing IL8RA/B (RiPS‐IL8RA/B‐ECs), CCR2/5 (RiPS‐CCR2/5‐ECs), or both receptors (RiPS‐IL8RA/B+CCR2/5‐ECs) will inhibit inflammatory responses and neointima formation in balloon‐injured rat carotid artery. Twelve‐week‐old male Sprague‐Dawley rats underwent balloon injury of the right carotid artery and intravenous infusion of (a) saline vehicle, (b) control RiPS‐Null‐ECs (ECs transduced with empty virus), (c) RiPS‐IL8RA/B‐ECs, (d) RiPS‐CCR2/5‐ECs, or (e) RiPS‐IL8RA/B+CCR2/5‐ECs. Inflammatory mediator expression and leukocyte infiltration were measured in injured and uninjured arteries at 24 hours postinjury by enzyme‐linked immunosorbent assay (ELISA) and immunohistochemistry, respectively. Neointima formation was assessed at 14 days postinjury. RiPS‐ECs expressing the IL8RA/B or CCR2/5 homing device targeted the injured arteries and decreased injury‐induced inflammatory cytokine expression, neutrophil/macrophage infiltration, and neointima formation. Transfused RiPS‐ECs overexpressing IL8RA/B and/or CCR2/5 prevented inflammatory responses and neointima formation after vascular injury. Targeted delivery of iPS‐ECs with a homing device to inflammatory mediators in injured arteries provides a novel strategy for the treatment of cardiovascular diseases. Stem Cells Translational Medicine 2017;6:1168–1177 PMID:28233474

α-Fetoprotein as a modulator of the pro-inflammatory response of human keratinocytes

PubMed Central

Potapovich, AI; Pastore, S; Kostyuk, VA; Lulli, D; Mariani, V; De Luca, C; Dudich, EI; Korkina, LG

2009-01-01

Background and purpose: The immunomodulatory effects of α-fetoprotein (AFP) on lymphocytes and macrophages have been described in vitro and in vivo. Recombinant forms of human AFP have been proposed as potential therapeutic entities for the treatment of autoimmune diseases. We examined the effects of embryonic and recombinant human AFP on the spontaneous, UVA- and cytokine-induced pro-inflammatory responses of human keratinocytes. Experimental approach: Cultures of primary and immortalized human keratinocytes (HaCaT) and human blood T lymphocytes were used. The effects of AFP on cytokine expression were studied by bioplexed elisa and quantitative reverse transcriptase polymerase chain reaction assay. Kinase and nuclear factor kappa B (NFκB) phosphorylation were quantified by intracellular elisa. Nuclear activator protein 1 and NFκB DNA binding activity was measured by specific assays. Nitric oxide and H2O2 production and redox status were assessed by fluorescent probe and biochemical methods. Key results: All forms of AFP enhanced baseline expression of cytokines, chemokines and growth factors. AFP dose-dependently increased tumour necrosis factor alpha-stimulated granulocyte macrophage colony stimulating factor and interleukin 8 expression and decreased tumour necrosis factor alpha-induced monocyte chemotactic protein 1 and IP-10 (interferon gamma-produced protein of 10 kDa) expression. AFP induced a marked activator protein 1 activation in human keratinocytes. AFP also increased H2O2 and modulated nitrite/nitrate levels in non-stimulated keratinocytes whereas it did not affect these parameters or cytokine release from UVA-stimulated cells. Phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Akt1 but not NFκB was activated by AFP alone or by its combination with UVA. Conclusions and implications: Exogenous AFP induces activation of human keratinocytes, with de novo expression of a number of pro-inflammatory mediators and modulation of their pro-inflammatory response to cytokines or UVA. AFP may modulate inflammatory events in human skin. PMID:19785658

Ureaplasma isolates stimulate pro-inflammatory CC chemokines and matrix metalloproteinase-9 in neonatal and adult monocytes

PubMed Central

Silwedel, Christine; Fehrholz, Markus; Henrich, Birgit; Waaga-Gasser, Ana Maria; Claus, Heike; Speer, Christian P.

2018-01-01

Being generally regarded as commensal bacteria, the pro-inflammatory capacity of Ureaplasma species has long been debated. Recently, we confirmed Ureaplasma–driven pro-inflammatory cytokine responses and a disturbance of cytokine equilibrium in primary human monocytes in vitro. The present study addressed the expression of CC chemokines and matrix metalloproteinase-9 (MMP-9) in purified term neonatal and adult monocytes stimulated with serovar 8 of Ureaplasma urealyticum (Uu) and serovar 3 of U. parvum (Up). Using qRT-PCR and multi-analyte immunoassay, we assessed mRNA and protein expression of the monocyte chemotactic proteins 1 and 3 (MCP-1/3), the macrophage inflammatory proteins 1α and 1β (MIP-1α/β) as well as MMP-9. For the most part, both isolates stimulated mRNA expression of all given chemokines and MMP-9 in cord blood and adult monocytes (p<0.05 and p<0.01). These results were paralleled by Uu and Up-induced secretion of MCP-1 protein in both cells (neonatal: p<0.01, adult: p<0.05 and p<0.01). Release of MCP-3, MIP-1α, MIP-1β and MMP-9 was enhanced upon exposure to Up (neonatal: p<0.05, p<0.01 and p<0.001, respectively; adult: p<0.05). Co-stimulation of LPS-primed monocytes with Up increased LPS-induced MCP-1 release in neonatal cells (p<0.05) and aggravated LPS-induced MMP-9 mRNA in both cell subsets (neonatal: p<0.05, adult: p<0.01). Our results document considerable expression of pro-inflammatory CC chemokines and MMP-9 in human monocytes in response to Ureaplasma isolates in vitro, adding to our previous data. Findings from co-stimulated cells indicate that Ureaplasma may modulate monocyte immune responses to a second stimulus. PMID:29558521

Berberine ameliorates diabetic nephropathy by inhibiting TLR4/NF-κB pathway.

PubMed

Zhu, Liping; Han, Jiakai; Yuan, Rongrong; Xue, Lei; Pang, Wuyan

2018-03-31

Diabetic nephropathy (DN) is the leading cause of end-stage renal failure, contributing to severe morbidity and mortality in diabetic patients. Berberine (BBR) has been well characterized to exert renoprotective effects in DN progression. However, the action mechanism of BBR in DN remains to be fully understood. The DN rat model was generated by intraperitoneal injection of streptozotocin (STZ, 65 mg/kg body weight) while 30 mM high glucose (HG)-treated podocytes were used as an in vitro DN model. The fasting blood glucose level and ratio of kidney weight to body weight were measured after BBR treatment (50, 100, or 200 mg/kg) in STZ-induced DN rats. The renal injury parameters including 24-h urinary protein, blood urea nitrogen and serum creatinine were assessed. qRT-PCR was performed to detect the transcript amounts of inflammatory factors. The concentrations of inflammatory factors were evaluated by ELISA kits. Western blot analysis was conducted to measure the amounts of TLR4/NF-κB-related proteins. The apoptotic rate of podocytes was analyzed by flow cytometry using Annexin V/propidium iodide. Berberine reduced renal injury in STZ-induced DN rat model, as evidenced by the decrease in fasting blood glucose, ratio of kidney weight to body weight, 24-h urinary protein, serum creatinine, and blood urine nitrogen. BBR attenuated the systemic and renal cortex inflammatory response and inhibited TLR4/NF-κB pathway in STZ-induced DN rats and HG-induced podocytes. Also, HG-induced apoptosis of podocytes was lowered by BBR administration. Furthermore, blockade of TLR4/NF-κB pathway by resatorvid (TAK-242) or pyrrolidine dithiocarbamate aggravated the inhibitory effect of BBR on HG-induced inflammatory response and apoptosis in podocytes. Berberine ameliorated DN through relieving STZ-induced renal injury, inflammatory response, and podocyte HG-induced apoptosis via inactivating TLR4/NF-κB pathway.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruce, Colleen; Thomas, Paul S.

This pilot study was designed to assess whether a synthetic matrix metalloproteinase (MMP) inhibitor has anti-inflammatory properties in mild asthma. Tumor necrosis factor alpha (TNF{alpha}) has been shown to be an important cytokine in the pathogenesis of allergic airway inflammatory responses, and its release can be inhibited by MMP inhibitors. Twelve atopic asthmatic subjects received the MMP inhibitor marimastat (5 mg) or placebo, twice daily for 3 weeks, separated by a 6-week washout period in a randomized, double-blind, cross-over manner. All subjects underwent an allergen inhalation provocation test to Dermatophagoides pteronyssinus before and after each study phase. Spirometry, exhaled NOmore » (eNO) levels, differential sputum cell counts, an asthma symptom questionnaire, peak flow, and {beta}{sub 2}-agonist usage were measured. Nine subjects completed the study, and, when compared with placebo, marimastat reduced bronchial hyper-responsiveness to inhaled allergen in these subjects from an allergen PC{sub 20} of 22.2 AU/ml (95%CI 11.7-32.6) to 17.0 AU/ml (95%CI 7.6-26.4, P = 0.02). The marimastat phase showed a nonsignificant fall in sputum inflammatory cells. Marimastat did not modify eNO, FEV{sub 1}, asthma symptoms, or albuterol usage. In conclusion, airway responsiveness to allergen may be modified by a MMP inhibitor, perhaps via TNF{alpha} playing a role in airway inflammation and remodeling.« less

Microglia in Glia-Neuron Co-cultures Exhibit Robust Phagocytic Activity Without Concomitant Inflammation or Cytotoxicity.

PubMed

Adams, Alexandra C; Kyle, Michele; Beaman-Hall, Carol M; Monaco, Edward A; Cullen, Matthew; Vallano, Mary Lou

2015-10-01

A simple method to co-culture granule neurons and glia from a single brain region is described, and microglia activation profiles are assessed in response to naturally occurring neuronal apoptosis, excitotoxin-induced neuronal death, and lipopolysaccharide (LPS) addition. Using neonatal rat cerebellar cortex as a tissue source, glial proliferation is regulated by omission or addition of the mitotic inhibitor cytosine arabinoside (AraC). After 7-8 days in vitro, microglia in AraC(-) cultures are abundant and activated based on their amoeboid morphology, expressions of ED1 and Iba1, and ability to phagocytose polystyrene beads and the majority of neurons undergoing spontaneous apoptosis. Microglia and phagocytic activities are sparse in AraC(+) cultures. Following exposure to excitotoxic kainate concentrations, microglia in AraC(-) cultures phagocytose most dead neurons within 24 h without exacerbating neuronal loss or mounting a strong or sustained inflammatory response. LPS addition induces a robust inflammatory response, based on microglial expressions of TNF-α, COX-2 and iNOS proteins, and mRNAs, whereas these markers are essentially undetectable in control cultures. Thus, the functional effector state of microglia is primed for phagocytosis but not inflammation or cytotoxicity even after kainate exposure that triggers death in the majority of neurons. This model should prove useful in studying the progressive activation states of microglia and factors that promote their conversion to inflammatory and cytotoxic phenotypes.

Variable versus conventional lung protective mechanical ventilation during open abdominal surgery: study protocol for a randomized controlled trial.

PubMed

Spieth, Peter M; Güldner, Andreas; Uhlig, Christopher; Bluth, Thomas; Kiss, Thomas; Schultz, Marcus J; Pelosi, Paolo; Koch, Thea; Gama de Abreu, Marcelo

2014-05-02

General anesthesia usually requires mechanical ventilation, which is traditionally accomplished with constant tidal volumes in volume- or pressure-controlled modes. Experimental studies suggest that the use of variable tidal volumes (variable ventilation) recruits lung tissue, improves pulmonary function and reduces systemic inflammatory response. However, it is currently not known whether patients undergoing open abdominal surgery might benefit from intraoperative variable ventilation. The PROtective VARiable ventilation trial ('PROVAR') is a single center, randomized controlled trial enrolling 50 patients who are planning for open abdominal surgery expected to last longer than 3 hours. PROVAR compares conventional (non-variable) lung protective ventilation (CV) with variable lung protective ventilation (VV) regarding pulmonary function and inflammatory response. The primary endpoint of the study is the forced vital capacity on the first postoperative day. Secondary endpoints include further lung function tests, plasma cytokine levels, spatial distribution of ventilation assessed by means of electrical impedance tomography and postoperative pulmonary complications. We hypothesize that VV improves lung function and reduces systemic inflammatory response compared to CV in patients receiving mechanical ventilation during general anesthesia for open abdominal surgery longer than 3 hours. PROVAR is the first randomized controlled trial aiming at intra- and postoperative effects of VV on lung function. This study may help to define the role of VV during general anesthesia requiring mechanical ventilation. Clinicaltrials.gov NCT01683578 (registered on September 3 3012).

Comparison of the toxicity of diesel exhaust produced by bio- and fossil diesel combustion in human lung cells in vitro

NASA Astrophysics Data System (ADS)

Steiner, Sandro; Czerwinski, Jan; Comte, Pierre; Popovicheva, Olga; Kireeva, Elena; Müller, Loretta; Heeb, Norbert; Mayer, Andreas; Fink, Alke; Rothen-Rutishauser, Barbara

2013-12-01

Alternative fuels are increasingly combusted in diesel- and gasoline engines and the contribution of such exhausts to the overall air pollution is on the rise. Recent findings on the possible adverse effects of biodiesel exhaust are contradictive, at least partly resulting from the various fuel qualities, engine types and different operation conditions that were tested. However, most of the studies are biased by undesired interactions between the exhaust samples and biological culture media. We here report how complete, freshly produced exhausts from fossil diesel (B0), from a blend of 20% rapeseed-methyl ester (RME) and 80% fossil diesel (B20) and from pure rapeseed methyl ester (B100) affect a complex 3D cellular model of the human airway epithelium in vitro by exposing the cells at the air-liquid interface. The induction of pro-apoptotic and necrotic cell death, cellular morphology, oxidative stress, and pro-inflammatory responses were assessed. Compared to B0 exhaust, B20 exhaust decreased oxidative stress and pro-inflammatory responses, whereas B100 exhaust, depending on exposure duration, decreased oxidative stress but increased pro-inflammatory responses. The effects are only very weak and given the compared to fossil diesel higher ecological sustainability of biodiesel, it appears that - at least RME - can be considered a valuable alternative to pure fossil diesel.

Mangiferin ameliorates fatty liver via modulation of autophagy and inflammation in high-fat-diet induced mice.

PubMed

Wang, Hu; Zhu, Yang-Yang; Wang, Li; Teng, Tian; Zhou, Meng; Wang, Shu-Guang; Tian, Yi-Zhu; Du, Lei; Yin, Xiao-Xing; Sun, Ying

2017-12-01

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. The progression of NAFLD is complex and associated with inflammation, oxidative stress, autophagy, endoplasmic reticulum stress, and insulin resistance. Mangiferin, a natural C-glucosyl xanthone, has been reported to show multiple biological activities. The aim of this study was to investigate the therapeutic effect of mangiferin on NAFLD and the underlying molecular mechanism. We established a mouse model of NAFLD using a high-fat diet (HFD), and injected the mice with different doses of mangiferin (15, 30, and 60mg/kg, intraperitoneal) for 12 weeks. Liver tissue was assessed to evaluate changes in inflammatory responses, autophagy, and glycolipid metabolism. We found that mangiferin decreased body weight, as well as the levels of triglycerides and total cholesterol in plasma and the liver. It also increased glucose tolerance in HFD-fed mice. In addition, mangiferin decreased inflammatory responses by inhibiting the activities of nuclear factor kappa B and c-Jun N-terminal kinase, regulated autophagy via the AMP-activated protein kinase/mechanistic target of rapamycin signaling pathway, and improved glycolipid metabolism via modulation of the insulin receptor substrate/phosphoinositide 3-kinase/protein kinase B signaling pathway. This study demonstrated that mangiferin significantly ameliorates NAFLD development in HFD-fed mice by inhibiting inflammatory responses, activating autophagy, and improving glycolipid metabolism. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Soluble triggering receptor expressed on myeloid cells 1 and the diagnosis of sepsis.

PubMed

Barati, Mitra; Bashar, Farshid Rahimi; Shahrami, Reza; Zadeh, Mohammad Hossein Jarrah; Taher, Mahshid Talebi; Nojomi, Marzieh

2010-06-01

Early diagnosis and assessment of the systemic inflammatory response to infection are difficult with usual markers (fever, leukocytosis, C-reactive protein [CRP]). Triggering receptor expressed on myeloid cells-1 (TREM-1) expression on phagocytes is up-regulated by microbial products. We studied the ability of soluble TREM-1 (sTREM-1) to identify patients with sepsis. Plasma samples were obtained on intensive care unit admission from patients with systemic inflammatory response syndrome for sTREM-1 measurement. Soluble TREM-1, CRP concentrations and erythrocyte sedimentation rate (ESR) were higher in the sepsis group (n = 52) than in the non-infectious systemic inflammatory response syndrome group (n = 43; P = .00, .02, and .001, respectively). Soluble TREM-1, CRP concentrations, white blood cell count and ESR were higher in the sepsis group than in the non SIRS group (n = 37; P = .04, .00, .01, and .00, respectively). In a receiver-operating characteristic curve analysis, ESR, CRP and sTREM-1 had an area under the curve larger than 0.65 (P = .00), in distinguishing between septic and non-infectious SIRS patients. CRP, ESR, sTREM-1 had a sensitivity of 60%, 70% and 70% and a specificity of 60%, 69% and, 60% respectively in diagnosing infection in SIRS. C-reactive protein and ESR performed better than sTREM-1 and white blood cell count in diagnosing infection. Copyright (c) 2010. Published by Elsevier Inc.

REMIFENTANIL VS FENTANYL DURING DAY CASE DENTAL SURGERY IN PEOPLE WITH SPECIAL NEEDS: A COMPARATIVE, PILOT STUDY OF THEIR EFFECT ON STRESS RESPONSE AND POSTOPERATIVE PAIN.

PubMed

Sklika, Eirini; Kalimeris, Konstantinos; Perrea, Despina; Stavropoulos, Nikolaos; Kostopanagiotou, Georgia; Matsota, Paraskevi

2016-06-01

People with special needs undergoing dental surgery frequently require general anesthesia. We investigated the effect of remifentanil vs fentanyl on stress response and postoperative pain in people with special needs undergoing day-case dental surgery. Forty-six adult patients with cognitive impairment undergoing day-case dental surgery under general anesthesia were allocated to receive intraoperatively either fentanyl 50 μg iv bolus (group F, n = 23) or continuous infusion of remifentanil 0.5-1 μg/kg/min (group R, n = 23). Iintraoperative hemodynamic parameters were recorded and serum inflammatory mediators [tumor necrosis factor-α, substance-P], stress hormons (melatonin, cortisol) and β-endorphin were measured. Postoperative pain was assessed during the first postoperative 12 hours with the Wong-Baker faces pain-rating scale. Demographics were similar in two groups. The two groups did not differ regarding their effects on inflammatory mediators, stress hormons and postoperative pain scores. However, the use of remifentanil prevented intraoperative increases of arterial blood pressure and heart rate. Remifentanil and fentanyl did not affect differently stress and inflammatory hormones during day-case dental surgery, although remifentanil may render intraoperative management of hemodynamic responses easier. Both opioids are equally efficient for postoperative pain management following dental surgery in people with special needs.

Probiotic yogurt and acidified milk similarly reduce postprandial inflammation and both alter the gut microbiota of healthy, young men.

PubMed

Burton, Kathryn J; Rosikiewicz, Marta; Pimentel, Grégory; Bütikofer, Ueli; von Ah, Ueli; Voirol, Marie-Jeanne; Croxatto, Antony; Aeby, Sébastien; Drai, Jocelyne; McTernan, Philip G; Greub, Gilbert; Pralong, François P; Vergères, Guy; Vionnet, Nathalie

2017-05-01

Probiotic yogurt and milk supplemented with probiotics have been investigated for their role in 'low-grade' inflammation but evidence for their efficacy is inconclusive. This study explores the impact of probiotic yogurt on metabolic and inflammatory biomarkers, with a parallel study of gut microbiota dynamics. The randomised cross-over study was conducted in fourteen healthy, young men to test probiotic yogurt compared with milk acidified with 2 % d-(+)-glucono-δ-lactone during a 2-week intervention (400 g/d). Fasting assessments, a high-fat meal test (HFM) and microbiota analyses were used to assess the intervention effects. Baseline assessments for the HFM were carried out after a run-in during which normal milk was provided. No significant differences in the inflammatory response to the HFM were observed after probiotic yogurt compared with acidified milk intake; however, both products were associated with significant reductions in the inflammatory response to the HFM compared with the baseline tests (assessed by IL6, TNFα and chemokine ligand 5) (P<0·001). These observations were accompanied by significant changes in microbiota taxa, including decreased abundance of Bilophila wadsworthia after acidified milk (log 2-fold-change (FC)=-1·5, P adj=0·05) and probiotic yogurt intake (FC=-1·3, P adj=0·03), increased abundance of Bifidobacterium species after acidified milk intake (FC=1·4, P adj=0·04) and detection of Lactobacillus delbrueckii spp. bulgaricus (FC=7·0, P adj<0·01) and Streptococcus salivarius spp. thermophilus (FC=6·0, P adj<0·01) after probiotic yogurt intake. Probiotic yogurt and acidified milk similarly reduce postprandial inflammation that is associated with a HFM while inducing distinct changes in the gut microbiota of healthy men. These observations could be relevant for dietary treatments that target 'low-grade' inflammation.

Acute and chronic stress and the inflammatory response in hyperprolactinemic rats.

PubMed

Ochoa-Amaya, J E; Malucelli, B E; Cruz-Casallas, P E; Nasello, A G; Felicio, L F; Carvalho-Freitas, M I R

2010-01-01

Prolactin (PRL), a hormone produced by the pituitary gland, has multiple physiological functions, including immunoregulation. PRL can also be secreted in response to stressful stimuli. During stress, PRL has been suggested to oppose the immunosuppressive effects of inflammatory mediators. Therefore, the aim of the present study was to analyze the effects of short- and long-term hyperprolactinemia on the inflammatory response in rats subjected to acute or chronic cold stress. Inflammatory edema was induced by carrageenan in male rats, and hyperprolactinemia was induced by injections of the dopamine receptor antagonist domperidone. The volume of inflammatory edema was measured by plethysmography after carrageenan injection. Additionally, the effects of hyperprolactinemia on body weight and serum corticosterone levels were evaluated. Five days of domperidone-induced hyperprolactinemia increased the volume of inflammatory edema. No differences in serum corticosterone levels were observed between groups. No significant differences were found among 30 days domperidone-induced hyperprolactinemic animals subjected to acute stress and the inflammatory response observed in chronic hyperprolactinemic animals subjected to chronic stress. The results suggest that short-term hyperprolactinemia has pro-inflammatory effects. Because such an effect was not observed in long-term hyperprolactinemic animals, PRL-induced tolerance seems likely. We suggest that short-term hyperprolactinemia may act as a protective factor in rats subjected to acute stress. These data suggest that hyperprolactinemia and stress interact differentially according to the time period. Copyright 2010 S. Karger AG, Basel.

Treatment with a New Peroxisome Proliferator-Activated Receptor Gamma Agonist, Pyridinecarboxylic Acid Derivative, Increases Angiogenesis and Reduces Inflammatory Mediators in the Heart of Trypanosoma cruzi-Infected Mice.

PubMed

Penas, Federico Nicolás; Carta, Davide; Dmytrenko, Ganna; Mirkin, Gerado A; Modenutti, Carlos Pablo; Cevey, Ágata Carolina; Rada, Maria Jimena; Ferlin, Maria Grazia; Sales, María Elena; Goren, Nora Beatriz

2017-01-01

Trypanosoma cruzi infection induces an intense inflammatory response in diverse host tissues. The immune response and the microvascular abnormalities associated with infection are crucial aspects in the generation of heart damage in Chagas disease. Upon parasite uptake, macrophages, which are involved in the clearance of infection, increase inflammatory mediators, leading to parasite killing. The exacerbation of the inflammatory response may lead to tissue damage. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that exerts important anti-inflammatory effects and is involved in improving endothelial functions and proangiogenic capacities. In this study, we evaluated the intermolecular interaction between PPARγ and a new synthetic PPARγ ligand, HP 24 , using virtual docking. Also, we showed that early treatment with HP 24 , decreases the expression of NOS2, a pro-inflammatory mediator, and stimulates proangiogenic mediators (vascular endothelial growth factor A, CD31, and Arginase I) both in macrophages and in the heart of T. cruzi -infected mice. Moreover, HP 24 reduces the inflammatory response, cardiac fibrosis and the levels of inflammatory cytokines (TNF-α, interleukin 6) released by macrophages of T. cruzi -infected mice. We consider that PPARγ agonists might be useful as coadjuvants of the antiparasitic treatment of Chagas disease, to delay, reverse, or preclude the onset of heart damage.

Treatment of inflammatory facial acne vulgaris in Chinese patients with the 1450-nm diode laser: a pilot study

NASA Astrophysics Data System (ADS)

Liu, Huaxu; Dang, Yongyan; Wang, Zhan; Ma, Li; Ren, Qiushi

2007-02-01

The 1450-nm diode laser has been found to be effective for the treatment of inflammatory acne in USA, Europe and Japan. However, there is no report on its efficacy in Chinese acne vulgaris patients. We conduct this pilot study to evaluate the efficacy and safety of the 1450-nm diode laser in the treatment of inflammatory facial acne vulgaris in Chinese patients. Nineteen patients with inflammatory facial acne were treated with the 1450-nm diode laser at 4- to 6-week intervals. Clinical photographs and lesion counts were obtained at baseline and after each treatment. Subjective evaluation of response to treatment and pain was assessed using a questionnaire. In our study, clinical improvement was seen in all patients and was generally dramatic. Lesion counts decreased 34% after one treatment (p<0.01), 56% after two treatments (p<0.01), and 81% after three treatments (p<0.01). However, the treatment-related pain was comparatively hard to be tolerated in Chinese patitents, and the other main adverse effect was the hyper-pigmentation after treatments (36.84%, 7/19).

[The contribution of inflammatory process in pathogenesis and natural history of atrial fibrillation].

PubMed

Zyśko, Dorota; Gajek, Jacek; Mazurek, Walentyna

2005-02-01

The inflammatory process plays important role in pathogenesis of some cardiovascular diseases. Atrial fibrillation is atrial arrhythmia with rapid, asynchronous activation of atrial myocytes. The inflammatory process can be responsible for atrial electrical and anatomical remodeling and therefore shifts towards arrhythmia persistence. The presence of systemic inflammation may be assessed by means of C-reactive protein (CRP) measurement. Maximal concentration of CRP coincidences with the peak of paroxysmal atrial fibrillation occurrence in patients after cardiac surgery. In patients with sinus rhythm the concentration of CRP is a risk factor for this arrhythmia in long-term follow-up. In patients with atrial fibrillation mean CRP concentration is 2-fold higher comparing to control group. CRP concentration is higher in patients with chronic than paroxysmal form of this arrhythmia. High CRP level predicts worse results of direct current cardioversion and more frequent paroxysms of atrial fibrillation during follow-up. Besides of, the patients with echocardiographic signs of thromboembolic risk have higher CRP levels than control subjects. There is no data about the influence of anti-inflammatory therapy on atrial fibrillation or its recurrences.

Intraoperative crystalloid overload leads to substantial inflammatory infiltration of intestinal anastomoses-a histomorphological analysis.

PubMed

Kulemann, Birte; Timme, Sylvia; Seifert, Gabriel; Holzner, Philipp A; Glatz, Torben; Sick, Olivia; Chikhladze, Sophia; Bronsert, Peter; Hoeppner, Jens; Werner, Martin; Hopt, Ulrich T; Marjanovic, Goran

2013-09-01

It has been shown that crystalloid fluid-overload promotes anastomotic instability. As physiologic anastomotic healing requires the sequential infiltration of different cells, we hypothesized this to be altered by liberal fluid regimes and performed a histomorphological analysis. 36 Wistar rats were randomized into 4 groups (n=8-10 rats/group) and treated with either liberal (+) or restrictive (-) perioperative crystalline (Jonosteril = Cry) or colloidal fluid (Voluven = Col). Anastomotic samples were obtained on postoperative day 4, routinely stained and histophathologically reviewed. Anastomotic healing was assessed using a semiquantitative score, assessing inflammatory cells, anastomotic repair and collagenase activity. Overall, the crystalloid overload group (Cry (+)) showed the worst healing score (P < 0.01). A substantial increase of lymphocytes and macrophages was found in this group compared to the other three (P < 0.01). Both groups that received colloidal fluid (Col (+) and Col (-)) as well as the group that received restricted crystalloid fluid resuscitation (Cry (-)) had better intestinal healing. Collagenase activity was significantly higher in the Cry (+) group. Intraoperative infusion of high-volume crystalloid fluid leads to a pathological anastomotic inflammatory response with a marked infiltration of leukocytes and macrophages resulting in accelerated collagenolysis. Copyright © 2013 Mosby, Inc. All rights reserved.

Immunizing pigs with Ascaris suum hemoglobin increases the inflammatory response in the liver but fails to induce a protective immunity

USDA-ARS?s Scientific Manuscript database

To determine whether purified Ascaris suum hemoglobin (AsHb) is a suitable vaccine candidate for the control of Ascaris infections, pigs were 30 vaccinated with AsHb in combination with QuilA adjuvant and challenged with A. suum eggs. The number of liver lesions and worms in the intestine was assess...

The rat closely mimics oxidative stress and inflammation in humans after exercise but not after exercise combined with vitamin C administration.

PubMed

Veskoukis, Aristidis S; Goutianos, Georgios; Paschalis, Vassilis; Margaritelis, Nikos V; Tzioura, Aikaterini; Dipla, Konstantina; Zafeiridis, Andreas; Vrabas, Ioannis S; Kyparos, Antonios; Nikolaidis, Michalis G

2016-04-01

The purpose of the present study was to directly compare oxidative stress and inflammation responses between rats and humans. We contrasted rat and human oxidative stress and inflammatory responses to exercise (pro-oxidant stimulus) and/or vitamin C (anti-oxidant stimulus) administration. Vitamin C was administered orally in both species (16 mg kg(-1) of body weight). Twelve redox biomarkers and seven inflammatory biomarkers were determined in plasma and erythrocytes pre- and post-exercise or pre- and post-exercise combined with vitamin C administration. Exercise increased oxidative stress and induced an inflammatory state in rats and humans. There were only 1/19 significant species × exercise interactions (catalase), indicating similar responses to exercise between rats and humans in redox and inflammatory biomarkers. Vitamin C decreased oxidative stress and increased antioxidant capacity only in humans and did not affect the redox state of rats. In contrast, vitamin C induced an anti-inflammatory state only in rats and did not affect the inflammatory state of humans. There were 10/19 significant species × vitamin C interactions, indicating that rats poorly mimic human oxidative stress and inflammatory responses to vitamin C administration. Exercise after acute vitamin C administration altered redox state only in humans and did not affect the redox state of rats. On the contrary, inflammation biomarkers changed similarly after exercise combined with vitamin C in both rats and humans. The rat adequately mimics human responses to exercise in basic blood redox/inflammatory profile, yet this is not the case after exercise combined with vitamin C administration.

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

PubMed Central

Prabhu, Sumanth D.; Frangogiannis, Nikolaos G.

2016-01-01

In adult mammals, massive sudden loss of cardiomyocytes following infarction overwhelms the limited regenerative capacity of the myocardium, resulting in formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of pro-inflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/CCL2). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response following myocardial infarction. Dysregulation of immune pathways, impaired suppression of post-infarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for prevention of post-infarction heart failure. PMID:27340270

Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Youn, Gi Soo; Kwon, Dong-Joo; Ju, Sung Mi

HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrolmore » induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes. - Highlights: • Celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory genes. • Celastrol inhibited HIV-1 Tat -induced activation of JNK MAPK. • Celastrol inhibited HIV-1 Tat-induced activation of both NF-κB and AP-1. • Celastrol inhibited HIV-1 Tat-induced inflammatory responses via HO-1 induction.« less

Tat-CBR1 inhibits inflammatory responses through the suppressions of NF-κB and MAPK activation in macrophages and TPA-induced ear edema in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Young Nam; Kim, Dae Won; Jo, Hyo Sang

Human carbonyl reductase 1 (CBR1) plays a crucial role in cell survival and protects against oxidative stress response. However, its anti-inflammatory effects are not yet clearly understood. In this study, we examined whether CBR1 protects against inflammatory responses in macrophages and mice using a Tat-CBR1 protein which is able to penetrate into cells. The results revealed that purified Tat-CBR1 protein efficiently transduced into Raw 264.7 cells and inhibited lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2), nitric oxide (NO) and prostaglandin E{sub 2} (PGE{sub 2}) expression levels. In addition, Tat-CBR1 protein leads to decreased pro-inflammatory cytokine expression through suppression of nuclear transcription factor-kappaB (NF-κB)more » and mitogen activated protein kinase (MAPK) activation. Furthermore, Tat-CBR1 protein inhibited inflammatory responses in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation when applied topically. These findings indicate that Tat-CBR1 protein has anti-inflammatory properties in vitro and in vivo through inhibition of NF-κB and MAPK activation, suggesting that Tat-CBR1 protein may have potential as a therapeutic agent against inflammatory diseases. - Highlights: • Transduced Tat-CBR1 reduces LPS-induced inflammatory mediators and cytokines. • Tat-CBR1 inhibits MAPK and NF-κB activation. • Tat-CBR1 ameliorates inflammation response in vitro and in vivo. • Tat-CBR1 may be useful as potential therapeutic agent for inflammation.« less

Idiopathic inflammatory myositis.

PubMed

Tieu, Joanna; Lundberg, Ingrid E; Limaye, Vidya

2016-02-01

Knowledge on idiopathic inflammatory myopathy (IIM) has evolved with the identification of myositis-associated and myositis-specific antibodies, development of histopathological classification and the recognition of how these correlate with clinical phenotype and response to therapy. In this paper, we outline key advances in diagnosis and histopathology, including the more recent identification of antibodies associated with immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Ongoing longitudinal observational cohorts allow further classification of these patients with IIM, their predicted clinical course and response to specific therapies. Registries have been developed worldwide for this purpose. A challenging aspect in IIM, a multisystem disease with multiple clinical subtypes, has been defining disease status and clinically relevant improvement. Tools for assessing activity and damage are now recognised to be important in determining disease activity and guiding therapeutic decision-making. The International Myositis Assessment and Clinical Studies (IMACS) group has developed such tools for use in research and clinical settings. There is limited evidence for specific treatment strategies in IIM. With significant development in the understanding of IIM and improved classification, longitudinal observational cohorts and trials using validated outcome measures are necessary, to provide important information for evidence-based care in the clinical setting. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Calcium hydroxide associated with a new vehicle: Psidium cattleianum leaf extracts. Tissue response evaluation.

PubMed

Valentim, Diego; Bueno, Carlos Roberto Emerenciano; Marques, Vanessa Abreu Sanches; Vasques, Ana Maria Veiga; Cury, Marina Tolomei Sandoval; Cintra, Luciano Tavares Angelo; Dezan, Eloi

2017-07-03

The aim of this study was to evaluate edemogenic activity and subcutaneous inflammatory reaction induced by Psidium cattleianum leaf extracts associated with Ca(OH)2. Thirty male Wistar rats, split equally into three groups [aqueous extract + Ca(OH)2; ethanolic extract + Ca(OH)2; and propylene glycol + Ca(OH)2], were assessed every 3 h or 6 h (five animals in each period). Under general anesthesia, 0.2 mL of 1% Evans blue per 100 g of body weight was injected into the penile vein and each combination to be evaluated was subcutaneously injected into the dorsal region 30 min thereafter. Edemogenic activity was analyzed by spectrophotometry (λ=630 nm). For inflammatory reaction analysis, 50 rats received four polyethylene tubes (three experimental groups) and an empty tube (control group). The assessments were made at 7, 15, 30, 60, and 90 days, followed by hematoxylin-eosin staining and by the assignment of scores for evaluation of tissue response intensity. Ethanolic extract + Ca(OH)2 yielded the largest edemogenic activity at 3 h. Intergroup differences at 6 h were not significant. The histological analysis showed progressive repair over time (p<0.05) and aqueous and ethanolic extracts produced similar responses to those of the control and Ca(OH)2 + propylene glycol groups. Psidium cattleianum leaf extracts used as Ca(OH)2 vehicles evoked similar tissue response when compared to Ca(OH)2 associated with propylene glycol.

CORK Study in Cystic Fibrosis: Sustained Improvements in Ultra-Low-Dose Chest CT Scores After CFTR Modulation With Ivacaftor.

PubMed

Ronan, Nicola J; Einarsson, Gisli G; Twomey, Maria; Mooney, Denver; Mullane, David; NiChroinin, Muireann; O'Callaghan, Grace; Shanahan, Fergus; Murphy, Desmond M; O'Connor, Owen J; Shortt, Cathy A; Tunney, Michael M; Eustace, Joseph A; Maher, Michael M; Elborn, J Stuart; Plant, Barry J

2018-02-01

Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment. Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed. Significant improvements in FEV 1 , BMI, and sweat chloride levels were observed post-ivacaftor treatment. Improvement in ultra-low-dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)-1β, IL-6, and IL-8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03). Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Inflammatory and Metabolic Responses to Different Resistance Training on Chronic Obstructive Pulmonary Disease: A Randomized Control Trial.

PubMed

Silva, Bruna S de Alencar; Lira, Fábio S; Rossi, Fabrício E; Ramos, Dionei; Uzeloto, Juliana S; Freire, Ana P C F; de Lima, Fabiano F; Gobbo, Luís A; Ramos, Ercy M C

2018-01-01

Background: Low-grade inflammation can be present in chronic obstructive pulmonary disease (COPD), which may affect the regulation of muscle protein and body metabolism. Regular exercise show improvement in muscle strength and dyspnea in patients with COPD, however, the response to training on inflammatory and metabolic disorders is unclear. In this study, we compared the effects of resistance training using weight machines and elastic resistance (bands and tubes) on the inflammatory and metabolic responses in patients with COPD. Methods: Patients with COPD were randomized into three groups: elastic band group (EBG), elastic tube group (ETG), and weight machines equipment group (MG). EBG and ETG were analyzed together [elastic group (EG)]. The participants were evaluated for pulmonary function (spirometry), peripheral muscle strength (digital dynamometry), IL-6, TNF-α, IL-10, IL-15 (Immunoassay), glucose, triacylglycerol, total cholesterol, HDL-c, and albumin levels (Enzymatic colorimetric). Blood samples were collected to assess the acute and chronic exercise responses after 12 weeks of training protocol. Results: The patient's mean age was 71.53 ± 6.97 years old. FEV 1 (percent predicted) was 50.69 ± 16.67 and 45.40 ± 15.15% for EG and MG, respectively ( p = 0.28). All groups increased muscle strength ( p < 0.05) with no differences between groups. The acute response to exercise after 12 weeks of training showed improvement of inflammation when compared to baseline. Regarding the chronic effects, it was observed a decrease of all cytokines, except IL-10 ( p < 0.05). After 12 weeks of training, the analysis of the metabolic profile presented a reduction in glucose concentration ( p < 0.01), with no differences between groups ( p = 0.30) and a decrease in triacylglycerol for the EG ( p > 0.01). Conclusions: Training with elastic resistances or conventional weight machines showed improvement of inflammation response after 12 weeks of training. Chronically, both training groups showed anti-inflammatory effects, with the EG showing a strong tendency to improve IL-10/TNF-α ratio and IL-10 levels. RBR-6V9SJJ.

VIP modulates the pro-inflammatory maternal response, inducing tolerance to trophoblast cells

PubMed Central

Fraccaroli, Laura; Alfieri, Julio; Larocca, Luciana; Calafat, Mario; Roca, Valeria; Lombardi, Eduardo; Ramhorst, Rosanna; Leirós, Claudia Pérez

2009-01-01

Background and purpose Successful embryo implantation is followed by a local pro-inflammatory and Th1 response, subsequently controlled by a Th2 response. Vasoactive intestinal peptide (VIP) has anti-inflammatory effects and promotes tolerogenic/Th2 responses while favouring embryonic development. We investigated the potential regulatory role of VIP on human trophoblast cells, maternal pro-inflammatory responses and trophoblast-maternal leukocyte interactions. Experimental approach We tested VIP effects directly on a trophoblast cell line (Swan 71 cells) and after co-culture with maternal peripheral blood mononuclear cells (PBMCs) as models of the feto-maternal dialogue. We also co-cultured maternal and paternal PBMCs to test effects of endogenous VIP on maternal alloresponses. Key results Swan 71 cells express VPAC1 receptors and VIP induced their proliferation and the expression of leukaemia inhibitor factor, a pro-implantatory marker. After interaction with trophoblast cells, VIP increased Foxp3, the proportion of CD4+CD25+Foxp3+ cells within maternal PBMCs and transforming growth factor β expression. Also, during the trophoblast-maternal PBMCs interaction, VIP reduced pro-inflammatory mediators [interleukin (IL)-6, monocyte chemoattractant protein 1, nitric oxide], while increasing IL-10. Trophoblast cells produced VIP which dose-dependently suppressed allomaternal responses, accompanied by reduced expression of the T cell transcription factor, T-bet. Conclusions and implications Vasoactive intestinal peptide induced pro-implantatory markers and trophoblast cell proliferation, while controlling the initial pro-inflammatory response, by increasing maternal regulatory T cells and anti-inflammatory cytokines. As an autocrine regulatory peptide VIP might contribute to fetal survival through two mechanisms; a direct trophic effect on trophoblast cells and an immunomodulatory effect that favours tolerance to fetal antigens. PMID:19133995

Modulating the Biologic Activity of Mesenteric Lymph after Traumatic Shock Decreases Systemic Inflammation and End Organ Injury.

PubMed

Langness, Simone; Costantini, Todd W; Morishita, Koji; Eliceiri, Brian P; Coimbra, Raul

2016-01-01

Trauma/hemorrhagic shock (T/HS) causes the release of pro-inflammatory mediators into the mesenteric lymph (ML), triggering a systemic inflammatory response and acute lung injury (ALI). Direct and pharmacologic vagal nerve stimulation prevents gut barrier failure and alters the biologic activity of ML after injury. We hypothesize that treatment with a pharmacologic vagal agonist after T/HS would attenuate the biologic activity of ML and prevent ALI. ML was collected from male Sprague-Dawley rats after T/HS, trauma-sham shock (T/SS) or T/HS with administration of the pharmacologic vagal agonist CPSI-121. ML samples from each experimental group were injected into naïve mice to assess biologic activity. Blood samples were analyzed for changes in STAT3 phosphorylation (pSTAT3). Lung injury was characterized by histology, permeability and immune cell recruitment. T/HS lymph injected in naïve mice caused a systemic inflammatory response characterized by hypotension and increased circulating monocyte pSTAT3 activity. Injection of T/HS lymph also resulted in ALI, confirmed by histology, lung permeability and increased recruitment of pulmonary macrophages and neutrophils to lung parenchyma. CPSI-121 attenuated T/HS lymph-induced systemic inflammatory response and ALI with stable hemodynamics and similar monocyte pSTAT3 levels, lung histology, lung permeability and lung immune cell recruitment compared to animals injected with lymph from T/SS. Treatment with CPSI-121 after T/HS attenuated the biologic activity of the ML and decreased ALI. Given the superior clinical feasibility of utilizing a pharmacologic approach to vagal nerve stimulation, CPSI-121 is a potential treatment strategy to limit end organ dysfunction after injury.

Short-term inhalation of stainless steel welding fume causes sustained lung toxicity but no tumorigenesis in lung tumor susceptible A/J mice.

PubMed

Zeidler-Erdely, Patti C; Battelli, Lori A; Stone, Sam; Chen, Bean T; Frazer, David G; Young, Shih-Houng; Erdely, Aaron; Kashon, Michael L; Andrews, Ronnee; Antonini, James M

2011-02-01

Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at-risk population for development of lung cancer. Our objective was to expose, by inhalation, lung tumor susceptible (A/J) and resistant C57BL/6J (B6) mice to stainless steel (SS) welding fume containing carcinogenic metals and characterize the lung-inflammatory and tumorigenic response. Male mice were exposed to air or gas metal arc (GMA)-SS welding fume at 40 mg/m(3)×3 h/day for 6 and 10 days. At 1, 4, 7, 10, 14, and 28 days after 10 days of exposure, bronchoalveolar lavage (BAL) was done. Lung cytotoxicity, permeability, inflammatory cytokines, and cell differentials were analyzed. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 78 weeks after 6 and 10 days of exposure. Inhalation of GMA-SS fume caused an early, sustained macrophage and lymphocyte response followed by a gradual neutrophil influx and the magnitudes of these differed between the mouse strains. Monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNF-α) were increased in both strains while the B6 also had increased interleukin-6 (IL-6) protein. BAL measures of cytotoxicity and damage were similar between the strains and significantly increased at all time points. Histopathology and tumorigenesis were unremarkable at 78 weeks. In conclusion, GMA-SS welding fume induced a significant and sustained inflammatory response in both mouse strains with no recovery by 28 days. Under our exposure conditions, GMA-SS exposure resulted in no significant tumor development in A/J mice.

Hemodynamic resuscitation with arginine vasopressin reduces lung injury after brain death in the transplant donor.

PubMed

Rostron, Anthony J; Avlonitis, Vassilios S; Cork, David M W; Grenade, Danielle S; Kirby, John A; Dark, John H

2008-02-27

The autonomic storm accompanying brain death leads to neurogenic pulmonary edema and triggers development of systemic and pulmonary inflammatory responses. Neurogenic vasoplegia exacerbates the pulmonary injury caused by brain death and primes the lung for ischemia reperfusion injury and primary graft dysfunction in the recipient. Donor resuscitation with norepinephrine ameliorates the inflammatory response to brain death, however norepinephrine has deleterious effects, particularly on the heart. We tested the hypothesis that arginine vasopressin is a suitable alternative to norepinephrine in managing the hypotensive brain dead donor. Brain death was induced in Wistar rats by intracranial balloon inflation. Pulmonary capillary leak was estimated using radioiodinated albumin. Development of pulmonary edema was assessed by measurement of wet and dry lung weights. Cell surface expression of CD11b/CD18 by neutrophils was determined using flow cytometry. Enzyme-linked immunosorbent assays were used to measure the levels of TNFalpha, IL-1beta, CINC-1, and CINC-3 in serum and bronchoalveolar lavage. Quantitative reverse-transcription polymerase chain reaction was used to determine the expression of cytokine mRNA (IL-1beta, CINC-1 and CINC-3) in lung tissue. There was a significant increase in pulmonary capillary permeability, wet/dry lung weight ratios, neutrophil integrin expression and pro-inflammatory cytokines in serum (TNFalpha, IL-1beta, CINC-1 and CINC-3), bronchoalveolar lavage (TNFalpha and IL-1beta) and lung tissue (IL-1beta and CINC-1) in braindead animals compared to controls. Correction of neurogenic hypotension with either arginine vasopressin or norepinephrine limits edema, reduces pulmonary capillary leak, and modulates systemic and pulmonary inflammatory responses to brain death. Arginine vasopressin and norepinephrine are equally effective in treating the hypotensive pulmonary donor in this rodent model.

Piperine Inhibits the Activities of Platelet Cytosolic Phospholipase A2 and Thromboxane A2 Synthase without Affecting Cyclooxygenase-1 Activity: Different Mechanisms of Action Are Involved in the Inhibition of Platelet Aggregation and Macrophage Inflammatory Response

PubMed Central

Son, Dong Ju; Akiba, Satoshi; Hong, Jin Tae; Yun, Yeo Pyo; Hwang, Seock Yeon; Park, Young Hyun; Lee, Sung Eun

2014-01-01

PURPOSE: Piperine, a major alkaloid of black pepper (Piper nigrum) and long pepper (Piper longum), was shown to have anti-inflammatory activity through the suppression of cyclooxygenase (COX)-2 gene expression and enzyme activity. It is also reported to exhibit anti-platelet activity, but the mechanism underlying this action remains unknown. In this study, we investigated a putative anti-platelet aggregation mechanism involving arachidonic acid (AA) metabolism and how this compares with the mechanism by which it inhibits macrophage inflammatory responses; METHODS: Rabbit platelets and murine macrophage RAW264.7 cells were treated with piperine, and the effect of piperine on the activity of AA-metabolizing enzymes, including cytosolic phospholipase A2 (cPLA2), COX-1, COX-2, and thromboxane A2 (TXA2) synthase, as well as its effect on AA liberation from the plasma membrane components, were assessed using isotopic labeling methods and enzyme immunoassay kit; RESULTS: Piperine significantly suppressed AA liberation by attenuating cPLA2 activity in collagen-stimulated platelets. It also significantly inhibited the activity of TXA2 synthase, but not of COX-1, in platelets. These results suggest that piperine inhibits platelet aggregation by attenuating cPLA2 and TXA2 synthase activities, rather than through the inhibition of COX-1 activity. On the other hand, piperine significantly inhibited lipopolysaccharide-induced generation of prostaglandin (PG)E2 and PGD2 in RAW264.7 cells by suppressing the activity of COX-2, without effect on cPLA2; CONCLUSION: Our findings indicate that piperine inhibits platelet aggregation and macrophage inflammatory response by different mechanisms. PMID:25153972

Applicability of avidin protein coated mesoporous silica nanoparticles as drug carriers in the lung

NASA Astrophysics Data System (ADS)

van Rijt, S. H.; Bölükbas, D. A.; Argyo, C.; Wipplinger, K.; Naureen, M.; Datz, S.; Eickelberg, O.; Meiners, S.; Bein, T.; Schmid, O.; Stoeger, T.

2016-04-01

Mesoporous silica nanoparticles (MSNs) exhibit unique drug delivery properties and are thus considered as promising candidates for next generation nano-medicines. In particular, inhalation into the lungs represents a direct, non-invasive delivery route for treating lung disease. To assess MSN biocompatibility in the lung, we investigated the bioresponse of avidin-coated MSNs (MSN-AVI), as well as aminated (uncoated) MSNs, after direct application into the lungs of mice. We quantified MSN distribution, clearance rate, cell-specific uptake, and inflammatory responses to MSNs within one week after instillation. We show that amine-functionalized (MSN-NH2) particles are not taken up by lung epithelial cells, but induced a prolonged inflammatory response in the lung and macrophage cell death. In contrast, MSN-AVI co-localized with alveolar epithelial type 1 and type 2 cells in the lung in the absence of sustained inflammatory responses or cell death, and showed preferential epithelial cell uptake in in vitro co-cultures. Further, MSN-AVI particles demonstrated uniform particle distribution in mouse lungs and slow clearance rates. Thus, we provide evidence that avidin functionalized MSNs (MSN-AVI) have the potential to serve as versatile biocompatible drug carriers for lung-specific drug delivery.Mesoporous silica nanoparticles (MSNs) exhibit unique drug delivery properties and are thus considered as promising candidates for next generation nano-medicines. In particular, inhalation into the lungs represents a direct, non-invasive delivery route for treating lung disease. To assess MSN biocompatibility in the lung, we investigated the bioresponse of avidin-coated MSNs (MSN-AVI), as well as aminated (uncoated) MSNs, after direct application into the lungs of mice. We quantified MSN distribution, clearance rate, cell-specific uptake, and inflammatory responses to MSNs within one week after instillation. We show that amine-functionalized (MSN-NH2) particles are not taken up by lung epithelial cells, but induced a prolonged inflammatory response in the lung and macrophage cell death. In contrast, MSN-AVI co-localized with alveolar epithelial type 1 and type 2 cells in the lung in the absence of sustained inflammatory responses or cell death, and showed preferential epithelial cell uptake in in vitro co-cultures. Further, MSN-AVI particles demonstrated uniform particle distribution in mouse lungs and slow clearance rates. Thus, we provide evidence that avidin functionalized MSNs (MSN-AVI) have the potential to serve as versatile biocompatible drug carriers for lung-specific drug delivery. Electronic supplementary information (ESI) available: Synthesis of MSN particles. Characterisation of MSN particles (Fig. S1 and S2), DLS measurements of MSNs over time, lymphocyte and PMN cell count after MSN exposure (Fig. S3). Toxicity in BAL cytospins controls, phalloidin staining on BAL cytospins of MSN-NH2 exposed mice (Fig. S4), nanoparticle distribution in lung cryo-slices of Balb/c mice exposed to 100 μg MSNs (Fig. S5). Balb/c mice cryo-slices exposed to MSN-AVI for 1 or 7 days, co-stained with alveolar epithelial cell type 1 marker or with alveolar epithelial cell type 2 marker (Fig. S6), DiD selective labeling in a co-culture set-up (Fig. S7). See DOI: 10.1039/c5nr04119h

Amplification and propagation of interleukin-1β signaling by murine brain endothelial and glial cells.

PubMed

Krasnow, Stephanie M; Knoll, J Gabriel; Verghese, Santhosh Chakkaramakkil; Levasseur, Peter R; Marks, Daniel L

2017-07-01

During acute infections and chronic illnesses, the pro-inflammatory cytokine interleukin-1β (IL-1β) acts within the brain to elicit metabolic derangements and sickness behaviors. It is unknown which cells in the brain are the proximal targets for IL-1β with respect to the generation of these illness responses. We performed a series of in vitro experiments to (1) investigate which brain cell populations exhibit inflammatory responses to IL-1β and (2) examine the interactions between different IL-1β-responsive cell types in various co-culture combinations. We treated primary cultures of murine brain microvessel endothelial cells (BMEC), astrocytes, and microglia with PBS or IL-1β, and then performed qPCR to measure inflammatory gene expression or immunocytochemistry to evaluate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. To evaluate whether astrocytes and/or BMEC propagate inflammatory signals to microglia, we exposed microglia to astrocyte-conditioned media and co-cultured endothelial cells and glia in transwells. Treatment groups were compared by Student's t tests or by ANOVA followed by Bonferroni-corrected t tests. IL-1β increased inflammatory gene expression and NF-κB activation in primary murine-mixed glia, enriched astrocyte, and BMEC cultures. Although IL-1β elicited minimal changes in inflammatory gene expression and did not induce the nuclear translocation of NF-κB in isolated microglia, these cells were more robustly activated by IL-1β when co-cultured with astrocytes and/or BMEC. We observed a polarized endothelial response to IL-1β, because the application of IL-1β to the abluminal endothelial surface produced a more complex microglial inflammatory response than that which occurred following luminal IL-1β exposure. Inflammatory signals are detected, amplified, and propagated through the CNS via a sequential and reverberating signaling cascade involving communication between brain endothelial cells and glia. We propose that the brain's innate immune response differs depending upon which side of the blood-brain barrier the inflammatory stimulus arises, thus allowing the brain to respond differently to central vs. peripheral inflammatory insults.

ROLE OF TOLL LIKE RECEPTORS ON PULMONARY INFLAMMATORY RESPONSES TO SIZE FRACTIONATED COMBUSTION AND AMBIENT AIR PARTICLES.

EPA Science Inventory

C3H/HeJ mice feature a single point mutation in the Toll like receptor 4 gene which renders these animals resistant to a number of pro-inflammatory agents including lipopolysaccharide and ozone. This study compared pulmonary inflammatory responses in endotoxin resistant (C3H/HeJ...

(−)-Epigallocatechin Gallate Targets Notch to Attenuate the Inflammatory Response in the Immediate Early Stage in Human Macrophages

PubMed Central

Wang, Tengfei; Xiang, Zemin; Wang, Ya; Li, Xi; Fang, Chongye; Song, Shuang; Li, Chunlei; Yu, Haishuang; Wang, Han; Yan, Liang; Hao, Shumei; Wang, Xuanjun; Sheng, Jun

2017-01-01

Inflammation plays important roles at different stages of diabetes mellitus, tumorigenesis, and cardiovascular diseases. (−)-Epigallocatechin gallate (EGCG) can attenuate inflammatory responses effectively. However, the immediate early mechanism of EGCG in inflammation remains unclear. Here, we showed that EGCG attenuated the inflammatory response in the immediate early stage of EGCG treatment by shutting off Notch signaling and that the effect did not involve the 67-kDa laminin receptor, the common receptor for EGCG. EGCG eliminated mature Notch from the cell membrane and the nuclear Notch intercellular domain, the active form of Notch, within 2 min by rapid degradation via the proteasome pathway. Transcription of the Notch target gene was downregulated simultaneously. Knockdown of Notch 1/2 expression by RNA interference impaired the downregulation of the inflammatory response elicited by EGCG. Further study showed that EGCG inhibited lipopolysaccharide-induced inflammation and turned off Notch signaling in human primary macrophages. Taken together, our results show that EGCG targets Notch to regulate the inflammatory response in the immediate early stage. PMID:28443100

Cefotaxime Treatment of Pelvic Inflammatory Disease

PubMed Central

Monson, Thomas P.; Miller, Timothy T.; Nolan, Charles M.

1981-01-01

We studied cefotaxime in the treatment of gonococcal and nongonococcal pelvic inflammatory disease. Cefotaxime was uniformly effective against gonococcal pelvic inflammatory disease. However, 4 of 11 patients with nongonococcal pelvic inflammatory disease had a suboptimal response. PMID:6275789

Involvement of cholinergic and adenosinergic systems on the branchial immune response of experimentally infected silver catfish with Streptococcus agalactiae.

PubMed

Baldissera, M D; Souza, C F; Doleski, P H; Moreira, K L S; da Veiga, M L; da Rocha, M I U M; Santos, R C V; Baldisserotto, B

2018-01-01

It has been recognized that the cholinergic and adenosinergic systems have an essential role in immune and inflammatory responses during bacterial fish pathogens, such as the enzymes acetylcholinesterase (AChE) and adenosine deaminase (ADA), which are responsible for catalysis of the anti-inflammatory molecules acetylcholine (ACh) and adenosine (Ado) respectively. Thus, the aim of this study was to investigate the involvement of the cholinergic and adenosinergic systems on the immune response and inflammatory process in gills of experimentally infected Rhamdia quelen with Streptococcus agalactiae. Acetylcholinesterase activity decreased, while ACh levels increased in gills of infected animals compared to uninfected animals. On the other hand, a significant increase in ADA activity with a concomitant decrease in Ado levels was observed in infected animals compared to uninfected animals. Based on this evidence, we concluded that infection by S. agalactiae in silver catfish alters the cholinergic and adenosinergic systems, suggesting the involvement of AChE and ADA activities on immune and inflammatory responses, regulating the ACh and Ado levels. In summary, the downregulation of AChE activity exerts an anti-inflammatory profile in an attempt to reduce or prevent the tissue damage, while the upregulation of ADA activity exerts a pro-inflammatory profile, contributing to disease pathophysiology. © 2017 John Wiley & Sons Ltd.

Amniotic Fluid Protein Profiles of Intraamniotic Inflammatory Response to Ureaplasma spp. and Other Bacteria

PubMed Central

Kacerovsky, Marian; Celec, Peter; Vlkova, Barbora; Skogstrand, Kristin; Hougaard, David M.; Cobo, Teresa; Jacobsson, Bo

2013-01-01

Objective This study aimed to evaluate the amniotic fluid protein profiles and the intensity of intraamniotic inflammatory response to Ureaplasma spp. and other bacteria, using the multiplex xMAP technology. Methods A retrospective cohort study was undertaken in the Department of Obstetrics and Gynecology, University Hospital Hradec Kralove, Czech Republic. A total of 145 pregnant women with preterm prelabor rupture of membranes between gestational age 24+0 and 36+6 weeks were included in the study. Amniocenteses were performed. The presence of Ureaplasma spp. and other bacteria was evaluated using 16S rRNA gene sequencing. The levels of specific proteins were determined using multiplex xMAP technology. Results The presence of Ureaplasma spp. and other bacteria in the amniotic fluid was associated with increased levels of interleukin (IL)-6, IL-8, IL-10, brain-derived neurotropic factor, granulocyte macrophage colony stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and matrix metalloproteinasis-9. Ureaplasma spp. were also associated with increased levels of neurotropin-3 and triggering receptor expressed on myeloid cells-1. Conclusions The presence of Ureaplasma spp. in the amniotic fluid is associated with a slightly different protein profile of inflammatory response, but the intensity of inflammatory response to Ureaplasma spp. is comparable with the inflammatory response to other bacteria. PMID:23555967

Amniotic fluid protein profiles of intraamniotic inflammatory response to Ureaplasma spp. and other bacteria.

PubMed

Kacerovsky, Marian; Celec, Peter; Vlkova, Barbora; Skogstrand, Kristin; Hougaard, David M; Cobo, Teresa; Jacobsson, Bo

2013-01-01

This study aimed to evaluate the amniotic fluid protein profiles and the intensity of intraamniotic inflammatory response to Ureaplasma spp. and other bacteria, using the multiplex xMAP technology. A retrospective cohort study was undertaken in the Department of Obstetrics and Gynecology, University Hospital Hradec Kralove, Czech Republic. A total of 145 pregnant women with preterm prelabor rupture of membranes between gestational age 24+0 and 36+6 weeks were included in the study. Amniocenteses were performed. The presence of Ureaplasma spp. and other bacteria was evaluated using 16S rRNA gene sequencing. The levels of specific proteins were determined using multiplex xMAP technology. The presence of Ureaplasma spp. and other bacteria in the amniotic fluid was associated with increased levels of interleukin (IL)-6, IL-8, IL-10, brain-derived neurotropic factor, granulocyte macrophage colony stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and matrix metalloproteinasis-9. Ureaplasma spp. were also associated with increased levels of neurotropin-3 and triggering receptor expressed on myeloid cells-1. The presence of Ureaplasma spp. in the amniotic fluid is associated with a slightly different protein profile of inflammatory response, but the intensity of inflammatory response to Ureaplasma spp. is comparable with the inflammatory response to other bacteria.

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

PubMed

Romme Christensen, Jeppe; Komori, Mika; von Essen, Marina Rode; Ratzer, Rikke; Börnsen, Lars; Bielekova, Bibi; Sellebjerg, Finn

2018-05-01

Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Antinociceptive and anti-inflammatory effects of the methanolic stem bark extract of Antrocaryon klaineanum Pierre (Anacardiaceae) in mice and rat.

PubMed

Fongang, Annie Laure Magne; Laure Nguemfo, Edwige; Djouatsa Nangue, Yolande; Bogning Zangueu, Calvin; Fouokeng, Yannick; Azebaze, Anatole Guy Blaise; José Llorent-Martínez, Eulogio; Córdova, Maria Luisa Fernández-de; Bertrand Dongmo, Alain; Vierling, Wolfgang

2017-05-05

Antrocaryon klaineanum is used by traditional healers to treat many disorders including pain and inflammatory diseases. This study aimed to evaluate the analgesic and antiinflammatory activities of methanol extract of A. klaineanum in mice and rats. Reverse phase high-performance liquid chromatography (RP-HPLC) was performed to establish the chromatographic fingerprint and to identify various chemical components of the plant extract. The anti-nociceptive activity of methanol extract of A. klaineanum was assessed using the acetic acid-induced abdominal constriction model, formalin test, capsaicin and cinnamaldehyde induced-neurogenic pain and hot plate test. Anti-inflammatory activity was assessed on carrageenan-induced inflammation. Extract was administrated orally at 200, 400 and 600mg/kg. Phytochemical analysis indicated the presence of proanthocyanidins, phenolic acids and flavonoids. The results of anti-nociceptive and anti-inflammatory activities showed that methanol extract significantly (p<0.01) reduced the pain induced by acetic acid with an inhibition percentage of 45.49% (600mg/kg). In the formalin test, the extract also significantly (p<0.01) reduced linking time in both phase (neurogenic and inflammatory) of the test with inhibition percentage of 56.28% and 60.73% respectively at the dose of 600mg/kg. The methanol extract of A. klaineanum significantly (P<0.001) reduced neurogenic pain linking time induced by capsaicin and cinnamaldehyde by 82.54% and 75.94% at the highest dose (600mg/kg) respectively. More over the extract significantly increase the reaction time in hot plate test. In the inflammatory test, the plant extract significantly reduced the carrageen induced rat paw oedema from 30min to 6h with a maximum percentage inhibition of 89.88% (6h) at the dose of 600mg/kg. These results demonstrate that the methanol extract of A. klaineanum may possess analgesic and anti-inflammatory effects and provide support of the traditional use of this plant in the treatment of different pain and inflammatory conditions. Further investigation could reveal metabolites of the extract responsible for the observed effects. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Expression and Function of Anti-Inflammatory Interleukins: The Other Side of the Vascular Response to Injury

PubMed Central

Cuneo, Anthony A.; Autieri, Michael V.

2012-01-01

Common to multiple vascular diseases, including atherosclerosis, interventional restenosis, and transplant vasculopathy, is a localized inflammatory reaction. Activated vascular smooth muscle cells (VSMC) respond to local inflammation and migrate from the media into the lumen of the vessel where they proliferate and synthesize cytokines which they respond to in an autocrine fashion, sustaining the progression of the lesion. The deleterious effects of pro-inflammatory cytokines, particularly immunomodulatory interleukins, on vascular pathophysiology and development of these maladaptive processes have been the subject of intense study. Although a great deal of attention has been given to the negative effects of pro-inflammatory cytokines and interleukins, relatively little has been reported on the potentially beneficial paracrine and autocrine effects of anti-inflammatory interleukins on the vascular response to injury. The vast majority of emphasis on secretion and function of anti-inflammatory mediators has been placed on leukocytes. Consequently, the role of non-immune cells, and direct effects of anti-inflammatory interleukins on vascular cells is poorly understood. We will review the molecular mechanisms whereby anti-inflammatory interleukins inhibit signal transduction and gene expression in inflammatory cells. We will review studies in which beneficial “indirect” effects of anti-inflammatory interleukins on progression of vascular disease are achieved by modulation of immune function. We will also present the limited studies in which “direct” effects of these interleukins on VSMC and endothelial cells dampen the vascular response to injury. We propose that expression of immunomodulatory cytokines by activated vasculature may represent an auto-regulatory feed back mechanism to promote resolution of the vascular response to injury. PMID:19601851

Treatment with Sulforaphane Produces Antinociception and Improves Morphine Effects during Inflammatory Pain in Mice.

PubMed

Redondo, Alejandro; Chamorro, Pablo Aníbal Ferreira; Riego, Gabriela; Leánez, Sergi; Pol, Olga

2017-12-01

The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts potent antioxidative and anti-inflammatory effects; however, its participation in the modulation of chronic inflammatory pain and on the antinociceptive effects of μ -opioid receptor (MOR) agonists has not been evaluated. We investigated whether the induction of Nrf2 could alleviate chronic inflammatory pain and augment the analgesic effects of morphine and mechanisms implicated. In male C57BL/6 mice with inflammatory pain induced by complete Freund's adjuvant (CFA) subplantarly administered, we assessed: 1) antinociceptive actions of the administration of 5 and 10 mg/kg of a Nrf2 activator, sulforaphane (SFN); and 2) effects of SFN on the antinociceptive actions of morphine and on protein levels of Nrf2, heme oxygenase 1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO1) enzymes, microglial activation and inducible nitric oxide synthase (NOS2) overexpression, as well as on mitogen-activated protein kinase (MAPK) and MOR expression in the spinal cord and paw of animals with inflammatory pain. Results showed that treatment with SFN inhibited allodynia and hyperalgesia induced by CFA and increased the local antinociceptive actions of morphine. This treatment also augmented the expression of Nrf2, HO-1, NQO1, and MOR, and inhibited NOS2 and CD11b/c overexpression and MAPK phosphorylation induced by inflammation. Thus, this study shows that the induction of Nrf2 might inhibit inflammatory pain and enhance the analgesic effects of morphine by inhibiting oxidative stress and inflammatory responses induced by peripheral inflammation. This study suggests the administration of SFN alone and in combination with morphine are potential new ways of treating chronic inflammatory pain. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Anti-inflammatory effects of fimasartan via Akt, ERK, and NFκB pathways on astrocytes stimulated by hemolysate.

PubMed

Yang, Xiu-Li; Kim, Chi Kyung; Kim, Tae Jung; Sun, Jing; Rim, Doeun; Kim, Young-Ju; Ko, Sang-Bae; Jang, Hyunduk; Yoon, Byung-Woo

2016-02-01

The aim of this study was to investigate whether fimasartan, a novel angiotensin II receptor blocker, modulates hemolysate-induced inflammation in astrocytes. We stimulated astrocytes with hemolysate to induce hemorrhagic inflammation in vitro. Astrocytes were pretreated with fimasartan and then incubated with hemolysate at different durations. Anti-inflammatory cell signaling molecules including Akt, extracellular signal regulated kinase (ERK), NFκB and cyclooxygenase-2 (COX-2) were assessed by western blotting. Pro-inflammatory mediators were evaluated by real-time RT-PCR and ELISA. The stimulation by hemolysate generated a robust activation of inflammatory signaling pathways in astrocytes. Hemolysate increased the phosphorylation of Akt at 1 h, and ERK1/2 at 20 min compared with the control group and promoted the degradation of IκBα. Pretreated fimasartan significantly decreased hemolysate-induced phosphorylation of Akt and ERK1/2. In addition, fimasartan also suppressed NFκB-related inflammatory pathways induced by hemolysate, including reduction of the gene expression of NFκB, and decreased nuclear translocation of NFκB and degradation of IκB. This reduction of inflammatory upstream pathways decreased the expression of inflammatory end-products: COX-2 and interleukin-1 (IL-1β). Furthermore, the expression of COX-2 was attenuated by both Akt inhibitor (LY294002) and ERK inhibitor (U0126), and IκBα degradation was suppressed by LY294002. These results demonstrate that pretreatment with fimasartan to astrocytes suppresses the inflammatory responses induced by hemolysate. Akt, ERK and NFκB were associated with hemolysate-induced COX-2 and IL-1β expression. Based on these mechanisms, fimasartan could be a candidate anti-inflammatory regulator for the treatment of intracerebral hemorrhage.

Anti-inflammatory evaluation and characterization of leaf extract of Ananas comosus.

PubMed

Kargutkar, Samira; Brijesh, S

2018-04-01

Ananas comosus (L.) Merr (Pineapple) is a tropical plant with an edible fruit. In the present study, the potential anti-inflammatory activity of A. comosus leaf extract (ALE) was studied. ALE prepared using soxhlet apparatus was subjected to preliminary qualitative phytochemical analysis and quantitative estimations of flavonoids and tannins. The components present in ALE were identified using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). Inhibitory effects of ALE on protein denaturation, and proteinase activity were assessed. Its effect on secretion of pro-inflammatory cytokines and inflammatory mediators by lipopolysaccharide-stimulated macrophages was also analyzed. Further, its anti-inflammatory activity in carrageenan-induced inflammatory rat model was examined. The preliminary qualitative phytochemical analysis revealed presence of flavonoids, phenols, tannins, carbohydrates, glycosides, and proteins in the extract. Total flavonoids and total tannins were 0.17 ± 0.006 mg equivalent of quercetin/g of ALE and 4.04 ± 0.56 mg equivalent of gallic acid/g of ALE. LC-MS analysis identified the presence of 4-hydroxy pelargonic acid, 3,4,5-trimethoxycinnamic and 4-methoxycinnamic acid, whereas GC-MS analysis identified the presence of campesterol and ethyl isoallocholate that have been previously reported for anti-inflammatory activity. ALE showed significant inhibition of protein denaturation and proteinase activity and also controlled secretion of tumour necrosis factor-α, interleukin-1β and prostaglandins, as well as the generation of reactive oxygen species by activated macrophages. ALE also significantly decreased carrageenan-induced acute paw edema. The study, therefore, identified the components present in ALE that may be responsible for its anti-inflammatory activity and thus demonstrated its potential use against acute inflammatory diseases.

Natural Products: Insights into Leishmaniasis Inflammatory Response

PubMed Central

Rodrigues, Igor A.; Mazotto, Ana Maria; Cardoso, Verônica; Alves, Renan L.; Amaral, Ana Claudia F.; Silva, Jefferson Rocha de Andrade; Pinheiro, Anderson S.; Vermelho, Alane B.

2015-01-01

Leishmaniasis is a vector-borne disease that affects several populations worldwide, against which there are no vaccines available and the chemotherapy is highly toxic. Depending on the species causing the infection, the disease is characterized by commitment of tissues, including the skin, mucous membranes, and internal organs. Despite the relevance of host inflammatory mediators on parasite burden control, Leishmania and host immune cells interaction may generate an exacerbated proinflammatory response that plays an important role in the development of leishmaniasis clinical manifestations. Plant-derived natural products have been recognized as bioactive agents with several properties, including anti-protozoal and anti-inflammatory activities. The present review focuses on the antileishmanial activity of plant-derived natural products that are able to modulate the inflammatory response in vitro and in vivo. The capability of crude extracts and some isolated substances in promoting an anti-inflammatory response during Leishmania infection may be used as part of an effective strategy to fight the disease. PMID:26538837

Inflammatory responses to psychological stress in fatigued breast cancer survivors: relationship to glucocorticoids.

PubMed

Bower, Julienne E; Ganz, Patricia A; Aziz, Najib; Olmstead, Richard; Irwin, Michael R; Cole, Steve W

2007-03-01

Fatigue is a common problem following cancer treatment and our previous studies suggest that a chronic inflammatory process might contribute to cancer-related fatigue. However, immune responses to challenge have not yet been evaluated among individuals with cancer-related fatigue, and it is not known what mechanisms drive increased levels of inflammatory markers in fatigued cancer survivors. We have previously reported that fatigued breast cancer survivors show a blunted cortisol response to an experimental psychological stressor. In this report, we focus on inflammatory responses to this stressor and their relationship to circulating glucocorticoids and cellular sensitivity to glucocorticoid inhibition. Relative to non-fatigued control survivors, participants experiencing persistent fatigue showed significantly greater increases in LPS-stimulated production of IL-1beta and IL-6 following the stressor (Group x Time interaction: p<.05). Fatigued participants did not show any difference in cellular sensitivity to cortisol inhibition of cytokine production, but they did show significantly less salivary cortisol increase in the aftermath of the stressor. Moreover, blunted cortisol responses were associated with significantly increased production of IL-6 in response to LPS stimulation (p<.05). These data provide further evidence of enhanced inflammatory processes in fatigued breast cancer survivors and suggest that these processes may stem in part from decreased glucocorticoid response to stress.

Uric acid promotes an acute inflammatory response to sterile cell death in mice

PubMed Central

Kono, Hajime; Chen, Chun-Jen; Ontiveros, Fernando; Rock, Kenneth L.

2010-01-01

Necrosis stimulates inflammation, and this response is medically relevant because it contributes to the pathogenesis of a number of diseases. It is thought that necrosis stimulates inflammation because dying cells release proinflammatory molecules that are recognized by the immune system. However, relatively little is known about the molecular identity of these molecules and their contribution to responses in vivo. Here, we investigated the role of uric acid in the inflammatory response to necrotic cells in mice. We found that dead cells not only released intracellular stores of uric acid but also produced it in large amounts postmortem as nucleic acids were degraded. Using newly developed Tg mice that have reduced levels of uric acid either intracellularly and/or extracellularly, we found that uric acid depletion substantially reduces the cell death–induced inflammatory response. Similar results were obtained with pharmacological treatments that reduced uric acid levels either by blocking its synthesis or hydrolyzing it in the extracellular fluids. Importantly, uric acid depletion selectively inhibited the inflammatory response to dying cells but not to microbial molecules or sterile irritant particles. Collectively, our data identify uric acid as a proinflammatory molecule released from dying cells that contributes significantly to the cell death–induced inflammatory responses in vivo. PMID:20501947

Th1/Th2 immune responses and oxidative stress in caprine flea allergy dermatitis.

PubMed

Ajith, Y; Dimri, U; Gopalakrishnan, A; Madhesh, E; Jhambh, R; Joshi, V; Devi, G

2017-12-01

Flea allergy dermatitis (FAD) is the common, often neglected skin disease of goats caused mainly by Ctenocephalides felis. This study aimed to evaluate the immuno-oxidative pathobiology of FAD in goats. Twelve goats from the same herd were divided into two groups of six animals each. The group I (FAD) included animals with natural flea infestation and severe dermatitis lesions. The group II (Healthy control) animals were free from any parasitic infestation. To assess the pathological changes, the markers of oxidative stress (lipid peroxidation, reduced glutathione and total antioxidant capacity), and immune status (Tumour necrosis factor alpha, Interleukin 10, Transforming growth factor beta 1 and Th1/Th2 cytokine ratio) were evaluated from the blood and the serum samples. Remarkable oxidative stress and severe inflammatory response with Th2 cytokine dominance were observed in flea infested animals. Highly antigenic agents of fleas, either secretory or excretory or structural, induced severe inflammatory responses and significant oxidative stress in caprine FAD. Massive release of cytokines may be responsible for severe skin inflammation and lesions in FAD in contrast to other Th2 dominant ectoparasitic skin conditions of goats'. © 2017 John Wiley & Sons Ltd.

Safety, Clinical Response, and Microbiome Findings Following Fecal Microbiota Transplant in Children With Inflammatory Bowel Disease.

PubMed

Goyal, Alka; Yeh, Andrew; Bush, Brian R; Firek, Brian A; Siebold, Leah M; Rogers, Matthew Brian; Kufen, Adam D; Morowitz, Michael J

2018-01-18

The role of fecal microbiota transplant (FMT) in the treatment of pediatric inflammatory bowel disease (IBD) is unknown. The aims of this study were to assess safety, clinical response, and gut microbiome alterations in children with Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). In this open-label, single-center prospective trial, patients with IBD refractory to medical therapy underwent a single FMT by upper and lower endoscopy. Adverse events, clinical response, gut microbiome, and biomarkers were assessed at baseline, 1 week, 1 month, and 6 months following FMT. Twenty-one subjects were analyzed, with a median age of 12 years, of whom 57% and 28% demonstrated clinical response at 1 and 6 months post-FMT, respectively. Two CD patients were in remission at 6 months. Adverse events attributable to FMT were mild to moderate and self-limited. Patients prior to FMT showed decreased species diversity and significant microbiome compositional differences characterized by increased Enterobacteriaceae, Enterococcus, Haemophilus, and Fusobacterium compared with donors and demonstrated increased species diversity at 30 days post-FMT. At 6 months, these changes shifted toward baseline. Clinical responders had a higher relative abundance of Fusobacterium and a lower diversity at baseline, as well as a greater shift toward donor-like microbiome after FMT compared with nonresponders. A single FMT is relatively safe and can result in a short-term response in young patients with active IBD. Responders possessed increased Fusobacterium prior to FMT and demonstrated more significant microbiome changes compared with nonresponders after FMT. Microbiome characteristics may help in predicting response. © 2018 Crohn’s & Colitis Foundation of America. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Regulation of mitochondrial biogenesis and its intersection with inflammatory responses.

PubMed

Cherry, Anne D; Piantadosi, Claude A

2015-04-20

Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis and antioxidant gene expression. Recent evidence suggests that mitochondrial biogenesis and mitophagy are coupled through redox pathways; for instance, parkin, which regulates mitophagy in chronic inflammation, may also modulate mitochondrial biogenesis and is upregulated through NF-κB. Further research on parkin in acute inflammation is ongoing. This highlights certain common features of the host response to acute and chronic inflammation, but caution is warranted in extrapolating findings across inflammatory conditions. Inflammatory mitochondrial dysfunction and oxidative stress initiate further inflammatory responses through DAMP/PRR interactions and by inflammasome activation, stimulating mitophagy. A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve our approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation.

Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges.

PubMed

Huang, Shuaibo; Frangogiannis, Nikolaos G

2018-05-01

In the infarcted heart, the damage-associated molecular pattern proteins released by necrotic cells trigger both myocardial and systemic inflammatory responses. Induction of chemokines and cytokines and up-regulation of endothelial adhesion molecules mediate leukocyte recruitment in the infarcted myocardium. Inflammatory cells clear the infarct of dead cells and matrix debris and activate repair by myofibroblasts and vascular cells, but may also contribute to adverse fibrotic remodelling of viable segments, accentuate cardiomyocyte apoptosis and exert arrhythmogenic actions. Excessive, prolonged and dysregulated inflammation has been implicated in the pathogenesis of complications and may be involved in the development of heart failure following infarction. Studies in animal models of myocardial infarction (MI) have suggested the effectiveness of pharmacological interventions targeting the inflammatory response. This article provides a brief overview of the cell biology of the post-infarction inflammatory response and discusses the use of pharmacological interventions targeting inflammation following infarction. Therapy with broad anti-inflammatory and immunomodulatory agents may also inhibit important repair pathways, thus exerting detrimental actions in patients with MI. Extensive experimental evidence suggests that targeting specific inflammatory signals, such as the complement cascade, chemokines, cytokines, proteases, selectins and leukocyte integrins, may hold promise. However, clinical translation has proved challenging. Targeting IL-1 may benefit patients with exaggerated post-MI inflammatory responses following infarction, not only by attenuating adverse remodelling but also by stabilizing the atherosclerotic plaque and by inhibiting arrhythmia generation. Identification of the therapeutic window for specific interventions and pathophysiological stratification of MI patients using inflammatory biomarkers and imaging strategies are critical for optimal therapeutic design. © 2018 The British Pharmacological Society.

Macrophage Response to UHMWPE Submitted to Accelerated Ageing in Hydrogen Peroxide

PubMed Central

Rocha, Magda F.G.; Mansur, Alexandra A.P.; Martins, Camila P.S.; Barbosa-Stancioli, Edel F.; Mansur, Herman S.

2010-01-01

Ultra-high molecular weight polyethylene (UHMWPE) has been the most commonly used bearing material in total joint arthroplasty. Wear and oxidation fatigue resistance of UHMWPE are regarded as two important properties to extend the longevity of knee prostheses. The present study investigated the accelerated ageing of UHMWPE in hydrogen peroxide highly oxidative chemical environment. The sliced samples of UHMWPE were oxidized in a hydrogen peroxide solution for 120 days with their total level of oxidation (Iox) characterized by Fourier Transformed Infrared Spectroscopy (FTIR). The potential inflammatory response, cell viability and biocompatibility of such oxidized UHMWPE systems were assessed by a novel biological in vitro assay based on the secretion of nitric oxide (NO) by activated murine macrophages with gamma interferon (IFN-γ) cytokine and lipopolysaccharide (LPS). Furthermore, macrophage morphologies in contact with UHMWPE oxidized surfaces were analyzed by cell spreading-adhesion procedure using scanning electron microscopy (SEM). The results have given significant evidence that the longer the period of accelerated aging of UHMWPE the higher was the macrophage inflammatory equivalent response based on NO secretion analysis. PMID:20721321

The lipid A of Burkholderia multivorans C1576 smooth-type lipopolysaccharide and its pro-inflammatory activity in a cystic fibrosis airways model.

PubMed

Ieranò, Teresa; Cescutti, Paola; Leone, Maria Rosaria; Luciani, Alessandro; Rizzo, Roberto; Raia, Valeria; Lanzetta, Rosa; Parrilli, Michelangelo; Maiuri, Luigi; Silipo, Alba; Molinaro, Antonio

2010-12-01

Cystic fibrosis is an autosomal recessive disorder and it is characterised by chronic bacterial airway infection which leads to progressive lung deterioration, sometimes with fatal outcome. Burkholderia multivorans and Burkholderia cenocepacia are the species responsible for most of the infections of cystic fibrosis patients. Lipopolysaccharide endotoxins (LPSs) are among the foremost factors of pathogenesis of Gram-negative infection and, in particular, lipid A is the endotoxic portion of LPS responsible for eliciting host innate immune response. In this work, the complete primary structure of the lipid A from B. multivorans C1576 has been defined and, further, its pro-inflammatory activity in a cystic fibrosis airways model is shown. The structure of B. multivorans lipid A was attained by chemical, mass spectrometry and nuclear magnetic resonance analyses whereas its biological activity was assessed on the intestinal epithelial cell line CACO-2 cells, on the airway epithelial IB3-1 cells, carrying the ΔF508/W1282X CFTR mutation and on an ex vivo model of culture explants of nasal polyps.

Antibiotic and Anti-Inflammatory Therapies for Cystic Fibrosis

PubMed Central

Chmiel, James F.; Konstan, Michael W.; Elborn, J. Stuart

2013-01-01

Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and an unremitting inflammatory response, which are responsible for most of CF morbidity and mortality. The median expected survival has increased from <6 mo in 1940 to >38 yr now. This dramatic improvement, although not great enough, is due to the development of therapies directed at secondary disease pathologies, especially antibiotics. The importance of developing treatments directed against the vigorous inflammatory response was realized in the 1990s. New therapies directed toward the basic defect are now visible on the horizon. However, the impact of these drugs on downstream pathological consequences is unknown. It is likely that antibiotics and anti-inflammatory drugs will remain an important part of the maintenance regimen for CF in the foreseeable future. Current and future antibiotic and anti-inflammatory therapies for CF are reviewed. PMID:23880054

A New Human 3D-Liver Model Unravels the Role of Galectins in Liver Infection by the Parasite Entamoeba histolytica

PubMed Central

Petropolis, Debora B.; Faust, Daniela M.; Deep Jhingan, Gagan; Guillen, Nancy

2014-01-01

Investigations of human parasitic diseases depend on the availability of appropriate in vivo animal models and ex vivo experimental systems, and are particularly difficult for pathogens whose exclusive natural hosts are humans, such as Entamoeba histolytica, the protozoan parasite responsible for amoebiasis. This common infectious human disease affects the intestine and liver. In the liver sinusoids E. histolytica crosses the endothelium and penetrates into the parenchyma, with the concomitant initiation of inflammatory foci and subsequent abscess formation. Studying factors responsible for human liver infection is hampered by the complexity of the hepatic environment and by the restrictions inherent to the use of human samples. Therefore, we built a human 3D-liver in vitro model composed of cultured liver sinusoidal endothelial cells and hepatocytes in a 3D collagen-I matrix sandwich. We determined the presence of important hepatic markers and demonstrated that the cell layers function as a biological barrier. E. histolytica invasion was assessed using wild-type strains and amoebae with altered virulence or different adhesive properties. We showed for the first time the dependence of endothelium crossing upon amoebic Gal/GalNAc lectin. The 3D-liver model enabled the molecular analysis of human cell responses, suggesting for the first time a crucial role of human galectins in parasite adhesion to the endothelial cells, which was confirmed by siRNA knockdown of galectin-1. Levels of several pro-inflammatory cytokines, including galectin-1 and -3, were highly increased upon contact of E. histolytica with the 3D-liver model. The presence of galectin-1 and -3 in the extracellular medium stimulated pro-inflammatory cytokine release, suggesting a further role for human galectins in the onset of the hepatic inflammatory response. These new findings are relevant for a better understanding of human liver infection by E. histolytica. PMID:25211477

Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia induce distinct host responses

PubMed Central

McConnell, Kevin W.; McDunn, Jonathan E.; Clark, Andrew T.; Dunne, W. Michael; Dixon, David J.; Turnbull, Isaiah R.; DiPasco, Peter J.; Osberghaus, William F.; Sherman, Benjamin; Martin, James R.; Walter, Michael J.; Cobb, J. Perren; Buchman, Timothy G.; Hotchkiss, Richard S.; Coopersmith, Craig M.

2009-01-01

Objective Pathogens that cause pneumonia may be treated in a targeted fashion by antibiotics, but if this therapy fails, treatment involves only non-specific supportive measures, independent of the inciting infection. The purpose of this study was to determine whether host response is similar following disparate infections with similar mortalities. Design Prospective, randomized controlled study. Setting Animal laboratory in a university medical center. Interventions Pneumonia was induced in FVB/N mice by either Streptococcus pneumoniae or two different concentrations of Pseudomonas aeruginosa. Plasma and bronchoalveolar lavage fluid from septic animals was assayed by a microarray immunoassay measuring 18 inflammatory mediators at multiple timepoints. Measurements and Main Results The host response was dependent upon the causative organism as well as kinetics of mortality, but the pro- and anti- inflammatory response was independent of inoculum concentration or degree of bacteremia. Pneumonia caused by different concentrations of the same bacteria, Pseudomonas aeruginosa, also yielded distinct inflammatory responses; however, inflammatory mediator expression did not directly track the severity of infection. For all infections, the host response was compartmentalized, with markedly different concentrations of inflammatory mediators in the systemic circulation and the lungs. Hierarchical clustering analysis resulted in the identification of 5 distinct clusters of the host response to bacterial infection. Principal components analysis correlated pulmonary MIP-2 and IL-10 with progression of infection while elevated plasma TNFsr2 and MCP-1 were indicative of fulminant disease with >90% mortality within 48 hours. Conclusions Septic mice have distinct local and systemic responses to Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia. Targeting specific host inflammatory responses induced by distinct bacterial infections could represent a potential therapeutic approach in the treatment of sepsis. PMID:19770740

[Persistence of chronic inflammatory responses, role in the development of chronic pancreatitis, obesity and pancreatic cancer].

PubMed

Khristich, T N

2014-11-01

The purpose of the review--to analyze the basic data of the role of chronic low-intensity inflammatory response as general biological process in the development and progression of chronic pancreatitis, obesity, and pancreatic cancer. Highlighted evidence from epidemiological studies showing that chronic pancreatitis and obesity are independent risk factors for pancreatic cancer, regardless of diabetes. Studied role of adipokines as Cytokines regulating of immune inflammatory response. Draws attention to the staging of pancreatic cancer in obesity.

Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia.

PubMed

Torgrimson-Ojerio, Britta; Ross, Rebecca L; Dieckmann, Nathan F; Avery, Stephanie; Bennett, Robert M; Jones, Kim D; Guarino, Anthony J; Wood, Lisa J

2014-12-15

Exercise intolerance, as evidenced by a worsening of pain, fatigue, and stiffness after novel exertion, is a key feature of fibromyalgia (FM). In this pilot study, we investigate whether; insufficient muscle repair processes and impaired anti-inflammatory mechanisms result in an exaggerated pro-inflammatory cytokine response to exhaustive exercise, and consequently a worsening of muscle pain, stiffness and fatigue in the days post-exercise. We measured changes in muscle pain and tenderness, fatigue, stiffness, and serum levels of neuroendocrine and inflammatory cytokine markers in 20 women with FM and 16 healthy controls (HCs) before and after exhaustive treadmill exercise. Compared to HCs, FM participants failed to mount the expected anti-inflammatory response to exercise and experienced a worsening of symptoms post-exercise. However, changes in post-exertional symptoms were not mediated by post-exertional changes in pro-inflammatory cytokine levels. Implications of these findings are discussed. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Glucocorticoids shift arachidonic acid metabolism toward endocannabinoid synthesis: a non-genomic anti-inflammatory switch

PubMed Central

Malcher-Lopes, Renato; Franco, Alier; Tasker, Jeffrey G.

2008-01-01

Glucocorticoids are capable of exerting both genomic and non-genomic actions in target cells of multiple tissues, including the brain, which trigger an array of electrophysiological, metabolic, secretory and inflammatory regulatory responses. Here, we have attempted to show how glucocorticoids may generate a rapid anti-inflammatory response by promoting arachidonic acid-derived endocannabinoid biosynthesis. According to our hypothesized model, non-genomic action of glucocorticoids results in the global shift of membrane lipid metabolism, subverting metabolic pathways toward the synthesis of the anti-inflammatory endocannabinoids, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), and away from arachidonic acid production. Post-transcriptional inhibition of cyclooxygenase-2 (COX2) synthesis by glucocorticoids assists this mechanism by suppressing the synthesis of pro-inflammatory prostaglandins as well as endocannabinoid-derived prostanoids. In the central nervous system (CNS) this may represent a major neuroprotective system, which may cross-talk with leptin signaling in the hypothalamus allowing for the coordination between energy homeostasis and the inflammatory response. PMID:18295199

The orphan nuclear receptor TLX regulates hippocampal transcriptome changes induced by IL-1β.

PubMed

Ó'Léime, Ciarán S; Hoban, Alan E; Hueston, Cara M; Stilling, Roman; Moloney, Gerard; Cryan, John F; Nolan, Yvonne M

2018-05-01

TLX is an orphan nuclear receptor highly expressed within neural progenitor cells (NPCs) in the hippocampus where is regulates proliferation. Inflammation has been shown to have negative effects on hippocampal function as well as on NPC proliferation. Specifically, the pro-inflammatory cytokine IL-1β suppresses NPC proliferation as well as TLX expression in the hippocampus. However, it is unknown whether TLX itself is involved in regulating the inflammatory response in the hippocampus. To explore the role of TLX in inflammation, we assessed changes in the transcriptional landscape of the hippocampus of TLX knockout mice (TLX -/- ) compared to wildtype (WT) littermate controls with and without intrahippocampal injection of IL-1β using a whole transcriptome RNA sequencing approach. We demonstrated that there is an increase in the transcription of genes involved in the promotion of inflammation and regulation of cell chemotaxis (Tnf, Il1b, Cxcr1, Cxcr2, Tlr4) and a decrease in the expression of genes relating to synaptic signalling (Lypd1, Syt4, Cplx2) in cannulated TLX -/- mice compared to WT controls. We demonstrate that mice lacking in TLX share a similar increase in 176 genes involved in regulating inflammation (e.g. Cxcl1, Tnf, Il1b) as WT mice injected with IL-1β into the hippocampus. Moreover, TLX -/- mice injected with IL-1β displayed a blunted transcriptional profile compared to WT mice injected with IL-1β. Thus, TLX -/- mice, which already have an exaggerated inflammatory profile after cannulation surgery, are primed to respond differently to an inflammatory stimulus such as IL-1β. Together, these results demonstrate that TLX regulates hippocampal inflammatory transcriptome response to brain injury (in this case cannulation surgery) and cytokine stimulation. Copyright © 2018 Elsevier Inc. All rights reserved.

Differential release and deposition of S100A8/A9 proteins in inflamed upper airway tissue.

PubMed

Van Crombruggen, Koen; Vogl, Thomas; Pérez-Novo, Claudina; Holtappels, Gabriele; Bachert, Claus

2016-01-01

Intracellular Ca(2+)-binding S100A8/A9 proteins gain novel functions when released during inflammation. The exact outcome of their extracellular function depends on the local tissue environment in which they are released; both anti-inflammatory and pro-inflammatory responses are described, modulating the immune system by binding Toll-like receptor (TLR)-4 or the receptor for advanced glycation end-products (RAGE). However, the contribution of the proteins in the pathophysiology of chronic rhinosinusitis (CRS) remains unclear.Homomeric S100A8 and S100A9, and heteromeric S100A8/A9 proteins were evaluated in CRS with/without nasal polyps (CRSw/sNP) and controls. Functional responses were assessed in polyp tissue stimulated with S100 proteins in the presence of TLR-4 and RAGE blocking antibodies.S100A8, S100A9 and S100A8/A9 protein levels were significantly higher in CRSwNP patients, showing increased deposition on extracellular matrix (ECM) structures of CRSwNP tissue in contrast to CRSsNP and controls. In the presence of Staphylococcus aureus, S100A8/A9 is released from neutrophils and from the ECM. Extracellular S100A8 and S100A9 proteins induced increased levels of diverse inflammatory mediators via TLR-4 engagement.The inflammatory/remodelling characteristics of CRSwNP specifically allow increased retention of S100A8, S100A9 and S100A8/A9 proteins in the ECM of CRSwNP tissue. Upon release, homodimeric proteins act as a local danger signal inducing inflammatory mediators, predominantly via TLR-4 activation. Copyright ©ERS 2016.

Sulfur mustard analog, 2-chloroethyl ethyl sulfide-induced skin injury involves DNA damage and induction of inflammatory mediators, in part via oxidative stress, in SKH-1 hairless mouse skin

PubMed Central

Jain, Anil K.; Tewari-Singh, Neera; Gu, Mallikarjuna; Inturi, Swetha; White, Carl W.; Agarwal, Rajesh

2011-01-01

Bifunctional alkyalating agent, Sulfur mustard (SM)-caused cutaneous injury is characterized by inflammation and delayed blistering. Our recent studies demonstrated that 2-chloroethyl ethyl sulfide (CEES), a monofunctional analog of SM that can be used in laboratory settings, induces oxidative stress. This could be the major cause of the activation of Akt/MAP kinase and AP1/NF-κB pathways that are linked to the inflammation and microvesication, and histopathological alterations in SKH-1 hairless mouse skin. To further establish a link between CEES-induced DNA damage and signaling pathways and inflammatory responses, skin samples from mice exposed to 2 or 4 mg CEES for 9–48 h were subjected to molecular analysis. Our results show a strong CEES-induced phosphorylation of H2A.X and an increase in COX-2, iNOS, and MMP-9 levels, indicating the involvement of DNA damage and inflammation in CEES-caused skin injury in male and female mice. Since, our recent studies showed reduction in CEES-induced inflammatory responses by glutathione (GSH), we further assessed the role of oxidative stress in CEES-caused DNA damage and the induction of inflammatory molecules. Oral GSH (300mg/kg) administration 1 h before CEES exposure attenuated the increase in both CEES-induced H2A.X phosphorylation (59%) as well as expression of COX-2 (68%), iNOS (53%) and MMP-9 (54%). Collectively, our results indicate that CEES-induced skin injuries involve DNA damage and an induction of inflammatory mediators, at least in part via oxidative stress. This study could help in identifying countermeasures that alone or in combination, can target the unveiled pathways for reducing skin injuries in humans by SM. PMID:21722719

Mononuclear cell secretome protects from experimental autoimmune myocarditis.

PubMed

Hoetzenecker, Konrad; Zimmermann, Matthias; Hoetzenecker, Wolfram; Schweiger, Thomas; Kollmann, Dagmar; Mildner, Michael; Hegedus, Balazs; Mitterbauer, Andreas; Hacker, Stefan; Birner, Peter; Gabriel, Christian; Gyöngyösi, Mariann; Blyszczuk, Przemyslaw; Eriksson, Urs; Ankersmit, Hendrik Jan

2015-03-14

Supernatants of serum-free cultured mononuclear cells (MNC) contain a mix of immunomodulating factors (secretome), which have been shown to attenuate detrimental inflammatory responses following myocardial ischaemia. Inflammatory dilated cardiomyopathy (iDCM) is a common cause of heart failure in young patients. Experimental autoimmune myocarditis (EAM) is a CD4+ T cell-dependent model, which mirrors important pathogenic aspects of iDCM. The aim of this study was to determine the influence of MNC secretome on myocardial inflammation in the EAM model. BALB/c mice were immunized twice with an alpha myosin heavy chain peptide together with Complete Freund adjuvant. Supernatants from mouse mononuclear cells were collected, dialysed, and injected i.p. at Day 0, Day 7, or Day 14, respectively. Myocarditis severity, T cell responses, and autoantibody formation were assessed at Day 21. The impact of MNC secretome on CD4+ T cell function and viability was evaluated using in vitro proliferation and cell viability assays. A single high-dose application of MNC secretome, injected at Day 14 after the first immunization, effectively attenuated myocardial inflammation. Mechanistically, MNC secretome induced caspase-8-dependent apoptosis in autoreactive CD4+ T cells. MNC secretome abrogated myocardial inflammation in a CD4+ T cell-dependent animal model of autoimmune myocarditis. This anti-inflammatory effect of MNC secretome suggests a novel and simple potential treatment concept for inflammatory heart diseases. © The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.

Silymarin Prevents Restraint Stress-Induced Acute Liver Injury by Ameliorating Oxidative Stress and Reducing Inflammatory Response.

PubMed

Kim, Sou Hyun; Oh, Dal-Seok; Oh, Ji Youn; Son, Tae Gen; Yuk, Dong Yeon; Jung, Young-Suk

2016-04-01

Silymarin is a flavonoid extracted from the milk thistle Silybum marianum. It has been reported to prevent liver injuries induced by various chemicals or toxins. Our recent study suggested that silymarin induces hepatic synthesis of glutathione by increasing cysteine availability, which may consequently contribute to increased antioxidant capacity of the liver. In the present study, we investigated the effects of silymarin on acute liver injury induced by restraint stress. Silymarin (100 mg/kg) was orally administered to BALB/c mice every 12 h (3 times in total). After the last dose, mice were subjected to restraint stress for 6 h, and serum levels of aspartate and alanine aminotransferases, and hepatic levels of lipid peroxidation were determined. Hepatic levels of sulfur-containing metabolites such as methionine, S-adenosylmethionine, cysteine, and glutathione were also measured. The level of pro-inflammatory mediators in both liver and serum was determined. To study the mechanism of the effects of silymarin, we assessed Jun N-terminal kinase (JNK) activation and apoptotic signaling. Restraint stress induced severe oxidative stress and increased mRNA levels of pro-inflammatory mediators; both effects of restraint stress were significantly inhibited by silymarin. Moreover, administration of silymarin significantly prevented acute liver injury induced by restraint stress by blocking JNK activation and subsequently apoptotic signaling. In conclusion, these results suggest that the inhibition of restraint stress-induced liver injury by silymarin is due at least in part to its anti-oxidant activity and its ability to suppress the inflammatory response.

Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning: reversal by sulforaphane.

PubMed

Hernández-Rabaza, Vicente; Cabrera-Pastor, Andrea; Taoro-González, Lucas; Malaguarnera, Michele; Agustí, Ana; Llansola, Marta; Felipo, Vicente

2016-02-16

Patients with liver cirrhosis and minimal hepatic encephalopathy (MHE) show mild cognitive impairment and spatial learning dysfunction. Hyperammonemia acts synergistically with inflammation to induce cognitive impairment in MHE. Hyperammonemia-induced neuroinflammation in hippocampus could contribute to spatial learning impairment in MHE. Two main aims of this work were: (1) to assess whether chronic hyperammonemia increases inflammatory factors in the hippocampus and if this is associated with microglia and/or astrocytes activation and (2) to assess whether hyperammonemia-induced neuroinflammation in the hippocampus is associated with altered membrane expression of glutamate and GABA receptors and spatial learning impairment. There are no specific treatments for cognitive alterations in patients with MHE. A third aim was to assess whether treatment with sulforaphane enhances endogenous the anti-inflammatory system, reduces neuroinflammation in the hippocampus of hyperammonemic rats, and restores spatial learning and if normalization of receptor membrane expression is associated with learning improvement. We analyzed the following in control and hyperammonemic rats, treated or not with sulforaphane: (1) microglia and astrocytes activation by immunohistochemistry, (2) markers of pro-inflammatory (M1) (IL-1β, IL-6) and anti-inflammatory (M2) microglia (Arg1, YM-1) by Western blot, (3) membrane expression of GABA, AMPA, and NMDA receptors using the BS3 cross-linker, and (4) spatial learning using the radial maze. The results reported show that hyperammonemia induces astrocytes and microglia activation in the hippocampus, increasing pro-inflammatory cytokines IL-1β and IL-6. This is associated with altered membrane expression of AMPA, NMDA, and GABA receptors which would be responsible for altered neurotransmission and impairment of spatial learning in the radial maze. Treatment with sulforaphane promotes microglia differentiation from pro-inflammatory M1 to anti-inflammatory M2 phenotype and reduces activation of astrocytes in hyperammonemic rats. This reduces neuroinflammation, normalizes membrane expression of glutamate and GABA receptors, and restores spatial learning in hyperammonemic rats. Hyperammonemia-induced neuroinflammation impairs glutamatergic and GABAergic neurotransmission by altering membrane expression of glutamate and GABA receptors, resulting in impaired spatial learning. Sulforaphane reverses all these effects. Treatment with sulforaphane could be useful to improve cognitive function in cirrhotic patients with minimal or clinical hepatic encephalopathy.

Long-term Pulmonary Responses to Quadweekly Intermittent Intratracheal Spray Instillations of Magnetite (Fe3O4) Nanoparticles for 52 Weeks in Fischer 344 Rats.

PubMed

Tada, Yukie; Yano, Norio; Takahashi, Hiroshi; Yuzawa, Katsuhiro; Ando, Hiroshi; Kubo, Yoshikazu; Nagasawa, Akemichi; Inomata, Akiko; Ogata, Akio; Nakae, Dai

2013-12-01

Information about potential risks of iron nanomaterials is still limited, while a wide variety of applications are expected. We recently reported acute phase responses of male and female Fischer 344 rats after a single intratracheal spray instillation of Fe3O4 nanoparticles (magnetite), clearly showing dose-dependent pulmonary inflammatory changes (Tada et al., J Toxicol Pathol 25, 233-239, 2012). The present study assessed long-term responses of male and female Fischer 344 rats to multiple administrations of magnetite. Ten-week-old male and female Fischer 344 rats (n=20/group) were exposed to a total of 13 quadweekly intermittent intratracheal spray instillations of magnetite during the experimental period of 52 weeks, at doses of 0, 0.2 (low), 1.0 (medium) and 5.0 (high-dose) mg/kg body weight per administration. Absolute and relative lung weights of the high-dose group were significantly higher than those of the control group. Macroscopically, slight enlargement and scattered black patches were recognized in the lungs and the lung-associated lymph nodes of the high-dose group. Histopathologically, infiltration of macrophages phagocytosing magnetite (all dose groups) and of chronic inflammatory cells (medium- and high-dose males and high-dose females), alveolar bronchiolization and granuloma (high-dose group) were observed. In addition, alveolar hyperplasias were observed in some rats of the high-dose group, and cytoplasmic overexpression of β-catenin protein was immunohistochemically found in such lesions. The present results clearly show that instilled magnetite causes chronic inflammatory responses in the lung. These responses occur in a dose-dependent manner without apparent differences among sexes.

Interleukin-6 (IL-6) receptor/IL-6 fusion protein (Hyper IL-6) effects on the neonatal mouse brain: possible role for IL-6 trans-signaling in brain development and functional neurobehavioral outcomes.

PubMed

Brunssen, Susan H; Moy, Sheryl S; Toews, Arrel D; McPherson, Christopher A; Harry, G Jean

2013-01-01

Adverse neurodevelopmental outcomes are linked to perinatal production of inflammatory mediators, including interleukin 6 (IL-6). While a pivotal role for maternal elevation in IL-6 has been established in determining neurobehavioral outcomes in the offspring and considered the primary target mediating the fetal inflammatory response, questions remain as to the specific actions of IL-6 on the developing brain. CD-1 male mice received a subdural injection of the bioactive fusion protein, hyper IL-6 (HIL-6) on postnatal-day (PND)4 and assessed from preweaning until adulthood. Immunohistochemical evaluation of astrocytes and microglia and mRNA levels for pro-inflammatory cytokines and host response genes indicated no evidence of an acute neuroinflammatory injury response. HIL-6 accelerated motor development and increased reactivity to stimulation and number of entries in a light/dark chamber, decreased ability to learn to withhold a response in passive avoidance, and effected deficits in social novelty behavior. No changes were observed in motor activity, pre-pulse startle inhibition, or learning and memory in the Morris water maze or radial arm maze, as have been reported for models of more severe developmental neuroinflammation. In young animals, mRNA levels for MBP and PLP/DM20 decreased and less complexity of MBP processes in the cortex was evident by immunohistochemistry. The non-hydroxy cerebroside fraction of cerebral lipids was increased. These results provide evidence for selective effects of IL-6 signaling, particularly trans-signaling, in the developing brain in the absence of a general neuroinflammatory response. These data contribute to our further understanding of the multiple aspects of IL-6 signaling in the developing brain. Published by Elsevier Inc.

Role of Innate Immunity in a Model of Histidyl-tRNA Synthetase (Jo-1)-mediated Myositis

PubMed Central

Soejima, Makoto; Kang, Eun Ha; Gu, Xinyan; Katsumata, Yasuhiro; Clemens, Paula R.; Ascherman, Dana P.

2010-01-01

Objectives Previous work in humans and in animal models supports a key role for histidyl-tRNA synthetase (HRS=Jo-1) in the pathogenesis of idiopathic inflammatory myopathy. While most investigations have focused on the ability of HRS to trigger adaptive immune responses, in vitro studies clearly indicate that HRS possesses intrinsic chemokine-like properties capable of activating the innate immune system. The purpose of this study was therefore to examine the ability of HRS to direct innate immune responses in a murine model of myositis. Methods Following intramuscular immunization with soluble HRS in the absence of exogenous adjuvant, selected strains of mice were evaluated at different time points for histopathologic evidence of myositis. ELISA-based assessment of autoantibody formation and CFSE proliferation studies provided complementary measures of B and T cell responses triggered by HRS immunization. Results Compared to appropriate control proteins, a murine HRS fusion protein induced robust, statistically significant muscle inflammation in multiple congenic strains of C57BL/6 and NOD mice. Time course experiments revealed that this inflammatory response occurred as early as 7 days post immunization and persisted for up to 7 weeks. Parallel immunization strategies in DO11.10/Rag2−/− and C3H/HeJ (TLR4−/−) mice indicated that the ability of murine HRS to drive muscle inflammation was not dependent on B cell receptor or T cell receptor recognition and did not require TLR4 signaling. Conclusion Collectively, these experiments support a model in which HRS can trigger both innate and adaptive immune responses which culminate in severe muscle inflammation that is the hallmark of idiopathic inflammatory myopathy. PMID:21280002

Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes.

PubMed

O'Dwyer, Aoife M; Lajczak, Natalia K; Keyes, Jennifer A; Ward, Joseph B; Greene, Catherine M; Keely, Stephen J

2016-08-01

Monocytes are critical to the pathogenesis of inflammatory bowel disease (IBD) as they infiltrate the mucosa and release cytokines that drive the inflammatory response. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid with anti-inflammatory actions, has been proposed as a potential new therapy for IBD. However, its effects on monocyte function are not yet known. Primary monocytes from healthy volunteers or cultured U937 monocytes were treated with either the proinflammatory cytokine, TNFα (5 ng/ml) or the bacterial endotoxin, lipopolysaccharide (LPS; 1 μg/ml) for 24 h, in the absence or presence of UDCA (25-100 μM). IL-8 release into the supernatant was measured by ELISA. mRNA levels were quantified by qPCR and changes in cell signaling proteins were determined by Western blotting. Toxicity was assessed by measuring lactate dehydrogenase (LDH) release. UDCA treatment significantly attenuated TNFα-, but not LPS-driven, release of IL-8 from both primary and cultured monocytes. UDCA inhibition of TNFα-driven responses was associated with reduced IL-8 mRNA expression. Both TNFα and LPS stimulated NFκB activation in monocytes, while IL-8 release in response to both cytokines was attenuated by an NFκB inhibitor, BMS-345541. Interestingly, UDCA inhibited TNFα-, but not LPS-stimulated, NFκB activation. Finally, TNFα, but not LPS, induced phosphorylation of TNF receptor associated factor (TRAF2), while UDCA cotreatment attenuated this response. We conclude that UDCA specifically inhibits TNFα-induced IL-8 release from monocytes by inhibiting TRAF2 activation. Since such actions would serve to dampen mucosal immune responses in vivo, our data support the therapeutic potential of UDCA for IBD. Copyright © 2016 the American Physiological Society.

Effect of Kramecyne on the Inflammatory Response in Lipopolysaccharide-Stimulated Peritoneal Macrophages

PubMed Central

Sánchez-Miranda, E.; Lemus-Bautista, J.; Pérez, S.; Pérez-Ramos, J.

2013-01-01

Kramecyne is a new peroxide, it was isolated from Krameria cytisoides, methanol extract, and this plant was mostly found in North and South America. This compound showed potent anti-inflammatory activity; however, the mechanisms by which this compound exerts its anti-inflammatory effect are not well understood. In this study, we examined the effects of kramecyne on inflammatory responses in mouse lipopolysaccharide- (LPS-) induced peritoneal macrophages. Our findings indicate that kramecyne inhibits LPS-induced production of tumor necrosis factor (TNF-α) and interleukin- (IL-) 6. During the inflammatory process, levels of cyclooxygenase- (COX-) 2, nitric oxide synthase (iNOS), and nitric oxide (NO) increased in mouse peritoneal macrophages; however, kramecyne suppressed them significantly. These results provide novel insights into the anti-inflammatory actions and support its potential use in the treatment of inflammatory diseases. PMID:23573152

Modelling affective pain in mice: Effects of inflammatory hypersensitivity on place escape/avoidance behaviour, anxiety and hedonic state.

PubMed

Refsgaard, L K; Hoffmann-Petersen, J; Sahlholt, M; Pickering, D S; Andreasen, J T

2016-03-15

The place escape/avoidance paradigm (PEAP) has been used to assess the affective component of pain in rats. Using the Complete Freund's Adjuvant (CFA) model of inflammatory pain, the current study aimed at developing a mouse version of PEAP and investigating the relation between PEAP and other behavioural responses, namely anxiety-like behaviour, locomotor activity, and hedonic state. A novel paradigm assessing the affective component of pain in mice was developed by modifying the setup known from rat studies: Animals were forced to stay 2 × 5 min in the light and the dark area of a box while being stimulated with a suprathreshold filament on the untreated or treated paw, respectively. This was followed by a 30-min test with unrestricted movement. Anxiety-like behaviour, locomotor activity, and hedonic state were assessed with the elevated zero maze (EZM), an open field setup, and a saccharin preference test, respectively, and correlated with the PEAP behaviour to examine potentially confounding parameters of the novel paradigm. In the PEAP, CFA-treated animals spent more time in the light area. CFA also increased anxiety-like behaviour significantly, whereas locomotor activity was unaffected. A significant, albeit modest, reduction in saccharin preference was observed. PEAP responses showed no significant correlations with any other behavioural measure. The PEAP results suggest that this paradigm might be successfully applied in mice to study affective pain. CFA treatment was associated with increased anxiety-like behaviour and anhedonia; however, this appeared unrelated to the PEAP responses. Copyright © 2016 Elsevier B.V. All rights reserved.

Immune endophenotypes in children with Autism Spectrum Disorder

PubMed Central

Careaga, Milo; Rogers, Sally; Hansen, Robin L.; Amaral, David G.; de Water, Judy Van; Ashwood, Paul

2015-01-01

Background Autism Spectrum Disorder (ASD) is characterized by social communication deficits and restricted, repetitive patterns of behavior. Varied immunological findings have been reported in children with ASD. To address the question of heterogeneity in immune responses, we sought to examine the diversity of immune profiles within a representative cohort of boys with ASD. Methods Peripheral blood mononuclear cells (PBMC) from male children with ASD (n=50) and from typically developing (TD) age-matched male controls (n=16) were stimulated with either lipopolysaccharide (LPS) or phytohaemagglutinin (PHA). Cytokine production was assessed after stimulation. The ASD study population was clustered into subgroups based on immune responses and assessed for behavioral outcomes. Results Children with ASD who had a pro-inflammatory profile based on LPS stimulation were more developmentally impaired as assessed by the Mullen's Scale of Early Learning (MSEL). They also had greater impairments in social affect as measured by the Autism Diagnostic Observation Schedule (ADOS). These children also displayed more frequent sleep disturbances and episodes of aggression. Similarly, children with ASD and a more activated T cell cytokine profile after PHA stimulation were more developmentally impaired as measured by the MSEL. Conclusions Children with ASD may be phenotypically characterized based upon their immune profile. Those showing either a pro-inflammatory response or increased T cell activation/skewing display a more impaired behavioral profile than children with non-inflamed or non-T cell activated immune profiles. These data suggest that there may be several possible immune subphenotypes within the ASD population that correlate with more severe behavioral impairments. PMID:26493496

Efficacy and Safety of Anti-TNF-α Agents in Inflammatory Bowel Disease After Liver Transplant: A Case Series.

PubMed

Olmedo-Martín, R V; Amo-Trillo, V; González-Grande, R; Tenorio-González, E; Sánchez-García, O; de la Cruz-Lombardo, J; Rodrigo-López, J M; Jiménez-Pérez, M

2018-03-01

Ulcerative colitis (UC) and Crohn disease (CD) can appear de novo or worsen after liver transplant. Our aim was to assess the efficacy and safety of anti-tumor necrosis-alpha (anti-TNF-α) agents after transplantation. We reviewed the clinical database of our center searching for all liver transplant patients with inflammatory bowel disease who were treated with anti-TNF-α agents between 1997 and 2017. Clinical response was assessed from clinical activity indices 12 weeks after starting treatment. The median age of the 6 patients (3 women) was 37 years. Four patients were diagnosed before transplantation (2 UC and 2 CD), and in the other 2 the disease appeared de novo (1 UC and 1 CD). The indications for transplant were primary sclerosing cholangitis (n = 3), cryptogenic cirrhosis (n = 2), and hepatitis C virus cirrhosis (n = 1). Clinical response was seen in 3 of the 6 patients and, in the 3 cases for whom endoscopic data were available, no mucous healing was seen. The only adverse effects noted over a mean follow-up of 15 months were 1 cytomegalovirus infection and 1 severe infusion reaction to infliximab. No patients had recurrence of primary sclerosing cholangitis in the graft, and none of the patients died. Use of an anti-TNF-α agent in a liver transplant patient with inflammatory bowel disease may be an effective option, with an acceptable risk-benefit ratio. Further studies are required to confirm their use in this context. Copyright © 2017 Elsevier Inc. All rights reserved.

Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice.

PubMed

Tanaka, Ken-Ichiro; Sato, Keizo; Aoshiba, Kazutetsu; Azuma, Arata; Mizushima, Tohru

2012-06-15

Bronchodilators (such as ipratropium bromide), steroids (such as fluticasone propionate), and newly developed anti-inflammatory drugs (such as roflumilast) are used for patients with chronic obstructive pulmonary disease (COPD). We recently reported that lecithinized superoxide dismutase (PC-SOD) confers a protective effect in mouse models of COPD. We here examined the therapeutic effect of the combined administration of PC-SOD with ipratropium bromide on pulmonary emphysema and compared the effect of PC-SOD to other types of drugs. The severity of emphysema in mice was assessed by various criteria. Lung mechanics (elastance) and respiratory function (ratio of forced expiratory volume in the first 0.05 s to forced vital capacity) were assessed. Administration of PC-SOD by inhalation suppressed elastase-induced pulmonary emphysema, alteration of lung mechanics, and respiratory dysfunction. The concomitant intratracheal administration of ipratropium bromide did not alter the ameliorating effects of PC-SOD. Administration of ipratropium bromide, fluticasone propionate, or roflumilast alone did not suppress the elastase-induced increase in the pulmonary level of superoxide anion, pulmonary inflammatory response, pulmonary emphysema, alteration of lung mechanics, or respiratory dysfunction as effectively as did PC-SOD. PC-SOD, but not the other drugs, showed a therapeutic effect even when the drug was administered after the development of emphysema. PC-SOD also suppressed the cigarette smoke-induced pulmonary inflammatory response and increase in airway resistance. Based on these results, we consider that the inhalation of PC-SOD would be therapeutically beneficial for COPD.

Protective Effect of 2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione, Isolated from Averrhoa Carambola L., Against Palmitic Acid-Induced Inflammation and Apoptosis in Min6 Cells by Inhibiting the TLR4-MyD88-NF-κB Signaling Pathway.

PubMed

Xie, Qiuqiao; Zhang, Shijun; Chen, Chunxia; Li, Juman; Wei, Xiaojie; Xu, Xiaohui; Xuan, Feifei; Chen, Ning; Pham, Thithaihoa; Qin, Ni; He, Junhui; Ye, Fangxing; Huang, Wansu; Huang, Renbin; Wen, Qingwei

2016-01-01

Studies have demonstrated that 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione (DMDD), isolated from the roots of Averrhoa carambola L., has significant therapeutic potential for the treatment of diabetes. However, the protective effect of DMDD against pancreatic beta cell dysfunction has never been reported. We investigated whether DMDD protected against palmitic acid-induced dysfunction in pancreatic β-cell line Min6 cells by attenuating the inflammatory response and apoptosis and to shed light on its possible mechanism. Cell viability was assessed by CCK-8. Glucose-stimulated insulin secretion levels and inflammatory cytokines levels were examined by ELISA. Apoptosis was assessed by Annexin V-FITC/PI Flow cytometry assay, Hoechst 33342/PI double-staining assay, and Transmission electron microscopy assay. Relative quantitative real-time PCR and western blot were used to determine the expressions of genes and proteins. Cell viability and glucose-stimulated insulin secretion levels were increased in DMDD-pretreated Min6 cells. DMDD inhibited inflammatory cytokines IL-6, TNF-α and MCP-1 generations in palmitic acid (PA)-induced Min6 cells. Moreover, DMDD protected against PA-induced Min6 cells apoptosis and the expression of Cleaved-Caspase-3, -8 and -9 were down-regulated and the Bcl-2/Bax ratio was increased in DMDD-pretreated Min6 cells. In addition, the expression of TLR4, MyD88 and NF-κB were down-regulated in DMDD-pretreated Min6 cells and TAK-242-pretreated group cells. DMDD protected Min6 cells against PA-induced dysfunction by attenuating the inflammatory response and apoptosis, and its mechanism of this protection was associated with inhibiting the TLR4-MyD88-NF-κB signaling pathway. © 2016 The Author(s) Published by S. Karger AG, Basel.

A novel method for modeling facial allodynia associated with migraine in awake and freely moving rats

PubMed Central

Wieseler, Julie; Ellis, Amanda; Sprunger, David; Brown, Kim; McFadden, Andrew; Mahoney, John; Rezvani, Niloofar; Maier, Steven F.; Watkins, Linda R.

2009-01-01

Migraine is a neurovascular disorder that induces debilitating headaches associated with multiple symptoms including facial allodynia, characterized by heightened responsivity to normally innocuous mechanical stimuli. It is now well accepted that immune activation and immune-derived inflammatory mediators enhance pain responsivity, including in the trigeminal system. Nociceptive (“pain” responsive) trigeminal nerves densely innervate the cranial meninges. We have recently proposed that the meninges may serve as a previously unidentified, key interface between the peripheral immune system and the CNS with potential implications for understanding underlying migraine mechanisms. Our focus here is the development of a model for facial allodynia associated with migraine. We developed a model wherein an indwelling catheter is placed between the skull and dura, allowing immunogenic stimuli to be administered over the dura in awake and freely moving rats. Since the catheter does not contact the brain itself, any proinflammatory cytokines induced following manipulation derive from resident or recruited meningeal immune cells. While surgery alone does not alter immune activation markers, TNF or IL6 mRNA and/or protein, it does decrease gene expression and increase protein expression of IL-1 at 4 days after surgery. Using this model we show the induction of facial allodynia in response to supradural administration of either the HIV glycoprotein gp120 or inflammatory soup (bradykinin, histamine, serotonin, and prostaglandin E2), and the induction of hindpaw allodynia in our model after inflammatory soup. This model allows time and dose dependent assessment of the relationship between changes in meningeal inflammation and corresponding exaggerated pain behaviors. PMID:19837113

Reduction of inflammatory responses and enhancement of extracellular matrix formation by vanillin-incorporated poly(lactic-co-glycolic acid) scaffolds.

PubMed

Lee, Yujung; Kwon, Jeongil; Khang, Gilson; Lee, Dongwon

2012-10-01

Vanillin is one of the major components of vanilla, a commonly used flavoring agent and preservative and is known to exert potent antioxidant and anti-inflammatory activities. In this work, vanillin-incorporated poly(lactic-co-glycolic acid) (PLGA) films and scaffolds were fabricated to evaluate the effects of vanillin on the inflammatory responses and extracellular matrix (ECM) formation in vitro and in vivo. The incorporation of vanillin to PLGA films induced hydrophilic nature, resulting in the higher cell attachment and proliferation than the pure PLGA film. Vanillin also reduced the generation of reactive oxygen species (ROS) in cells cultured on the pure PLGA film and significantly inhibited the PLGA-induced inflammatory responses in vivo, evidenced by the reduced accumulation of inflammatory cells and thinner fibrous capsules. The effects of vanillin on the ECM formation were evaluated using annulus fibrous (AF) cell-seeded porous PLGA/vanillin scaffolds. PLGA/vanillin scaffolds elicited the more production of glycosaminoglycan and collagen than the pure PLGA scaffold, in a concentration-dependent manner. Based on the low level of inflammatory responses and enhanced ECM formation, vanillin-incorporated PLGA constructs make them promising candidates in the future biomedical applications.

Vitamin A supplementation increases ratios of proinflammatory to anti-inflammatory cytokine responses in pregnancy and lactation

PubMed Central

Cox, S E; Arthur, P; Kirkwood, B R; Yeboah-Antwi, K; Riley, E M

2006-01-01

Vitamin A supplementation reduces child mortality in populations at risk of vitamin A deficiency and may also reduce maternal mortality. One possible explanation for this is that vitamin A deficiency is associated with altered immune function and cytokine dysregulation. Vitamin A deficiency in pregnancy may thus compound the pregnancy-associated bias of cellular immune responses towards Th-2-like responses and exacerbate susceptibility to intracellular pathogens. We assessed mitogen and antigen-induced cytokine responses during pregnancy and lactation in Ghanaian primigravidae receiving either vitamin A supplementation or placebo. This was a double-blind, randomized, placebo-controlled trial of weekly vitamin A supplementation in pregnant and lactating women. Pregnancy compared to postpartum was associated with a suppression of cytokine responses, in particular of the proinflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF)-α. Mitogen-induced TNF-α responses were associated with a decreased risk of peripheral parasitaemia during pregnancy. Furthermore, vitamin A supplementation was significantly associated with an increased ratio of mitogen-induced proinflammatory cytokine (IFN-γ) to anti-inflammatory cytokine (IL-10) during pregnancy and in the postpartum period. The results of this study indicate that suppression of proinflammatory type 1 immune responses and hence immunity to intracellular infections, resulting from the combined effects of pregnancy and vitamin A deficiency, might be ameliorated by vitamin A supplementation. PMID:16734607

The inflammatory microenvironment in colorectal neoplasia.

PubMed

McLean, Mairi H; Murray, Graeme I; Stewart, Keith N; Norrie, Gillian; Mayer, Claus; Hold, Georgina L; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N Ashley G; Drew, Janice E; El-Omar, Emad M

2011-01-07

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

Development of an in vitro periodontal biofilm model for assessing antimicrobial and host modulatory effects of bioactive molecules.

PubMed

Millhouse, Emma; Jose, Anto; Sherry, Leighann; Lappin, David F; Patel, Nisha; Middleton, Andrew M; Pratten, Jonathan; Culshaw, Shauna; Ramage, Gordon

2014-06-28

Inflammation within the oral cavity occurs due to dysregulation between microbial biofilms and the host response. Understanding how different oral hygiene products influence inflammatory properties is important for the development of new products. Therefore, creation of a robust host-pathogen biofilm platform capable of evaluating novel oral healthcare compounds is an attractive option. We therefore devised a multi-species biofilm co-culture model to evaluate the naturally derived polyphenol resveratrol (RSV) and gold standard chlorhexidine (CHX) with respect to anti-biofilm and anti-inflammatory properties. An in vitro multi-species biofilm containing S. mitis, F. nucleatum, P. gingivalis and A. actinomycetemcomitans was created to represent a disease-associated biofilm and the oral epithelial cell in OKF6-TERT2. Cytotoxicity studies were performed using RSV and CHX. Multi-species biofilms were either treated with either molecule, or alternatively epithelial cells were treated with these prior to biofilm co-culture. Biofilm composition was evaluated and inflammatory responses quantified at a transcriptional and protein level. CHX was toxic to epithelial cells and multi-species biofilms at concentrations ranging from 0.01-0.2%. RSV did not effect multi-species biofilm composition, but was toxic to epithelial cells at concentrations greater than 0.01%. In co-culture, CHX-treated biofilms resulted in down regulation of the inflammatory chemokine IL-8 at both mRNA and protein level. RSV-treated epithelial cells in co-culture were down-regulated in the release of IL-8 protein, but not mRNA. CHX possesses potent bactericidal properties, which may impact downstream inflammatory mediators. RSV does not appear to have bactericidal properties against multi-species biofilms, however it did appear to supress epithelial cells from releasing inflammatory mediators. This study demonstrates the potential to understand the mechanisms by which different oral hygiene products may influence gingival inflammation, thereby validating the use of a biofilm co-culture model.

HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats.

PubMed

Marroquin Belaunzaran, Osiris; Kleber, Sascha; Schauer, Stefan; Hausmann, Martin; Nicholls, Flora; Van den Broek, Maries; Payeli, Sravan; Ciurea, Adrian; Milling, Simon; Stenner, Frank; Shaw, Jackie; Kollnberger, Simon; Bowness, Paul; Petrausch, Ulf; Renner, Christoph

2015-01-01

HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272-specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders. The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry. HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules. HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders.

HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats

PubMed Central

Marroquin Belaunzaran, Osiris; Kleber, Sascha; Schauer, Stefan; Hausmann, Martin; Nicholls, Flora; Van den Broek, Maries; Payeli, Sravan; Ciurea, Adrian; Milling, Simon; Stenner, Frank; Shaw, Jackie; Kollnberger, Simon; Bowness, Paul; Petrausch, Ulf; Renner, Christoph

2015-01-01

Objectives HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272–specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders. Methods The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry. Results HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules. Conclusion HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders. PMID:26125554

Dual Effects of Cell Free Supernatants from Lactobacillus acidophilus and Lactobacillus rhamnosus GG in Regulation of MMP-9 by Up-Regulating TIMP-1 and Down-Regulating CD147 in PMA- Differentiated THP-1 Cells

PubMed Central

Maghsood, Faezeh; Mirshafiey, Abbas; Farahani, Mohadese M.; Modarressi, Mohammad Hossein; Jafari, Parvaneh; Motevaseli, Elahe

2018-01-01

Objective Recent studies have reported dysregulated expression of matrix metalloproteinases (MMPs), especially MMP-2, MMP-9, tissue inhibitor of metalloproteinase-1, -2 (TIMP-1, TIMP-2), and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) in activated macrophages of patients with inflammatory diseases. Therefore, MMP-2, MMP-9, and their regulators may represent a new target for treatment of inflammatory diseases. Probiotics, which are comprised of lactic acid bacteria, have the potential to modulate inflammatory responses. In this experimental study, we investigated the anti-inflammatory effects of cell-free supernatants (CFS) from Lactobacillus acidophilus (L. acidophilus) and L. rhamnosus GG (LGG) in phorbol myristate acetate (PMA)-differentiated THP-1 cells. Materials and Methods In this experimental study, PMA-differentiated THP-1 cells were treated with CFS from L. acidophilus, LGG and uninoculated bacterial growth media (as a control). The expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNAs were determined using real-time quantitative reverse transcription polymerase chain reaction (RT- PCR). The levels of cellular surface expression of CD147 were assessed by flow cytometry, and the gelatinolytic activity of MMP-2 and MMP-9 were determined by zymography. Results Our results showed that CFS from both L. acidophilus and LGG significantly inhibited the gene expression of MMP-9 (P=0.0011 and P=0.0005, respectively), increased the expression of TIMP-1 (P<0.0001), decreased the cell surface expression of CD147 (P=0.0307 and P=0.0054, respectively), and inhibited the gelatinolytic activity of MMP-9 (P=0.0003 and P<0.0001, respectively) in PMA-differentiated THP-1 cells. Although, MMP-2 expression and activity and TIMP-2 expression remained unchanged. Conclusion Our results indicate that CFS from L. acidophilus and LGG possess anti-inflammatory properties and can modulate the inflammatory response. PMID:29105390

Cytotoxicity and anti-inflammatory effects of zinc ions and eugenol during setting of ZOE in immortalized human oral keratinocytes grown as three-dimensional spheroids.

PubMed

Lee, Jung-Hwan; Lee, Hae-Hyoung; Kim, Kyoung-Nam; Kim, Kwang-Mahn

2016-05-01

The objective of this study is to assess the cytotoxic and anti-inflammatory effects of ZOE cement during setting in two-dimensional (2D) or three-dimensional (3D) cultures of immortalized human oral keratinocytes (IHOKs) with determining the extract components responsible for these effects. Extracts of mixed ZOE at different stages of setting were analyzed by a digital pH meter, ICP-MS, and GC-MS. Serial concentrations of extract and their mixture of ZnCl2, ZnSO4·H2O, and eugenol liquid were added to the 2D and 3D IHOK cultures to determine the half maximal effective concentration in investigating the cause of cytotoxicity by means of WST assay and to investigate mRNA expression levels of inflammatory cytokines by RT-PCR. Zn(2+) and eugenol (4-19 ppm) were detected in the extracts. In the early setting stage, significant cytotoxicity was observed in the 2D and 3D IHOK cultures (P<0.05). The EC50 of Zn(2+) from ZnCl2 was 5-44 ppm in both cultures, whereas the EC50 of eugenol was not detectable under 100 ppm. Along with the lower levels of inflammatory cytokine gene expressions in the extract, treatment of the 2D IHOKs with Zn(2+) alone and treatment of the 3D IHOKs with Zn(2+) plus eugenol resulted in significantly lower expression levels of IL-1β, IL-6, and IL-8 (P<0.05). The cytotoxic effect of ZOE on IHOKs was greater during the setting stage owing to the presence of Zn(2+). The anti-inflammatory response to ZOE was induced by a combination of Zn(2+) and eugenol. Cytotoxic and anti-inflammatory effects differed between the 2D and 3D IHOK cultures. Copyright © 2016. Published by Elsevier Ltd.

Attenuating the Systemic Inflammatory Response to Adult Cardiopulmonary Bypass: A Critical Review of the Evidence Base

PubMed Central

Landis, R. Clive; Brown, Jeremiah R.; Fitzgerald, David; Likosky, Donald S.; Shore-Lesserson, Linda; Baker, Robert A.; Hammon, John W.

2014-01-01

Abstract: A wide range of pharmacological, surgical, and mechanical pump approaches have been studied to attenuate the systemic inflammatory response to cardiopulmonary bypass, yet no systematically based review exists to cover the scope of anti-inflammatory interventions deployed. We therefore conducted an evidence-based review to capture “self-identified” anti-inflammatory interventions among adult cardiopulmonary bypass procedures. To be included, trials had to measure at least one inflammatory mediator and one clinical outcome, specified in the “Outcomes 2010” consensus statement. Ninety-eight papers satisfied inclusion criteria and formed the basis of the review. The review identified 33 different interventions and approaches to attenuate the systemic inflammatory response. However, only a minority of papers (35 of 98 [35.7%]) demonstrated any clinical improvement to one or more of the predefined outcome measures (most frequently myocardial protection or length of intensive care unit stay). No single intervention was supported by strong level A evidence (multiple randomized controlled trials [RCTs] or meta-analysis) for clinical benefit. Interventions at level A evidence included off-pump surgery, minimized circuits, biocompatible circuit coatings, leukocyte filtration, complement C5 inhibition, preoperative aspirin, and corticosteroid prophylaxis. Interventions at level B evidence (single RCT) for minimizing inflammation included nitric oxide donors, C1 esterase inhibition, neutrophil elastase inhibition, propofol, propionyl-L-carnitine, and intensive insulin therapy. A secondary analysis revealed that suppression of at least one inflammatory marker was necessary but not sufficient to confer clinical benefit. The most effective interventions were those that targeted multiple inflammatory pathways. These observations are consistent with a “multiple hit” hypothesis, whereby clinically effective suppression of the systemic inflammatory response requires hitting multiple inflammatory targets simultaneously. Further research is warranted to evaluate if combinations of interventions that target multiple inflammatory pathways are capable of synergistically reducing inflammation and improving outcomes after cardiopulmonary bypass. PMID:26357785

Inhibitory effects of aspirin-triggered resolvin D1 on spinal nociceptive processing in rat pain models.

PubMed

Meesawatsom, Pongsatorn; Burston, James; Hathway, Gareth; Bennett, Andrew; Chapman, Victoria

2016-09-02

Harnessing the actions of the resolvin pathways has the potential for the treatment of a wide range of conditions associated with overt inflammatory signalling. Aspirin-triggered resolvin D1 (AT-RvD1) has robust analgesic effects in behavioural models of pain; however, the potential underlying spinal neurophysiological mechanisms contributing to these inhibitory effects in vivo are yet to be determined. This study investigated the acute effects of spinal AT-RvD1 on evoked responses of spinal neurones in vivo in a model of acute inflammatory pain and chronic osteoarthritic (OA) pain and the relevance of alterations in spinal gene expression to these neurophysiological effects. Pain behaviour was assessed in rats with established carrageenan-induced inflammatory or monosodium iodoacetate (MIA)-induced OA pain, and changes in spinal gene expression of resolvin receptors and relevant enzymatic pathways were examined. At timepoints of established pain behaviour, responses of deep dorsal horn wide dynamic range (WDR) neurones to transcutaneous electrical stimulation of the hind paw were recorded pre- and post direct spinal administration of AT-RvD1 (15 and 150 ng/50 μl). AT-RvD1 (15 ng/50 μl) significantly inhibited WDR neurone responses to electrical stimuli at C- (29 % inhibition) and Aδ-fibre (27 % inhibition) intensities. Both wind-up (53 %) and post-discharge (46 %) responses of WDR neurones in carrageenan-treated animals were significantly inhibited by AT-RvD1, compared to pre-drug response (p < 0.05). These effects were abolished by spinal pre-administration of a formyl peptide receptor 2 (FPR2/ALX) antagonist, butoxy carbonyl-Phe-Leu-Phe-Leu-Phe (BOC-2) (50 μg/50 μl). AT-RvD1 did not alter evoked WDR neurone responses in non-inflamed or MIA-treated rats. Electrophysiological effects in carrageenan-inflamed rats were accompanied by a significant increase in messenger RNA (mRNA) for chemerin (ChemR23) receptor and 5-lipoxygenase-activating protein (FLAP) and a decrease in 15-lipoxygenase (15-LOX) mRNA in the ipsilateral spinal cord of the carrageenan group, compared to controls. Our data suggest that peripheral inflammation-mediated changes in spinal FLAP expression may contribute to the novel inhibitory effects of spinal AT-RvD1 on WDR neuronal excitability, which are mediated by FPR2/ALX receptors. Inflammatory-driven changes in this pathway may offer novel targets for inflammatory pain treatment.

Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases.

PubMed

Solleiro-Villavicencio, Helena; Rivas-Arancibia, Selva

2018-01-01

In a state of oxidative stress, there is an increase of reactive species, which induce an altered intracellular signaling, leading to dysregulation of the inflammatory response. The inability of the antioxidant defense systems to modulate the proinflammatory response is key to the onset and progression of neurodegenerative diseases. The aim of this work is to review the effect of the state of oxidative stress on the loss of regulation of the inflammatory response on the microglia and astrocytes, the induction of different CD4 + T cell populations in neuroinflammation, as well as its role in some neurodegenerative diseases. For this purpose, an intentional search of original articles, short communications, and reviews, was carried out in the following databases: PubMed, Scopus, and Google Scholar. The articles reviewed included the period from 1997 to 2017. With the evidence obtained, we conclude that the loss of redox balance induces alterations in the differentiation and number of CD4 + T cell subpopulations, leading to an increase in Th1 and Th17 response. This contributes to the development of neuroinflammation as well as loss of the regulation of the inflammatory response in neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and Multiple Sclerosis (MS). In contrast, regulatory T cells (Tregs) and Th2 modulate the inflammatory response of effect of T cells, microglia, and astrocytes. In this respect, it has been found that the mobilization of T cells with anti-inflammatory characteristics toward damaged regions of the CNS can provide neuroprotection and become a therapeutic strategy to control inflammatory processes in neurodegeneration.

Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases

PubMed Central

Solleiro-Villavicencio, Helena; Rivas-Arancibia, Selva

2018-01-01

In a state of oxidative stress, there is an increase of reactive species, which induce an altered intracellular signaling, leading to dysregulation of the inflammatory response. The inability of the antioxidant defense systems to modulate the proinflammatory response is key to the onset and progression of neurodegenerative diseases. The aim of this work is to review the effect of the state of oxidative stress on the loss of regulation of the inflammatory response on the microglia and astrocytes, the induction of different CD4+T cell populations in neuroinflammation, as well as its role in some neurodegenerative diseases. For this purpose, an intentional search of original articles, short communications, and reviews, was carried out in the following databases: PubMed, Scopus, and Google Scholar. The articles reviewed included the period from 1997 to 2017. With the evidence obtained, we conclude that the loss of redox balance induces alterations in the differentiation and number of CD4+T cell subpopulations, leading to an increase in Th1 and Th17 response. This contributes to the development of neuroinflammation as well as loss of the regulation of the inflammatory response in neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and Multiple Sclerosis (MS). In contrast, regulatory T cells (Tregs) and Th2 modulate the inflammatory response of effect of T cells, microglia, and astrocytes. In this respect, it has been found that the mobilization of T cells with anti-inflammatory characteristics toward damaged regions of the CNS can provide neuroprotection and become a therapeutic strategy to control inflammatory processes in neurodegeneration. PMID:29755324

Endogenous hydrogen sulfide regulates histone demethylase JMJD3-mediated inflammatory response in LPS-stimulated macrophages and in a mouse model of LPS-induced septic shock.

PubMed

Liu, Siyu; Wang, Xiling; Pan, Lilong; Wu, Weijun; Yang, Di; Qin, Ming; Jia, Wanwan; Xiao, Chenxi; Long, Fen; Ge, Junbo; Liu, Xinhua; Zhu, YiZhun

2018-03-01

Overproduction of inflammatory mediators contributes to uncontrolled inflammation during endotoxin shock. Cystathionine-γ-lyase (CSE), an enzyme involved in hydrogen sulfide (H 2 S) biosynthesis, has potential anti-inflammatory activity in a variety of inflammatory diseases. Jumonji domain-containing protein 3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in macrophage activation, but its function in CSE-mediated anti-inflammatory activities remains unknown. In the present study CSE was found to be upregulated in macrophages and mouse lipopolysaccharide (LPS) challenge models. LPS stimulation also enhanced the activation of JMJD3 and decreased H3K27me3 levels. JMJD3 knockdown upregulated H3K27me3 levels and attenuated the LPS-mediated inflammatory response. CSE knockout amplified the inflammatory cascade by increasing JMJD3 expression in septic mice. Similarly, enhanced production of inflammatory mediators by macrophages was mitigated by CSE overexpression via inhibition of JMJD3 expression. This is the first report indicating that inflammation enhanced CSE/H 2 S system biosynthesis, that in turn attenuated the LPS-triggered inflammatory response by regulating JMJD3 expression. Thus, the CSE/H 2 S system represents an epigenetic-based modification mechanism to prevent uncontrolled inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

Metabolomic characterization of laborers exposed to welding fumes.

PubMed

Wang, Kuo-Ching; Kuo, Ching-Hua; Tian, Tze-Feng; Tsai, Mong-Hsun; Chiung, Yin-Mei; Hsiech, Chun-Ming; Tsai, Sung-Jeng; Wang, San-Yuan; Tsai, Dong-Ming; Huang, Chiang-Ching; Tseng, Y Jane

2012-03-19

The complex composition of welding fumes, multiplicity of molecular targets, diverse cellular effects, and lifestyles associated with laborers vastly complicate the assessment of welding fume exposure. The urinary metabolomic profiles of 35 male welders and 16 male office workers at a Taiwanese shipyard were characterized via (1)H NMR spectroscopy and pattern recognition methods. Blood samples for the same 51 individuals were also collected, and the expression levels of the cytokines and other inflammatory markers were examined. This study dichotomized the welding exposure variable into high (welders) versus low (office workers) exposures to examine the differences of continuous outcome markers-metabolites and inflammatory markers-between the two groups. Fume particle assessments showed that welders were exposed to different concentrations of chromium, nickel, and manganese particles. Multivariate statistical analysis of urinary metabolomic patterns showed higher levels of glycine, taurine, betaine/TMAO, serine, S-sulfocysteine, hippurate, gluconate, creatinine, and acetone and lower levels of creatine among welders, while only TNF-α was significantly associated with welding fume exposure among all cytokines and other inflammatory markers measured. Of the identified metabolites, the higher levels of glycine, taurine, and betaine among welders were suspected to play some roles in modulating inflammatory and oxidative tissue injury processes. In this metabolomics experiment, we also discovered that the association of the identified metabolites with welding exposure was confounded by smoking, but not with drinking, which is a finding consistent with known modified response of inflammatory markers among smokers. Our results correspond with prior studies that utilized nonmetabolomic analytical techniques and suggest that the metabolomic profiling is an efficient method to characterize the overall effect of welding fume exposure and other confounders. © 2012 American Chemical Society

Central activation of the cholinergic anti-inflammatory pathway reduces surgical inflammation in experimental post-operative ileus.

PubMed

The, Fo; Cailotto, C; van der Vliet, J; de Jonge, W J; Bennink, R J; Buijs, R M; Boeckxstaens, G E

2011-07-01

Electrical stimulation of the vagus nerve reduces intestinal inflammation following mechanical handling, thereby shortening post-operative ileus in mice. Previous studies in a sepsis model showed that this cholinergic anti-inflammatory pathway can be activated pharmacologically by central administration of semapimod, an inhibitor of p38 mitogen-activated protein kinase. We therefore evaluated the effect of intracerebroventricular (i.c.v.) semapimod on intestinal inflammation and post-operative ileus in mice. Mice underwent a laparotomy or intestinal manipulation 1 h after i.c.v. pre-treatment with semapimod (1 µg·kg(-1) ) or saline. Drugs were administered through a cannula placed in the left lateral ventricle 1 week prior to experimentation. Twenty-four hours after surgery, gastric emptying was measured using scintigraphy, and the degree of intestinal inflammation was assessed. Finally, activation of brain regions was assessed using quantitative immunohistochemistry for c-fos. Intestinal manipulation induced inflammation of the manipulated intestine and significantly delayed gastric emptying, 24 h after surgery in saline-treated animals. Semapimod significantly reduced this inflammation and improved gastric emptying. Vagotomy enhanced the inflammatory response induced by intestinal manipulation and abolished the anti-inflammatory effect of semapimod. Semapimod but not saline induced a significant increase in c-fos expression in the paraventricular nucleus, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve. Our findings show that i.c.v. semapimod reduces manipulation-induced intestinal inflammation and prevented post-operative ileus. This anti-inflammatory effect depends on central activation of the vagus nerve. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Immuno-Modulatory and Anti-Inflammatory Effects of Dihydrogracilin A, a Terpene Derived from the Marine Sponge Dendrilla membranosa.

PubMed

Ciaglia, Elena; Malfitano, Anna Maria; Laezza, Chiara; Fontana, Angelo; Nuzzo, Genoveffa; Cutignano, Adele; Abate, Mario; Pelin, Marco; Sosa, Silvio; Bifulco, Maurizio; Gazzerro, Patrizia

2017-07-28

We assessed the immunomodulatory and anti-inflammatory effects of 9,11-dihydrogracilin A (DHG), a molecule derived from the Antarctic marine sponge Dendrilla membranosa . We used in vitro and in vivo approaches to establish DHG properties. Human peripheral blood mononuclear cells (PBMC) and human keratinocytes cell line (HaCaT cells) were used as in vitro system, whereas a model of murine cutaneous irritation was adopted for in vivo studies. We observed that DHG reduces dose dependently the proliferative response and viability of mitogen stimulated PBMC. In addition, DHG induces apoptosis as revealed by AnnexinV staining and downregulates the phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), signal transducer and activator of transcription (STAT) and extracellular signal-regulated kinase (ERK) at late time points. These effects were accompanied by down-regulation of interleukin 6 (IL-6) production, slight decrease of IL-10 and no inhibition of tumor necrosis factor-alpha (TNF-α) secretion. To assess potential properties of DHG in epidermal inflammation we used HaCaT cells; this compound reduces cell growth, viability and migration. Finally, we adopted for the in vivo study the croton oil-induced ear dermatitis murine model of inflammation. Of note, topical use of DHG significantly decreased mouse ear edema. These results suggest that DHG exerts anti-inflammatory effects and its anti-edema activity in vivo strongly supports its potential therapeutic application in inflammatory cutaneous diseases.

Adherent Human Alveolar Macrophages Exhibit a Transient Pro-Inflammatory Profile That Confounds Responses to Innate Immune Stimulation

PubMed Central

Tomlinson, Gillian S.; Booth, Helen; Petit, Sarah J.; Potton, Elspeth; Towers, Greg J.; Miller, Robert F.; Chain, Benjamin M.; Noursadeghi, Mahdad

2012-01-01

Alveolar macrophages (AM) are thought to have a key role in the immunopathogenesis of respiratory diseases. We sought to test the hypothesis that human AM exhibit an anti-inflammatory bias by making genome-wide comparisons with monocyte derived macrophages (MDM). Adherent AM obtained by bronchoalveolar lavage of patients under investigation for haemoptysis, but found to have no respiratory pathology, were compared to MDM from healthy volunteers by whole genome transcriptional profiling before and after innate immune stimulation. We found that freshly isolated AM exhibited a marked pro-inflammatory transcriptional signature. High levels of basal pro-inflammatory gene expression gave the impression of attenuated responses to lipopolysaccharide (LPS) and the RNA analogue, poly IC, but in rested cells pro-inflammatory gene expression declined and transcriptional responsiveness to these stimuli was restored. In comparison to MDM, both freshly isolated and rested AM showed upregulation of MHC class II molecules. In most experimental paradigms ex vivo adherent AM are used immediately after isolation. Therefore, the confounding effects of their pro-inflammatory profile at baseline need careful consideration. Moreover, despite the prevailing view that AM have an anti-inflammatory bias, our data clearly show that they can adopt a striking pro-inflammatory phenotype, and may have greater capacity for presentation of exogenous antigens than MDM. PMID:22768282

Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taylor, Cormac T.; Kent, Brian D.; Crinion, Sophie J.

Highlights: • Intermittent hypoxia (IH) leads to NF-κB activation in human primary adipocytes. • Adipocytes bear higher pro-inflammatory potential than other human primary cells. • IH leads to upregulation of multiple pro-inflammatory genes in human adipocytes. - Abstract: Introduction: Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmentedmore » inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. Methods and results: Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. Conclusion: Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key source of inflammatory mediators in OSA.« less

Translation Control: A Multifaceted Regulator of Inflammatory Response

PubMed Central

Mazumder, Barsanjit; Li, Xiaoxia; Barik, Sailen

2010-01-01

A robust innate immune response is essential to the protection of all vertebrates from infection, but it often comes with the price tag of acute inflammation. If unchecked, a runaway inflammatory response can cause significant tissue damage, resulting in myriad disorders, such as dermatitis, toxicshock, cardiovascular disease, acute pelvic and arthritic inflammatory diseases, and various infections. To prevent such pathologies, cells have evolved mechanisms to rapidly and specifically shut off these beneficial inflammatory activities before they become detrimental. Our review of recent literature, including our own work, reveals that the most dominant and common mechanism is translational silencing, in which specific regulatory proteins or complexes are recruited to cis-acting RNA structures in the untranslated regions of single or multiple mRNAs that code for the inflammatory protein(s). Enhancement of the silencing function may constitute a novel pharmacological approach to prevent immunity-related inflammation. PMID:20304832

Translation control: a multifaceted regulator of inflammatory response.

PubMed

Mazumder, Barsanjit; Li, Xiaoxia; Barik, Sailen

2010-04-01

A robust innate immune response is essential to the protection of all vertebrates from infection, but it often comes with the price tag of acute inflammation. If unchecked, a runaway inflammatory response can cause significant tissue damage, resulting in myriad disorders, such as dermatitis, toxic shock, cardiovascular disease, acute pelvic and arthritic inflammatory diseases, and various infections. To prevent such pathologies, cells have evolved mechanisms to rapidly and specifically shut off these beneficial inflammatory activities before they become detrimental. Our review of recent literature, including our own work, reveals that the most dominant and common mechanism is translational silencing, in which specific regulatory proteins or complexes are recruited to cis-acting RNA structures in the untranslated regions of single or multiple mRNAs that code for the inflammatory protein(s). Enhancement of the silencing function may constitute a novel pharmacological approach to prevent immunity-related inflammation.

Time to clinical response and remission for therapeutics in inflammatory bowel diseases: What should the clinician expect, what should patients be told?

PubMed Central

Vasudevan, Abhinav; Gibson, Peter R; van Langenberg, Daniel R

2017-01-01

An awareness of the expected time for therapies to induce symptomatic improvement and remission is necessary for determining the timing of follow-up, disease (re)assessment, and the duration to persist with therapies, yet this is seldom reported as an outcome in clinical trials. In this review, we explore the time to clinical response and remission of current therapies for inflammatory bowel disease (IBD) as well as medication, patient and disease related factors that may influence the time to clinical response. It appears that the time to therapeutic response varies depending on the indication for therapy (Crohn’s disease or ulcerative colitis). Agents with the most rapid time to clinical response included corticosteroids, calcineurin inhibitors, exclusive enteral nutrition, aminosalicylates and anti-tumor necrosis factor therapy which will work in most patients within the first 2 mo. Vedolizumab, methotrexate and thiopurines had a longer time to clinical response and can take several months to achieve maximal efficacy. Factors affecting the time to clinical response of therapies included use of concomitant therapy, disease duration, smoking status, disease phenotype and advanced age. There appears to be marked variation in time to clinical response for therapies used in IBD which is further influenced by disease and patient related factors. Understanding the expected time to therapeutic response is integral to inform further decision making, maintain a patient-centered approach and ensure treatment is given an appropriate timeframe to achieve maximal benefit prior to cessation. PMID:29085188

Time to clinical response and remission for therapeutics in inflammatory bowel diseases: What should the clinician expect, what should patients be told?

PubMed

Vasudevan, Abhinav; Gibson, Peter R; van Langenberg, Daniel R

2017-09-21

An awareness of the expected time for therapies to induce symptomatic improvement and remission is necessary for determining the timing of follow-up, disease (re)assessment, and the duration to persist with therapies, yet this is seldom reported as an outcome in clinical trials. In this review, we explore the time to clinical response and remission of current therapies for inflammatory bowel disease (IBD) as well as medication, patient and disease related factors that may influence the time to clinical response. It appears that the time to therapeutic response varies depending on the indication for therapy (Crohn's disease or ulcerative colitis). Agents with the most rapid time to clinical response included corticosteroids, calcineurin inhibitors, exclusive enteral nutrition, aminosalicylates and anti-tumor necrosis factor therapy which will work in most patients within the first 2 mo. Vedolizumab, methotrexate and thiopurines had a longer time to clinical response and can take several months to achieve maximal efficacy. Factors affecting the time to clinical response of therapies included use of concomitant therapy, disease duration, smoking status, disease phenotype and advanced age. There appears to be marked variation in time to clinical response for therapies used in IBD which is further influenced by disease and patient related factors. Understanding the expected time to therapeutic response is integral to inform further decision making, maintain a patient-centered approach and ensure treatment is given an appropriate timeframe to achieve maximal benefit prior to cessation.

Association of fecal calprotectin concentrations with disease severity, response to treatment, and other biomarkers in dogs with chronic inflammatory enteropathies

PubMed Central

Berghoff, Nora; Mansell, Joanne; Grützner, Niels; Parnell, Nolie K.; Gurtner, Corinne; Suchodolski, Jan S.; Steiner, Jörg M.

2018-01-01

Background Calprotectin is a marker of inflammation, but its clinical utility in dogs with chronic inflammatory enteropathies (CIE) is unknown. Objective Evaluation of fecal calprotectin in dogs with biopsy‐confirmed CIE. Animals 127 dogs. Methods Prospective case‐control study. Dogs were assigned a canine chronic enteropathy clinical activity index (CCECAI) score, and histologic lesions severity was assessed. Fecal calprotectin, fecal S100A12, and serum C‐reactive protein (CRP) were measured. Food‐ or antibiotic‐responsive cases (FRE/ARE, n = 13) were distinguished from steroid‐/immunosuppressant‐responsive or ‐refractory cases (SRE/IRE, n = 20). Clinical response to treatment in SRE/IRE dogs was classified as complete remission (CR), partial response (PR), or no response (NR). Results Fecal calprotectin correlated with CCECAI (ρ = 0.27, P = .0065) and fecal S100A12 (ρ = 0.90, P < .0001), some inflammatory criteria, and cumulative inflammation scores, but not serum CRP (ρ = 0.16, P = .12). Dogs with SRE/IRE had higher fecal calprotectin concentrations (median: 2.0 μg/g) than FRE/ARE dogs (median: 1.4 μg/g), and within the SRE/IRE group, dogs with PR/NR had higher fecal calprotectin (median: 37.0 μg/g) than dogs with CR (median: 1.6 μg/g). However, both differences did not reach statistical significance (both P = .10). A fecal calprotectin ≥15.2 μg/g separated both groups with 80% sensitivity (95% confidence interval [95%CI]: 28%‐100%) and 75% specificity (95%CI: 43%‐95%). Conclusions and Clinical Importance Fecal calprotectin could be a useful surrogate marker of disease severity in dogs with CIE, but larger longitudinal studies are needed to evaluate its utility in predicting the response to treatment. PMID:29460444

Fibrin(ogen) mediates acute inflammatory responses to biomaterials

PubMed Central

1993-01-01

Although "biocompatible" polymeric elastomers are generally nontoxic, nonimmunogenic, and chemically inert, implants made of these materials may trigger acute and chronic inflammatory responses. Early interactions between implants and inflammatory cells are probably mediated by a layer of host proteins on the material surface. To evaluate the importance of this protein layer, we studied acute inflammatory responses of mice to samples of polyester terephthalate film (PET) that were implanted intraperitoneally for short periods. Material preincubated with albumin is "passivated," accumulating very few adherent neutrophils or macrophages, whereas uncoated or plasma- coated PET attracts large numbers of phagocytes. Neither IgG adsorption nor surface complement activation is necessary for this acute inflammation; phagocyte accumulation on uncoated implants is normal in hypogammaglobulinemic mice and in severely hypocomplementemic mice. Rather, spontaneous adsorption of fibrinogen appears to be critical: (a) PET coated with serum or hypofibrinogenemic plasma attracts as few phagocytes as does albumin-coated material; (b) in contrast, PET preincubated with serum or hypofibrinogenemic plasma containing physiologic amounts of fibrinogen elicits "normal" phagocyte recruitment; (c) most importantly, hypofibrinogenemic mice do not mount an inflammatory response to implanted PET unless the material is coated with fibrinogen or the animals are injected with fibrinogen before implantation. Thus, spontaneous adsorption of fibrinogen appears to initiate the acute inflammatory response to an implanted polymer, suggesting an interesting nexus between two major iatrogenic effects of biomaterials: clotting and inflammation. PMID:8245787

Time-of-Day Dictates Transcriptional Inflammatory Responses to Cytotoxic Chemotherapy

PubMed Central

Borniger, Jeremy C.; Walker II, William H.; Gaudier-Diaz, Monica M.; Stegman, Curtis J.; Zhang, Ning; Hollyfield, Jennifer L.; Nelson, Randy J.; DeVries, A. Courtney

2017-01-01

Many cytotoxic chemotherapeutics elicit a proinflammatory response which is often associated with chemotherapy-induced behavioral alterations. The immune system is under circadian influence; time-of-day may alter inflammatory responses to chemotherapeutics. We tested this hypothesis by administering cyclophosphamide and doxorubicin (Cyclo/Dox), a common treatment for breast cancer, to female BALB/c mice near the beginning of the light or dark phase. Mice were injected intravenously with Cyclo/Dox or the vehicle two hours after lights on (zeitgeber time (ZT2), or two hours after lights off (ZT14). Tissue was collected 1, 3, 9, and 24 hours later. Mice injected with Cyclo/Dox at ZT2 lost more body mass than mice injected at ZT14. Cyclo/Dox injected at ZT2 increased the expression of several pro-inflammatory genes within the spleen; this was not evident among mice treated at ZT14. Transcription of enzymes within the liver responsible for converting Cyclo/Dox into their toxic metabolites increased among mice injected at ZT2; furthermore, transcription of these enzymes correlated with splenic pro-inflammatory gene expression when treatment occurred at ZT2 but not ZT14. The pattern was reversed in the brain; pro-inflammatory gene expression increased among mice injected at ZT14. These data suggest that inflammatory responses to chemotherapy depend on time-of-day and are tissue specific. PMID:28117419

Recent Patents and Emerging Therapeutics in the Treatment of Allergic Conjunctivitis

PubMed Central

Mishra, Gyan P.; Tamboli, Viral; Jwala, Jwala; Mitra, Ashim K.

2011-01-01

Ocular allergy is an inflammatory response of the conjunctival mucosa that also affects the cornea and eyelids. Allergic conjunctivitis includes seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis (GPC). In general, allergic conditions involve mast cell degranulation that leads to release of inflammatory mediators and activation of enzymatic cascades generating pro-inflammatory mediators. In chronic ocular inflammatory disorders associated with mast cell activation such as VKC and AKC constant inflammatory response is observed due to predominance of inflammatory mediators such as eosinophils and Th2-generated cytokines. Antihistamines, mast-cell stabilizers, non-steroidal anti-inflammatory agents, corticosteroids and immunomodulatory agents are commonly indicated for the treatment of acute and chronic allergic conjunctivitis. In recent years newer drug molecules have been introduced in the treatment of allergic conjunctivitis. This article reviews recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. PMID:21171952

Is depression an inflammatory condition? A review of available evidence.

PubMed

Hashmi, Ali Madeeh; Butt, Zeeshan; Umair, Muhammad

2013-07-01

The current review examines the relationship between depression and the inflammatory immune response. Mood disorders are a significant cause of morbidity and the etiology of depression is still not clearly understood. Many studies have shown links between inflammatory cytokines and mood disorders, including elevated level of cytokines like tumour necrosis factor-alpha (TNF alpha), Interleukins (IL-1,IL-6) and others. Raised levels of cytokines have been shown to increase depressive behaviour in animal models, while many anti-depressants reverse this behaviour alongside reducing the Central Nervous System (CNS) inflammatory response and reduction in the amounts of inflammatory cytokines. Cytokines reduce neurogenesis, Brain Derived Neurotrophic Factor (BDNF) and neuronal plasticity in the CNS, while many anti-depressants have been shown to reverse these processes. The considerations of anti-depressants as anti-inflammatory agents, and implication of other anti-inflammatory therapeutics for the treatment of depression are pointed out.

Neutrophil Apoptosis: Relevance to the Innate Immune Response and Inflammatory Disease

PubMed Central

Fox, Sarah; Leitch, Andrew E.; Duffin, Rodger; Haslett, Christopher; Rossi, Adriano G.

2010-01-01

Neutrophils are the most abundant cell type involved in the innate immune response. They are rapidly recruited to sites of injury or infection where they engulf and kill invading microorganisms. Neutrophil apoptosis, the process of programmed cell death that prevents the release of neutrophil histotoxic contents, is tightly regulated and limits the destructive capacity of neutrophil products to surrounding tissue. The subsequent recognition and phagocytosis of apoptotic cells by phagocytic cells such as macrophages is central to the successful resolution of an inflammatory response and it is increasingly apparent that the dying neutrophil itself exerts an anti-inflammatory effect through modulation of surrounding cell responses, particularly macrophage inflammatory cytokine release. Apoptosis may be delayed, induced or enhanced by micro-organisms dependent on their immune evasion strategies and the health of the host they encounter. There is now an established field of research aimed at understanding the regulation of apoptosis and its potential as a target for therapeutic intervention in inflammatory and infective diseases. This review focuses on the physiological regulation of neutrophil apoptosis with respect to the innate immune system and highlights recent advances in mechanistic understanding of apoptotic pathways and their therapeutic manipulation in appropriate and excessive innate immune responses. PMID:20375550

Effects of calcitriol (1, 25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice.

PubMed

Gui, Boxiang; Chen, Qin; Hu, Chuanxia; Zhu, Caihui; He, Guimei

2017-01-23

H9N2 influenza viruses circulate globally and are considered to have pandemic potential. The hyper-inflammatory response elicited by these viruses is thought to contribute to disease severity. Calcitriol plays an important role in modulating the immune response to viral infections. However, its unknown whether calcitriol can attenuate the inflammatory response elicited by H9N2 influenza virus infection. Human lung A549 epithelial cells were treated with calcitriol (100 nM) and then infected with an H9N2 influenza virus, or infected and then treated with calcitriol (30 nM). Culture supernatants were collected every 24 h post infection and the viral growth kinetics and inflammatory response were evaluated. Calcitriol (5 mg/kg) was administered daily by intraperitoneal injection to BABL/c mice for 15 days following H9N2 influenza virus infection. Mice were monitored for clinical signs of disease, lung pathology and inflammatory responses. Calcitriol treatment prior to and post infection with H9N2 influenza significantly decreased expression of the influenza M gene, IL-6, and IFN-β in A549 cells, but did not affect virus replication. In vivo, we found that calcitriol treatment significantly downregulated pulmonary inflammation in mice 2 days post-infection, but increased the inflammatory response 4 to 6 days post-infection. In contrast, the antiviral cytokine IFN-β was significantly higher in calcitriol-treated mice than in the untreated infected mice at 2 days post-infection, but lower than in untreated infected mice on days 4 and 8 post-infection. The elevated levels of pro-inflammatory cytokines and the decreased levels of antiviral cytokine are consistent with the period of maximum body weight loss and the lung damage in calcitriol-treated mice. These results suggest that calcitriol treatment might have a negative impact on the innate immune response elicited by H9N2 infection in mice, especially at the later stage of influenza virus infection. This study will provide some novel insights into the use of calcitriol to modulate the inflammatory response elicited by influenza virus infection in humans.

Role of Inflammatory Signaling in the Differential Effects of Saturated and Poly-unsaturated Fatty Acids on Peripheral Circadian Clocks.

PubMed

Kim, Sam-Moon; Neuendorff, Nichole; Chapkin, Robert S; Earnest, David J

2016-05-01

Inflammatory signaling may play a role in high-fat diet (HFD)-related circadian clock disturbances that contribute to systemic metabolic dysregulation. Therefore, palmitate, the prevalent proinflammatory saturated fatty acid (SFA) in HFD and the anti-inflammatory, poly-unsaturated fatty acid (PUFA), docosahexaenoic acid (DHA), were analyzed for effects on circadian timekeeping and inflammatory responses in peripheral clocks. Prolonged palmitate, but not DHA, exposure increased the period of fibroblast Bmal1-dLuc rhythms. Acute palmitate treatment produced phase shifts of the Bmal1-dLuc rhythm that were larger in amplitude as compared to DHA. These phase-shifting effects were time-dependent and contemporaneous with rhythmic changes in palmitate-induced inflammatory responses. Fibroblast and differentiated adipocyte clocks exhibited cell-specific differences in the time-dependent nature of palmitate-induced shifts and inflammation. DHA and other inhibitors of inflammatory signaling (AICAR, cardamonin) repressed palmitate-induced proinflammatory responses and phase shifts of the fibroblast clock, suggesting that SFA-mediated inflammatory signaling may feed back to modulate circadian timekeeping in peripheral clocks. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Leptin does not induce an inflammatory response in the murine placenta.

PubMed

Appel, S; Turnwald, E-M; Alejandre-Alcazar, M A; Ankerne, J; Rother, E; Janoschek, R; Wohlfarth, M; Vohlen, C; Schnare, M; Meißner, U; Dötsch, J

2014-06-01

Leptin is described as a pro-inflammatory signal in fat tissue, which is released from adipocytes and in turn activates immune cells. Also, leptin levels are known to be increased in pregnancies complicated with enhanced inflammatory processes in the placenta. Hence, we assumed that increased leptin amounts might contribute to inducing an inflammatory response in the placenta. To test this hypothesis, pregnant mice were continuously infused with recombinant murine leptin s. c. from day g13 to g16, resulting in a 3-fold increase of maternal circulating serum leptin levels. Dissected placentas were examined for the expression of pro-inflammatory cytokines IL-6 and TNF-alpha and the anti-inflammatory cytokine IL-10 using qPCR analysis. No changes were found except for TNF-alpha, which was slightly elevated upon leptin stimulation. However, TNF-alpha protein levels were not significantly higher in placentas from leptin treated mice. Also, leukocyte infiltration in the labyrinth section of placentas was not increased. In summary, our data demonstrate for the first time that elevated leptin levels alone do not induce an inflammatory response in the placenta. © Georg Thieme Verlag KG Stuttgart · New York.

Bioactive dietary peptides and amino acids in inflammatory bowel disease.

PubMed

Zhang, Hua; Hu, Chien-An A; Kovacs-Nolan, Jennifer; Mine, Yoshinori

2015-10-01

Inflammatory bowel disease (IBD), most commonly ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammation of the gastrointestinal tract. Patients affected with IBD experience symptoms including abdominal pain, persistent diarrhea, rectal bleeding, and weight loss. There is no cure for IBD; thus treatments typically focus on preventing complications, inducing and maintaining remission, and improving quality of life. During IBD, dysregulation of the intestinal immune system leads to increased production of pro-inflammatory cytokines, such as TNF-α and IL-6, and recruitment of activated immune cells to the intestine, causing tissue damage and perpetuating the inflammatory response. Recent biological therapies targeting specific inflammatory cytokines or pathways, in particular TNF-α, have shown promise, but not all patients respond to treatment, and some individuals become intolerant to treatment over time. Dietary peptides and amino acids (AAs) have been shown to modulate intestinal immune functions and influence inflammatory responses, and may be useful as alternative or ancillary treatments in IBD. This review focuses on dietary interventions for IBD treatment, in particular the role of dietary peptides and AAs in reducing inflammation, oxidative stress, and apoptosis in the gut, as well as recent advances in the cellular mechanisms responsible for their anti-inflammatory activity.

The influence of mineral trioxide aggregate on adaptive immune responses to endodontic pathogens in mice.

PubMed

Rezende, Taia Maria Berto; Vieira, Leda Quercia; Sobrinho, Antônio Paulino Ribeiro; Oliveira, Ricardo Reis; Taubman, Martin A; Kawai, Toshihisa

2008-09-01

This study assessed the influence of mineral trioxide aggregate (MTA) on adaptive immune responses. BALB/c mice were immunized with heat-killed Fusobacterium nucleatum (Fn) in MTA or other control adjuvants, and serum IgG responses to Fn were measured. Either Fn- or Peptostreptococcus anaerobius (Pa)-reactive memory T cells (Tm) were preincubated in vitro with/without MTA and restimulated with Fn or Pa. Tm proliferation and cytokine production were assessed. Compared with control groups, immunoglobulin G-antibody responses were upregulated in mice immunized with Fn in MTA in a similar manner to animals immunized with Fn in Freund's adjuvant or aluminum hydroxide adjuvant. Although MTA did not affect the upregulated expression of interleukin 10, tumor necrosis factor alpha, or RANKL by Tm, it suppressed the proliferation of Pa- or Fn-Tm and inhibited their production of Th1- or Th2-signature cytokines. MTA upregulated the adaptive humoral immune responses but had little or no effect on pro- or anti-inflammatory cytokine production by Tm.

Polyethylene glycol-functionalized poly (Lactic Acid-co-Glycolic Acid) and graphene oxide nanoparticles induce pro-inflammatory and apoptotic responses in Candida albicans-infected vaginal epithelial cells.

PubMed

Wagner, R Doug; Johnson, Shemedia J; Danielsen, Zhixia Yan; Lim, Jin-Hee; Mudalige, Thilak; Linder, Sean

2017-01-01

Mucous-penetrating nanoparticles consisting of poly lactic acid-co-glycolic acid (PLGA)-polyethylene glycol (PEG) could improve targeting of microbicidal drugs for sexually transmitted diseases by intravaginal inoculation. Nanoparticles can induce inflammatory responses, which may exacerbate the inflammation that occurs in the vaginal tracts of women with yeast infections. This study evaluated the effects of these drug-delivery nanoparticles on VK2(E6/E7) vaginal epithelial cell proinflammatory responses to Candida albicans yeast infections. Vaginal epithelial cell monolayers were infected with C. albicans and exposed to 100 μg/ml 49.5 nm PLGA-PEG nanospheres or 20 μg/ml 1.1 x 500 nm PEG-functionalized graphene oxide (GO-PEG) sheets. The cells were assessed for changes in mRNA and protein expression of inflammation-related genes by RT-qPCR and physiological markers of cell stress using high content analysis and flow cytometry. C. albicans exposure suppressed apoptotic gene expression, but induced oxidative stress in the cells. The nanomaterials induced cytotoxicity and programmed cell death responses alone and with C. albicans. PLGA-PEG nanoparticles induced mRNA expression of apoptosis-related genes and induced poly (ADP-ribose) polymerase (PARP) cleavage, increased BAX/BCL2 ratios, and chromatin condensation indicative of apoptosis. They also induced autophagy, endoplasmic reticulum stress, and DNA damage. They caused the cells to excrete inflammatory recruitment molecules chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-1α (IL1A), interleukin-1β (IL1B), calprotectin (S100A8), and tumor necrosis factor α (TNF). GO-PEG nanoparticles induced expression of necrosis-related genes and cytotoxicity. They reduced autophagy and endoplasmic reticulum stress, and apoptotic gene expression responses. The results show that stealth nanoparticle drug-delivery vehicles may cause intracellular damage to vaginal epithelial cells by several mechanisms and that their use for intravaginal drug delivery may exacerbate inflammation in active yeast infections by increased inflammatory recruitment.