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Sample records for acute inflammation model

  1. Deciphering the complexity of acute inflammation using mathematical models.

    PubMed

    Vodovotz, Yoram

    2006-01-01

    Various stresses elicit an acute, complex inflammatory response, leading to healing but sometimes also to organ dysfunction and death. We constructed both equation-based models (EBM) and agent-based models (ABM) of various degrees of granularity--which encompass the dynamics of relevant cells, cytokines, and the resulting global tissue dysfunction--in order to begin to unravel these inflammatory interactions. The EBMs describe and predict various features of septic shock and trauma/hemorrhage (including the response to anthrax, preconditioning phenomena, and irreversible hemorrhage) and were used to simulate anti-inflammatory strategies in clinical trials. The ABMs that describe the interrelationship between inflammation and wound healing yielded insights into intestinal healing in necrotizing enterocolitis, vocal fold healing during phonotrauma, and skin healing in the setting of diabetic foot ulcers. Modeling may help in understanding the complex interactions among the components of inflammation and response to stress, and therefore aid in the development of novel therapies and diagnostics.

  2. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models

    PubMed Central

    Li, Minmin; Lu, Chengwen; Zhang, Leiming; Zhang, Jianqiao; Du, Yuan; Duan, Sijin; Wang, Tian; Fu, Fenghua

    2015-01-01

    The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP) induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2) and cyclooxygenase- (COX-) 2. In CLP model, low dose of escin ameliorates endotoxin induced liver injury and intestinal mucosal injury and increases the expression of tight junction protein claudin-5 in mice. These findings suggest that escin effectively inhibits acute inflammation and reduces intestinal mucosal injury in animal models. PMID:26199634

  3. Effect of total phenolics from Laggera alata on acute and chronic inflammation models.

    PubMed

    Wu, Yihang; Zhou, Changxin; Song, Liyan; Li, Xiangping; Shi, Shuyun; Mo, Jianxia; Chen, Haiyong; Bai, Hua; Wu, Xiumei; Zhao, Jun; Zhang, Rongping; Hao, Xiaojiang; Sun, Handong; Zhao, Yu

    2006-11-24

    The anti-inflammatory effect of total phenolics from Laggera alata (TPLA) was evaluated with various in vivo models of both acute and chronic inflammations. In the acute inflammation tests, TPLA inhibited significantly xylene-induced mouse ear oedema, carrageenan-induced rat paw oedema and acetic acid-induced mouse vascular permeability. In the carrageenan-induced rat pleurisy model, TPLA significantly suppressed inflammatory exudate and leukocyte migration, reduced the serum levels of lysozyme (LZM) and malondialdehyde (MDA), increased the serum levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and also decreased the contents of total protein, nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in the pleural exudates. In the chronic inflammation experiment, TPLA inhibited significantly cotton pellet-induced rat granuloma. These results indicated that TPLA possesses potent anti-inflammatory activity on acute and chronic inflammation models. Its anti-inflammatory mechanisms are probably associated with the inhibition of prostaglandin formation, the influence on the antioxidant systems, and the suppression of LZM release. Furthermore, the total phenolic content of Laggera alata and its main component type was quantified, and its principle components were isolated and authenticated. Acute toxicity studies revealed that TPLA up to an oral dose of 8.5 g/kg body weight was almost nontoxic in mice.

  4. Rosiglitazone dampens pulmonary inflammation in a porcine model of acute lung injury.

    PubMed

    Mirakaj, Valbona; Mutz, Christian; Vagts, Dierk; Henes, Janek; Haeberle, Helene A; Husung, Susanne; König, Tony; Nöldge-Schomburg, Gabriele; Rosenberger, Peter

    2014-08-01

    The hallmarks of acute lung injury (ALI) are the compromised alveolar-capillary barrier and the extravasation of leukocytes into the alveolar space. Given the fact that the peroxisome proliferator-activated receptor-γ agonist rosiglitazone holds significant anti-inflammatory properties, we aimed to evaluate whether rosiglitazone could dampen these hallmarks of local pulmonary inflammation in a porcine model of lung injury. For this purpose, we used a model of lipopolysaccharide (LPS, 50 μg/kg)-induced ALI. One hundred twenty minutes following the infusion of LPS, we started the exposure to rosiglitazone through inhalation or infusion. We found that intravenous rosiglitazone significantly controlled local pulmonary inflammation as determined through the expression of cytokines within the alveolar compartment. Furthermore, we found a significant reduction of the protein concentration and neutrophil activity within the alveolar space. In summary, we therefore conclude that the treatment with rosiglitazone might dampen local pulmonary inflammation during the initial stages of ALI.

  5. Antiinflammatory activity of Phyllanthus emblica, Plumbago zeylanica and Cyperus rotundus in acute models of inflammation.

    PubMed

    Dang, G K; Parekar, R R; Kamat, S K; Scindia, A M; Rege, N N

    2011-06-01

    Experimental studies conducted earlier have proved that Phyllanthus emblica (Pe), Plumbago zeylanica (Pz) and Cyperus rotundus (Cr), plants from the medohara group of Ayurveda possess antiatherosclerotic activity. As inflammation is also one of the pathophysiological factors, it was of interest to evaluate whether these drugs exhibit any antiinflammatory activity. Two models of acute inflammation, namely carrageenan induced rat paw edema and acetic acid induced peritonitis in mice were used. In the model of carrageenan induced paw edema Pe, Pz and Cr showed a trend to reduce the edema while the combination of Pe + Pz (PI: 20.64%) showed results comparable to aspirin (23.74%). Whereas in a model of acetic acid induced peritonitis, all the plant drugs i.e. Pe, Pz, Cr and a combination of Pe + Pz showed a significant decrease in the protein content of the peritoneal exudates compared with the disease control group (p < 0.05), however, only Pe + Pz exhibited activity comparable to aspirin.

  6. Anti-inflammatory activity of Justicia prostrata gamble in acute and sub-acute models of inflammation.

    PubMed

    Sanmugapriya, E; Shanmugasundaram, P; Venkataraman, S

    2005-01-01

    In this study, the aqueous (AQJP) and alcoholic (ALJP) extracts of the whole plant of Justicia prostrata Gamble (Acanthaceae) were screened for their acute and subacute anti-inflammatory activities using carrageenan-induced acute inflammation and cotton-pellet-induced granuloma (subacute inflammation), respectively, in rats. In the carrageenan-induced rat paw oedema model, both extracts were found to exhibit maximum reduction in paw volume at the first hour in a dose-dependent manner. At the dose of 500 mg/kg p.o., both extracts AQJP and ALJP showed maximum inhibition (51.39% and 62.5%, respectively) in rat paw oedema volume at the first hour of carrageenan-induced acute inflammation. In the cotton pellet granuloma assay, AQJP and ALJP at the dose of 500 mg/kg p.o. suppressed the transudative, exudative and proliferative phases of chronic inflammation. These extracts were able to (i) reduce the lipid peroxide content of exudates and liver and (ii) normalize the increased activity of acid and alkaline phosphatases in serum and liver of cotton pellet granulomatous rats. Preliminary phytochemical screening revealed the presence of lignans, triterpenes and phenolic compounds in ALJP, whereas phenolic compounds and glycosides in AQJP. The anti-inflammatory properties of these extracts may possibly be due to the presence of phenolic compounds. The anti-inflammatory effects produced by the extracts at the dose of 500 mg/kg, p.o. was comparable with the reference drug diclofenac sodium (5 mg/kg p.o.).

  7. Acute salivary gland hypofunction in the duct ligation model in the absence of inflammation

    PubMed Central

    Correia, PN; Carpenter, GH; Osailan, SM; Paterson, KL; Proctor, GB

    2008-01-01

    Objective The commonly associated aetiology of salivary gland inflammation and salivary hypofunction has led to the widely held belief that inflammation causes salivary gland hypofunction. Indeed, our own recent study seemed to support this contention. Here, we tested the hypothesis that, in an acute duct ligation model, eliminating inflammation the submandibular gland would recover normal function. Materials and methods Ligation of the rat submandibular gland excretory duct for 24 h was used to induce inflammation and salivary gland hypofunction. A group of duct ligated rats was compared with a second group given dexamethasone, on the day of duct ligation. Twenty-four hours later salivary gland function was assessed and salivary glands were collected. Results Histology and myeloperoxidase activity assay revealed a profound decrease in inflammatory cell infiltration of ligated glands from rats given dexamethasone, compared with ligated glands in the absence of dexamethasone. Salivary flow rate evoked by methacholine was decreased (P < 0.01) by approximately 56% (ligated vs control, 79 ± 9 μl min−1 g−1vs 177 ± 11 μl min−1 g−1) and salivary flow from ligated dexamethasone-treated and ligated glands was similar. Conclusion Despite eliminating the inflammatory reaction in the ligated gland, salivary hypofunction was not reversed, suggesting that other mechanisms must be at work in the ligation-induced salivary hypofunction. PMID:18221457

  8. Isocitrate Treatment of Acute Anemia of Inflammation in a Mouse Model

    PubMed Central

    Kim, Airie; Fung, Eileen; Parikh, Sona G.; Gabayan, Victoria; Nemeth, Elizabeta; Ganz, Tomas

    2015-01-01

    Acute and severe anemia of inflammation (AI) is a common complication of various clinical syndromes, including fulminant infections, critical illness with multiorgan failure, and exacerbations of autoimmune diseases. Building on recent data showing beneficial results with isocitrate treatment for chronic low-grade AI in a rat model, we used a mouse model of acute and severe AI induced by intraperitoneal heat-killed Brucella abortus to determine if isocitrate would be effective in this more stringent application. Inflamed mice treated with isocitrate developed an early but transient improvement in hemoglobin compared to solvent-treated controls, with a robust improvement on day 7, and only a trend towards improvement by day 14. Reticulocyte counts were increased in treated mice transiently, with no significant difference by day 21. Serum erythropoietin (EPO) levels were similar in treated versus control mice, indicating that isocitrate increased sensitivity to EPO. Serum and tissue iron levels showed no significant differences between the treated and control mice, ruling out improved iron availability as the cause of the increased response to endogenous EPO. Compared to the milder rat model, much higher doses of isocitrate were required for a relatively modest benefit. PMID:26603720

  9. Characterisation of leukocytes in a human skin blister model of acute inflammation and resolution.

    PubMed

    Jenner, William; Motwani, Madhur; Veighey, Kristin; Newson, Justine; Audzevich, Tatsiana; Nicolaou, Anna; Murphy, Sharon; Macallister, Raymond; Gilroy, Derek W

    2014-01-01

    There is an increasing need to understand the leukocytes and soluble mediators that drive acute inflammation and bring about its resolution in humans. We therefore carried out an extensive characterisation of the cantharidin skin blister model in healthy male volunteers. A novel fluorescence staining protocol was designed and implemented, which facilitated the identification of cell populations by flow cytometry. We observed that at the onset phase, 24 h after blister formation, the predominant cells were CD16hi/CD66b+ PMNs followed by HLA-DR+/CD14+ monocytes/macrophages, CD11c+ and CD141+ dendritic cells as well as Siglec-8+ eosinophils. CD3+ T cells, CD19+ B cells and CD56+ NK cells were also present, but in comparatively fewer numbers. During resolution, 72 h following blister induction, numbers of PMNs declined whilst the numbers of monocyte/macrophages remain unchanged, though they upregulated expression of CD16 and CD163. In contrast, the overall numbers of dendritic cells and Siglec-8+ eosinophils increased. Post hoc analysis of these data revealed that of the inflammatory cytokines measured, TNF-α but not IL-1β or IL-8 correlated with increased PMN numbers at the onset. Volunteers with the greatest PMN infiltration at onset displayed the fastest clearance rates for these cells at resolution. Collectively, these data provide insight into the cells that occupy acute resolving blister in humans, the soluble mediators that may control their influx as well as the phenotype of mononuclear phagocytes that predominate the resolution phase. Further use of this model will improve our understanding of the evolution and resolution of inflammation in humans, how defects in these over-lapping pathways may contribute to the variability in disease longevity/chronicity, and lends itself to the screen of putative anti-inflammatory or pro-resolution therapies.

  10. Interleukin-33 drives activation of alveolar macrophages and airway inflammation in a mouse model of acute exacerbation of chronic asthma.

    PubMed

    Bunting, Melissa M; Shadie, Alexander M; Flesher, Rylie P; Nikiforova, Valentina; Garthwaite, Linda; Tedla, Nicodemus; Herbert, Cristan; Kumar, Rakesh K

    2013-01-01

    We investigated the role of interleukin-33 (IL-33) in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM) were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation.

  11. DO ACUTE PHASE PROTEINS REFLECT SEVERITY OF INFLAMMATION IN RAT MODELS OF POLLUTANT-INDUCED LUNG INJURY?

    EPA Science Inventory

    Title: DO ACUTE PHASE PROTEINS REFLECT THE SEVERITY OF INFLAMMATION IN RAT MODELS OF POLLUTANT-INDUCED LUNG INJURY?

    M. C. Schladweiler, BS 1, P. S. Gilmour, PhD 2, D. L. Andrews, BS 1, D. L. Costa, ScD 1, A. D. Ledbetter, BS 1, K. E. Pinkerton, PhD 3 and U. P. Kodavanti, ...

  12. The dynamics of acute inflammation

    NASA Astrophysics Data System (ADS)

    Kumar, Rukmini

    The acute inflammatory response is the non-specific and immediate reaction of the body to pathogenic organisms, tissue trauma and unregulated cell growth. An imbalance in this response could lead to a condition commonly known as "shock" or "sepsis". This thesis is an attempt to elucidate the dynamics of acute inflammatory response to infection and contribute to its systemic understanding through mathematical modeling and analysis. The models of immunity discussed use Ordinary Differential Equations (ODEs) to model the variation of concentration in time of the various interacting species. Chapter 2 discusses three such models of increasing complexity. Sections 2.1 and 2.2 discuss smaller models that capture the core features of inflammation and offer general predictions concerning the design of the system. Phase-space and bifurcation analyses have been used to examine the behavior at various parameter regimes. Section 2.3 discusses a global physiological model that includes several equations modeling the concentration (or numbers) of cells, cytokines and other mediators. The conclusions drawn from the reduced and detailed models about the qualitative effects of the parameters are very similar and these similarities have also been discussed. In Chapter 3, the specific applications of the biologically detailed model are discussed in greater detail. These include a simulation of anthrax infection and an in silico simulation of a clinical trial. Such simulations are very useful to biologists and could prove to be invaluable tools in drug design. Finally, Chapter 4 discusses the general problem of extinction of populations modeled as continuous variables in ODES is discussed. The average time to extinction and threshold are estimated based on analyzing the equivalent stochastic processes.

  13. Monocyte trafficking in acute and chronic inflammation.

    PubMed

    Ingersoll, Molly A; Platt, Andrew M; Potteaux, Stephane; Randolph, Gwendalyn J

    2011-10-01

    Environmental signals at the site of inflammation mediate rapid monocyte mobilization and dictate differentiation programs whereby these cells give rise to macrophages or dendritic cells. Monocytes participate in tissue healing, clearance of pathogens and dead cells, and initiation of adaptive immunity. However, recruited monocytes can also contribute to the pathogenesis of infection and chronic inflammatory disease, such as atherosclerosis. Here, we explore monocyte trafficking in the context of acute inflammation, relying predominantly on data from microbial infection models. These mechanisms will be compared to monocyte trafficking during chronic inflammation in experimental models of atherosclerosis. Recent developments suggest that monocyte trafficking shares common themes in diverse inflammatory diseases; however, important differences exist between monocyte migratory pathways in acute and chronic inflammation.

  14. A data-driven acute inflammation therapy

    PubMed Central

    2013-01-01

    Acute inflammation is a severe medical condition defined as an inflammatory response of the body to an infection. Its rapid progression requires quick and accurate decisions from clinicians. Inadequate and delayed decisions makes acute inflammation the 10th leading cause of death overall in United States with the estimated cost of treatment about $17 billion annually. However, despite the need, there are limited number of methods that could assist clinicians to determine optimal therapies for acute inflammation. We developed a data-driven method for suggesting optimal therapy by using machine learning model that is learned on historical patients' behaviors. To reduce both the risk of failure and the expense for clinical trials, our method is evaluated on a virtual patients generated by a mathematical model that emulates inflammatory response. In conducted experiments, acute inflammation was handled with two complimentary pro- and anti-inflammatory medications which adequate timing and doses are crucial for the successful outcome. Our experiments show that the dosage regimen assigned with our data-driven method significantly improves the percentage of healthy patients when compared to results by other methods used in clinical practice and found in literature. Our method saved 88% of patients that would otherwise die within a week, while the best method found in literature saved only 73% of patients. At the same time, our method used lower doses of medications than alternatives. In addition, our method achieved better results than alternatives when only incomplete or noisy measurements were available over time as well as it was less affected by therapy delay. The presented results provide strong evidence that models from the artificial intelligence community have a potential for development of personalized treatment strategies for acute inflammation. PMID:24565439

  15. Effect of dipeptidyl peptidase 4 inhibitors on acute and subacute models of inflammation in male Wistar rats: An experimental study

    PubMed Central

    Kagal, Urmila Anil; Angadi, Netravathi Basavaraj; Matule, Somnath Mallikarjun

    2017-01-01

    Introduction: The prevalence of Type 2 diabetes mellitus (T2DM) has reached alarming proportions due to the rapidly increasing rates of this disease worldwide. Preclinical and clinical studies have revealed elevated levels of inflammatory markers in a vast number of illnesses such as T2DM, obesity, and atherothrombosis collectively called metabolic syndrome leading to adverse cardiovascular events. Dipeptidyl peptidase 4 (DPP-4) inhibitors which are the enhancers of glucagon-like peptide 1 (GLP -1), could have anti-inflammatory potential which could help in reducing cardiovascular complications of diabetes and benefit patients suffering from the metabolic syndrome. Objective: The objective of this study was to analyze the effect of DPP-4 inhibitors, namely vildagliptin and saxagliptin on acute and subacute models of inflammation. Materials and Methods: Male Wistar rats were randomly divided into control, standard, and two treatment groups (6 animals in each group, total 24 animals). The animals received the drugs orally. The effects of vildagliptin and saxagliptin on inflammation were tested in acute (carrageenan-induced paw edema method) and subacute (grass pith and cotton pellet implantation method) models of inflammation. Results: Vildagliptin and saxagliptin used in the present study showed a significant anti-inflammatory activity in acute and subacute models of inflammation. Conclusion: The present study suggests that vildagliptin and saxagliptin have significant anti-inflammatory potential. Based on the findings of the present study and the available literature, it can be concluded that the anti-inflammatory potential of DPP-4 inhibitors could help to reduce the cardiovascular complications of Type 2 diabetes and the related cluster of metabolic disorders collectively called the metabolic syndrome. PMID:28251104

  16. Molecular Ultrasound Imaging of Tissue Inflammation Using an Animal Model of Acute Kidney Injury

    PubMed Central

    Hoyt, Kenneth; Warram, Jason M.; Wang, Dezhi; Ratnayaka, Sithira; Traylor, Amie; Agarwal, Anupam

    2016-01-01

    Purpose The objective of this study was to evaluate the use of molecular ultrasound (US) imaging for monitoring the early inflammatory effects following acute kidney injury. Procedures A population of rats underwent 30 min of renal ischemia (acute kidney injury, N=6) or sham injury (N=4) using established surgical methods. Animals were divided and molecular US imaging was performed during the bolus injection of a targeted microbubble (MB) contrast agent to either P-selectin or vascular cell adhesion molecule 1 (VCAM-1). Imaging was performed before surgery and 4 and 24 h thereafter. After manual segmentation of renal tissue space, the molecular US signal was calculated as the difference between time-intensity curve data before MB injection and after reaching steady-state US image enhancement. All animals were terminated after the 24 h imaging time point and kidneys excised for immunohistochemical (IHC) analysis. Results Renal inflammation was analyzed using molecular US imaging. While results using the P-selectin and VCAM-1 targeted MBs were comparable, it appears that the former was more sensitive to biomarker expression. All molecular US imaging measures had a positive correlation with IHC findings. Conclusions Acute kidney injury is a serious disease in need of improved noninvasive methods to help diagnose the extent of injury and monitor the tissue throughout disease progression. Molecular US imaging appears well suited to address this challenge and more research is warranted. PMID:25905474

  17. Acute Inflammation Loci Are Involved in Wound Healing in the Mouse Ear Punch Model.

    PubMed

    Canhamero, Tatiane; Garcia, Ludmila Valino; De Franco, Marcelo

    2014-09-01

    Significance: Molecular biology techniques are being used to aid in determining the mechanisms responsible for tissue repair without scar formation. Wound healing is genetically determined, but there have been few studies that examine the genes responsible for tissue regeneration in mammals. Research using genetic mapping is extremely important for understanding the molecular mechanisms involved in the different phases of tissue regeneration. This process is complex, but an early inflammatory phase appears to influence lesion closure, and the present study demonstrates that acute inflammation loci influence tissue regeneration in mice in a positive manner. Recent Advances: Mapping studies of quantitative trait loci (QTL) have been undertaken in recent years to examine candidate genes that participate in the regeneration phenotype. Our laboratory has identified inflammation modifier QTL for wound healing. Mouse lines selected for the maximum (AIRmax) or minimum (AIRmin) acute inflammatory reactivity (AIR) have been used to study not only the tissue repair but also the impact of the genetic control of inflammation on susceptibility to autoimmune, neoplasic, and infectious diseases. Murphy Roths Large and AIRmax mice are exclusive in their complete epimorphic regeneration, although middle-aged inbred mice may also be capable of healing. Critical Issues: Inflammatory reactions have traditionally been described in the literature as negative factors in the process of skin injury closure. Inflammation is exacerbated due to the early release of mediators or the intense release of factors that cause cell proliferation after injury. The initial release of these factors as well as the clean-up of the lesion microenvironment are both crucial for following events. In addition, the activation and repression of some genes related to the regeneration phenotype may modulate lesion closure, demonstrating the significance of genetic studies to better understand the mechanisms

  18. Acute Inflammation Loci Are Involved in Wound Healing in the Mouse Ear Punch Model

    PubMed Central

    Canhamero, Tatiane; Garcia, Ludmila Valino; De Franco, Marcelo

    2014-01-01

    Significance: Molecular biology techniques are being used to aid in determining the mechanisms responsible for tissue repair without scar formation. Wound healing is genetically determined, but there have been few studies that examine the genes responsible for tissue regeneration in mammals. Research using genetic mapping is extremely important for understanding the molecular mechanisms involved in the different phases of tissue regeneration. This process is complex, but an early inflammatory phase appears to influence lesion closure, and the present study demonstrates that acute inflammation loci influence tissue regeneration in mice in a positive manner. Recent Advances: Mapping studies of quantitative trait loci (QTL) have been undertaken in recent years to examine candidate genes that participate in the regeneration phenotype. Our laboratory has identified inflammation modifier QTL for wound healing. Mouse lines selected for the maximum (AIRmax) or minimum (AIRmin) acute inflammatory reactivity (AIR) have been used to study not only the tissue repair but also the impact of the genetic control of inflammation on susceptibility to autoimmune, neoplasic, and infectious diseases. Murphy Roths Large and AIRmax mice are exclusive in their complete epimorphic regeneration, although middle-aged inbred mice may also be capable of healing. Critical Issues: Inflammatory reactions have traditionally been described in the literature as negative factors in the process of skin injury closure. Inflammation is exacerbated due to the early release of mediators or the intense release of factors that cause cell proliferation after injury. The initial release of these factors as well as the clean-up of the lesion microenvironment are both crucial for following events. In addition, the activation and repression of some genes related to the regeneration phenotype may modulate lesion closure, demonstrating the significance of genetic studies to better understand the mechanisms

  19. Quantitative Assessment of Inflammation in a Porcine Acute Terminal Ileitis Model: US with a Molecularly Targeted Contrast Agent

    PubMed Central

    Wang, Huaijun; Felt, Stephen A.; Machtaler, Steven; Guracar, Ismayil; Luong, Richard; Bettinger, Thierry; Tian, Lu; Lutz, Amelie M.

    2015-01-01

    Purpose To evaluate the feasibility and reproducibility of ultrasonography (US) performed with dual-selectin–targeted contrast agent microbubbles (MBs) for assessment of inflammation in a porcine acute terminal ileitis model, with histologic findings as a reference standard. Materials and Methods The study had institutional Animal Care and Use Committee approval. Acute terminal ileitis was established in 19 pigs; four pigs served as control pigs. The ileum was imaged with clinical-grade dual P- and E-selectin–targeted MBs (MBSelectin) at increasing doses (0.5, 1.0, 2.5, 5.0, 10, and 20 × 108 MB per kilogram of body weight) and with control nontargeted MBs (MBControl). For reproducibility testing, examinations were repeated twice after the MBSelectin and MBControl injections. After imaging, scanned ileal segments were analyzed ex vivo both for inflammation grade (by using hematoxylin-eosin staining) and for expression of selectins (by using quantitative immunofluorescence analysis). Statistical analysis was performed by using the t test, intraclass correlation coefficients (ICCs), and Spearman correlation analysis. Results Imaging signal increased linearly (P < .001) between a dose of 0.5 and a dose of 5.0 × 108 MB/kg and plateaued between a dose of 10 and a dose of 20 × 108 MB/kg. Imaging signals were reproducible (ICC = 0.70), and administration of MBSelectin in acute ileitis resulted in a significantly higher (P < .001) imaging signal compared with that in control ileum and MBControl. Ex vivo histologic grades of inflammation correlated well with in vivo US signal (ρ = 0.79), and expression levels of both P-selectin (37.4% ± 14.7 [standard deviation] of vessels positive; P < .001) and E-selectin (31.2% ± 25.7) in vessels in the bowel wall of segments with ileitis were higher than in control ileum (5.1% ± 3.7 for P-selectin and 4.8% ± 2.3 for E-selectin). Conclusion Quantitative measurements of inflammation obtained by using dual-selectin–targeted US

  20. ISU201 enhances the resolution of airway inflammation in a mouse model of an acute exacerbation of asthma.

    PubMed

    Hiroshima, Yuka; Garthwaite, Linda; Hsu, Kenneth; Yoo, Hyouna; Park, Sang-Ho; Geczy, Carolyn L; Kumar, Rakesh K; Herbert, Cristan

    2015-01-01

    Glucocorticoids are commonly used for treating asthma and its exacerbations but have well-recognised adverse effects and are not always effective. Few alternative treatments exist. Using a murine model of an acute exacerbation of asthma, we assessed the ability of ISU201, a novel protein drug, to suppress the inflammatory response when administered after induction of an exacerbation. Sensitised mice were chronically challenged with a low mass concentration of aerosolised ovalbumin, and then received a single moderate-level challenge to simulate an allergen-induced exacerbation. ISU201 was administered to mice 2 and 8 hours later, while pulmonary inflammation and expression of mRNA for chemokines and proinflammatory cytokines were assessed after 4, 12, and 24 hours. Relative to vehicle-treated controls, ISU201 suppressed accumulation of pulmonary neutrophils and eosinophils, while accelerating the decline in CXCL1, TNF-α, and IL-6 in lavage fluid and lung tissue. ISU201 significantly reduced peak expression of mRNA for the chemokines Cxcl9 and Cxcl10, the adhesion molecules Icam1 and Vcam1, and the proinflammatory cytokines Il1b, Il12p40, and Csf1. The ability of ISU201 to promote resolution of inflammation suggests that it may have potential as an alternative to glucocorticoids in the management of asthma, including when administered after the onset of an acute exacerbation.

  1. Protective effects of hydroxytyrosol-supplemented refined olive oil in animal models of acute inflammation and rheumatoid arthritis.

    PubMed

    Silva, S; Sepodes, B; Rocha, J; Direito, R; Fernandes, A; Brites, D; Freitas, M; Fernandes, E; Bronze, M R; Figueira, M E

    2015-04-01

    Virgin olive oil is the primary source of fat in the Mediterranean diet, and its beneficial health effects have been related with oleic acid and phenolic compounds content. Hydroxytyrosol, a typical virgin olive oil phenolic compound, has beneficial antioxidant and anti-inflammatory properties as previously reported. The aim of this study was to evaluate the effect of hydroxytyrosol-supplemented refined olive oil at 0.5 and 5 mg/kg in a rodent model of rheumatoid arthritis. Rheumatoid arthritis was induced by intradermic administration, in male Wistar rats, of Freund's adjuvant with collagen type II on days 1 and 21. Hydroxytyrosol-supplemented refined olive oils were administrated by gavage from day 23 until day 35. The treatment at 5-mg/kg dose significantly decreased paw edema (P<.01), histological damage, cyclooxygenase-2 and inducible nitric oxide synthase expression, and markedly reduced the degree of bone resorption, soft tissue swelling and osteophyte formation, improving articular function in treated animals. Acute inflammation, induced by carrageenan, was also evaluated for hydroxytyrosol-supplemented refined olive oils at 0.5 and 5 mg/kg. Both doses significantly reduced paw edema (P<.001). Our results suggest that the supplementation of refined olive oil with hydroxytyrosol may be advantageous in rheumatoid arthritis with significant impact not only on chronic inflammation but also on acute inflammatory processes.

  2. Manipulating the air-filled zebrafish swim bladder as a neutrophilic inflammation model for acute lung injury

    PubMed Central

    Zhang, Yuefei; Liu, Hongcui; Yao, Junlin; Huang, Yanfeng; Qin, Shenlu; Sun, Zheng; Xu, Yingchun; Wan, Shu; Cheng, Hongqiang; Li, Chunqi; Zhang, Xue; Ke, Yuehai

    2016-01-01

    Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening diseases that are associated with high mortality rates due to treatment limitations. Neutrophils play key roles in the pathogenesis of ALI/ARDS by promoting the inflammation and injury of the alveolar microenvironment. To date, in vivo functional approaches have been limited by the inaccessibility to the alveolar sacs, which are located at the anatomical terminal of the respiratory duct in mammals. We are the first to characterize the swim bladder of the zebrafish larva, which is similar to the mammalian lung, as a real-time in vivo model for examining pulmonary neutrophil infiltration during ALI. We observed that the delivery of exogenous materials, including lipopolysaccharide (LPS), Poly IC and silica nanoparticles, by microinjection triggered significant time- and dose-dependent neutrophil recruitment into the swim bladder. Neutrophils infiltrated the LPS-injected swim bladder through the blood capillaries around the pneumatic duct or a site near the pronephric duct. An increase in the post-LPS inflammatory cytokine mRNA levels coincided with the in vivo neutrophil aggregation in the swim bladder. Microscopic examinations of the LPS-injected swim bladders further revealed in situ injuries, including epithelial distortion, endoplasmic reticulum swelling and mitochondrial injuries. Inhibitor screening assays with this model showed a reduction in neutrophil migration into the LPS-injected swim bladder in response to Shp2 inhibition. Moreover, the pharmacological suppression and targeted disruption of Shp2 in myeloid cells alleviated pulmonary inflammation in the LPS-induced ALI mouse model. Additionally, we used this model to assess pneumonia-induced neutrophil recruitment by microinjecting bronchoalveolar lavage fluid from patients into swim bladders; this injection enhanced neutrophil aggregation relative to the control. In conclusion, our findings

  3. Resolution of acute inflammation in the lung.

    PubMed

    Levy, Bruce D; Serhan, Charles N

    2014-01-01

    Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli, or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized proresolving mediators, specifically lipoxins, resolvins, protectins, and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung.

  4. Resolution of Acute Inflammation In The Lung

    PubMed Central

    Levy, Bruce D.; Serhan, Charles N.

    2015-01-01

    Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized pro-resolving mediators, specifically lipoxins, resolvins, protectins and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung. PMID:24313723

  5. Nutrition, Inflammation, and Acute Pancreatitis

    PubMed Central

    Petrov, Max

    2013-01-01

    Acute pancreatitis is acute inflammatory disease of the pancreas. Nutrition has a number of anti-inflammatory effects that could affect outcomes of patients with pancreatitis. Further, it is the most promising nonspecific treatment modality in acute pancreatitis to date. This paper summarizes the best available evidence regarding the use of nutrition with a view of optimising clinical management of patients with acute pancreatitis. PMID:24490104

  6. Feasibility of (68)Ga-labeled Siglec-9 peptide for the imaging of acute lung inflammation: a pilot study in a porcine model of acute respiratory distress syndrome.

    PubMed

    Retamal, Jaime; Sörensen, Jens; Lubberink, Mark; Suarez-Sipmann, Fernando; Borges, João Batista; Feinstein, Ricardo; Jalkanen, Sirpa; Antoni, Gunnar; Hedenstierna, Göran; Roivainen, Anne; Larsson, Anders; Velikyan, Irina

    2016-01-01

    There is an unmet need for noninvasive, specific and quantitative imaging of inherent inflammatory activity. Vascular adhesion protein-1 (VAP-1) translocates to the luminal surface of endothelial cells upon inflammatory challenge. We hypothesized that in a porcine model of acute respiratory distress syndrome (ARDS), positron emission tomography (PET) with sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) based imaging agent targeting VAP-1 would allow quantification of regional pulmonary inflammation. ARDS was induced by lung lavages and injurious mechanical ventilation. Hemodynamics, respiratory system compliance (Crs) and blood gases were monitored. Dynamic examination using [(15)O]water PET-CT (10 min) was followed by dynamic (90 min) and whole-body examination using VAP-1 targeting (68)Ga-labeled 1,4,7,10-tetraaza cyclododecane-1,4,7-tris-acetic acid-10-ethylene glycol-conjugated Siglec-9 motif peptide ([(68)Ga]Ga-DOTA-Siglec-9). The animals received an anti-VAP-1 antibody for post-mortem immunohistochemistry assay of VAP-1 receptors. Tissue samples were collected post-mortem for the radioactivity uptake, histology and immunohistochemistry assessment. Marked reduction of oxygenation and Crs, and higher degree of inflammation were observed in ARDS animals. [(68)Ga]Ga-DOTA-Siglec-9 PET showed significant uptake in lungs, kidneys and urinary bladder. Normalization of the net uptake rate (Ki) for the tissue perfusion resulted in 4-fold higher uptake rate of [(68)Ga]Ga-DOTA-Siglec-9 in the ARDS lungs. Immunohistochemistry showed positive VAP-1 signal in the injured lungs. Detection of pulmonary inflammation associated with a porcine model of ARDS was possible with [(68)Ga]Ga-DOTA-Siglec-9 PET when using kinetic modeling and normalization for tissue perfusion.

  7. Feasibility of 68Ga-labeled Siglec-9 peptide for the imaging of acute lung inflammation: a pilot study in a porcine model of acute respiratory distress syndrome

    PubMed Central

    Retamal, Jaime; Sörensen, Jens; Lubberink, Mark; Suarez-Sipmann, Fernando; Borges, João Batista; Feinstein, Ricardo; Jalkanen, Sirpa; Antoni, Gunnar; Hedenstierna, Göran; Roivainen, Anne; Larsson, Anders; Velikyan, Irina

    2016-01-01

    There is an unmet need for noninvasive, specific and quantitative imaging of inherent inflammatory activity. Vascular adhesion protein-1 (VAP-1) translocates to the luminal surface of endothelial cells upon inflammatory challenge. We hypothesized that in a porcine model of acute respiratory distress syndrome (ARDS), positron emission tomography (PET) with sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) based imaging agent targeting VAP-1 would allow quantification of regional pulmonary inflammation. ARDS was induced by lung lavages and injurious mechanical ventilation. Hemodynamics, respiratory system compliance (Crs) and blood gases were monitored. Dynamic examination using [15O]water PET-CT (10 min) was followed by dynamic (90 min) and whole-body examination using VAP-1 targeting 68Ga-labeled 1,4,7,10-tetraaza cyclododecane-1,4,7-tris-acetic acid-10-ethylene glycol-conjugated Siglec-9 motif peptide ([68Ga]Ga-DOTA-Siglec-9). The animals received an anti-VAP-1 antibody for post-mortem immunohistochemistry assay of VAP-1 receptors. Tissue samples were collected post-mortem for the radioactivity uptake, histology and immunohistochemistry assessment. Marked reduction of oxygenation and Crs, and higher degree of inflammation were observed in ARDS animals. [68Ga]Ga-DOTA-Siglec-9 PET showed significant uptake in lungs, kidneys and urinary bladder. Normalization of the net uptake rate (Ki) for the tissue perfusion resulted in 4-fold higher uptake rate of [68Ga]Ga-DOTA-Siglec-9 in the ARDS lungs. Immunohistochemistry showed positive VAP-1 signal in the injured lungs. Detection of pulmonary inflammation associated with a porcine model of ARDS was possible with [68Ga]Ga-DOTA-Siglec-9 PET when using kinetic modeling and normalization for tissue perfusion. PMID:27069763

  8. Proteomic Analysis of a Noninvasive Human Model of Acute Inflammation and Its Resolution: The Twenty-one Day Gingivitis Model

    PubMed Central

    2010-01-01

    The 21-day experimental gingivitis model, an established noninvasive model of inflammation in response to increasing bacterial accumulation in humans, is designed to enable the study of both the induction and resolution of inflammation. Here, we have analyzed gingival crevicular fluid, an oral fluid comprising a serum transudate and tissue exudates, by LC−MS/MS using Fourier transform ion cyclotron resonance mass spectrometry and iTRAQ isobaric mass tags, to establish meta-proteomic profiles of inflammation-induced changes in proteins in healthy young volunteers. Across the course of experimentally induced gingivitis, we identified 16 bacterial and 186 human proteins. Although abundances of the bacterial proteins identified did not vary temporally, Fusobacterium outer membrane proteins were detected. Fusobacterium species have previously been associated with periodontal health or disease. The human proteins identified spanned a wide range of compartments (both extracellular and intracellular) and functions, including serum proteins, proteins displaying antibacterial properties, and proteins with functions associated with cellular transcription, DNA binding, the cytoskeleton, cell adhesion, and cilia. PolySNAP3 clustering software was used in a multilayered analytical approach. Clusters of proteins that associated with changes to the clinical parameters included neuronal and synapse associated proteins. PMID:20662485

  9. Prostanoid receptors and acute inflammation in skin.

    PubMed

    Hohjoh, Hirofumi; Inazumi, Tomoaki; Tsuchiya, Soken; Sugimoto, Yukihiko

    2014-12-01

    Prostanoids such as prostaglandins (PGs) and thromboxanes exert a wide variety of actions via nine types of G protein-coupled receptors, including four PGE2 receptors (EPs) and two PGD2 receptors (DPs). Recent studies have revealed that prostanoids trigger or modulate acute inflammation in the skin via multiple mechanisms involving distinct receptors and molecules; PGE2 elicits vascular permeability and edema formation via EP3 receptor on mast cells, and PGE2 increases blood flow by eliciting vasodilatation via EP2/EP4 receptors on smooth muscle cells. PGD2-DP1 signaling plays a role in mast cell maturation and mast cell-mediated inflammation. Therefore, the local inhibition of specific prostanoid receptor signaling is expected to be an effective strategy for the prevention and treatment of acute inflammation.

  10. Anti-inflammatory and antinociceptive effects of salbutamol on acute and chronic models of inflammation in rats: involvement of an antioxidant mechanism.

    PubMed

    Uzkeser, Hulya; Cadirci, Elif; Halici, Zekai; Odabasoglu, Fehmi; Polat, Beyzagul; Yuksel, Tugba Nurcan; Ozaltin, Seda; Atalay, Fadime

    2012-01-01

    The possible role of β-2 adrenergic receptors in modulation of inflammatory and nociceptive conditions suggests that the β-2 adrenergic receptor agonist, salbutamol, may have beneficial anti-inflammatory and analgesic effects. Therefore, in this study, we induced inflammatory and nociceptive responses with carrageenan-induced paw edema or cotton-pellet-induced granuloma models, both of which result in oxidative stress. We hypothesized that salbutamol would prevent inflammatory and nociceptive responses by stimulating β-2 adrenergic receptors and the prevention of generation of ROS during the acute inflammation process in rats. Both doses of salbutamol used in the study (1 and 2 mg/kg) effectively blocked the acute inflammation and inflammatory nociception induced by carrageenan. In the cotton-pellet-induced granuloma test, both doses of salbutamol also significantly decreased the weight of granuloma tissue on the cotton pellets when compared to the control. Anti-inflammatory and analgesic effects of salbutamol were found to be comparable with those of indomethacin. Salbutamol decreased myeloperoxidase (MPO) activity and lipid peroxidation (LPO) level and increased the activity of superoxide dismutase (SOD) and level of glutathione (GSH) during the acute phase of inflammation. In conclusion, salbutamol can decrease acute and chronic inflammation, possibly through the stimulation of β-2 adrenergic receptors. This anti-inflammatory effect may be of significance in asthma treatment, where inflammation also takes part in the etiopathology. This study reveals that salbutamol has significant antioxidative effects, which at least partially explain its anti-inflammatory capabilities. These findings presented here may also shed light on the roles of β-2 adrenergic receptors in inflammatory and hyperalgesic conditions.

  11. Postischemic Inflammation in Acute Stroke

    PubMed Central

    Consoli, Arturo; Arnaboldi, Marco; Consoli, Domenico

    2017-01-01

    Cerebral ischemia is caused by arterial occlusion due to a thrombus or an embolus. Such occlusion induces multiple and concomitant pathophysiological processes that involve bioenergetic failure, acidosis, loss of cell homeostasis, excitotoxicity, and disruption of the blood-brain barrier. All of these mechanisms contribute to neuronal death, mainly via apoptosis or necrosis. The immune system is involved in this process in the early phases after brain injury, which contributes to potential enlargement of the infarct size and involves the penumbra area. Whereas inflammation and the immune system both exert deleterious effects, they also contribute to brain protection by stimulating a preconditioning status and to the concomitant repair of the injured parenchyma. This review describes the main phases of the inflammatory process occurring after arterial cerebral occlusion, with an emphasis on the role of single mediators. PMID:28079313

  12. Global sensitivity analysis of a mathematical model of acute inflammation identifies nonlinear dependence of cumulative tissue damage on host interleukin-6 responses.

    PubMed

    Mathew, Shibin; Bartels, John; Banerjee, Ipsita; Vodovotz, Yoram

    2014-10-07

    The precise inflammatory role of the cytokine interleukin (IL)-6 and its utility as a biomarker or therapeutic target have been the source of much debate, presumably due to the complex pro- and anti-inflammatory effects of this cytokine. We previously developed a nonlinear ordinary differential equation (ODE) model to explain the dynamics of endotoxin (lipopolysaccharide; LPS)-induced acute inflammation and associated whole-animal damage/dysfunction (a proxy for the health of the organism), along with the inflammatory mediators tumor necrosis factor (TNF)-α, IL-6, IL-10, and nitric oxide (NO). The model was partially calibrated using data from endotoxemic C57Bl/6 mice. Herein, we investigated the sensitivity of the area under the damage curve (AUCD) to the 51 rate parameters of the ODE model for different levels of simulated LPS challenges using a global sensitivity approach called Random Sampling High Dimensional Model Representation (RS-HDMR). We explored sufficient parametric Monte Carlo samples to generate the variance-based Sobol' global sensitivity indices, and found that inflammatory damage was highly sensitive to the parameters affecting the activity of IL-6 during the different stages of acute inflammation. The AUCIL6 showed a bimodal distribution, with the lower peak representing healthy response and the higher peak representing sustained inflammation. Damage was minimal at low AUCIL6, giving rise to a healthy response. In contrast, intermediate levels of AUCIL6 resulted in high damage, and this was due to the insufficiency of damage recovery driven by anti-inflammatory responses from IL-10 and the activation of positive feedback sustained by IL-6. At high AUCIL6, damage recovery was interestingly restored in some population of simulated animals due to the NO-mediated anti-inflammatory responses. These observations suggest that the host's health status during acute inflammation depends in a nonlinear fashion on the magnitude of the inflammatory stimulus

  13. Lymphatic Vascular Response to Acute Inflammation

    PubMed Central

    Lachance, Pier-Anne; Hazen, Amy; Sevick-Muraca, Eva M.

    2013-01-01

    During acute inflammation, functioning lymphatics are believed to reduce edema and to provide a transiting route for immune cells, but the extent at which the dermal lymphatic remodeling impacts lymphatic transport or the factors regulating these changes remains unclear. Herein we quantify the increase in lymphatic endothelial cells (LECs) and examine the expression of pro-angiogenenic and lymphangiogenic factors during acute cutaneous hypersensitivity (CHS). We found that LECs actively proliferate during CHS but that this proliferation does not affect the lymphatic vessel density. Instead, lymphatic remodeling is accompanied by lymphatic vessel leakiness and lower ejection of lymph fluid, which is observed only in the proximal lymphatic vessel draining the inflamed area. LECs and the immune cells release growth factors and cytokines during inflammation, which impact the lymphatic microenvironment and function. We identified that FGF-2, PLGF-2, HGF, EGF, and KC/CXCL17 are differentially expressed within tissues during acute CHS, but both VEGF-C and VEGF-D levels do not significantly change. Our results indicate that VEGF-C and VEGF-D are not the only players and other factors may be responsible for the LECs proliferation and altered lymphatic function in acute CHS. PMID:24086691

  14. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model

    PubMed Central

    Salem, Mohamed L.; Attia, Zeinab I.; Galal, Sohaila M.

    2015-01-01

    Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 × 105 cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund’s adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund’s Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti-tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b+Ly6G+, CD11b+Ly6G−, and CD11b+Ly6G−. We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID:26966565

  15. Topical Cathelicidin (LL-37) an Innate Immune Peptide Induces Acute Olfactory Epithelium Inflammation in a Mouse Model

    PubMed Central

    Alt, Jeremiah A.; Qin, Xuan; Pulsipher, Abigail; Orb, Quinn; Orlandi, Richard R.; Zhang, Jianxing; Schults, Austin; Jia, Wanjian; Presson, Angela P.; Prestwich, Glenn; Oottamasathien, Siam

    2017-01-01

    Background Cathelicidin (LL-37) is an endogenous innate immune peptide that is elevated in patients with chronic rhinosinusitis (CRS). The role of LL-37 in olfactory epithelium (OE) inflammation remains unknown. We hypothesized that 1) LL-37 topically delivered would elicit profound OE inflammation, and 2) LL-37 induced inflammation is associated with increased infiltration of neutrophils and mast cells. Methods To test our hypothesis we challenged C57BL/6 mice intranasally with increasing concentrations of LL-37. At 24 hours tissues were examined histologically and scored for inflammatory cell infiltrate, edema, and secretory hyperplasia. In separate experiments, fluorescently conjugated LL-37 was instilled and tissues were examined at 0.5 and 24 hours. To test our last hypothesis, we performed tissue myeloperoxidase (MPO) assays for neutrophil activity and immunohistochemistry for tryptase to determine the mean number of mast cells per mm2. Results LL-37 caused increased inflammatory cell infiltrate, edema, and secretory cell hyperplasia of the sinonasal mucosa with higher LL-37 concentrations yielding significantly more inflammatory changes (p < 0.01). Fluorescent LL-37 demonstrated global sinonasal epithelial binding and tissue distribution. Further, higher concentrations of LL-37 led to significantly greater MPO levels with dose-dependent increases in mast cell infiltration (p < 0.01). Conclusions LL-37 has dramatic inflammatory effects in the OE mucosa that is dose-dependent. The observed inflammatory changes in the olfactory mucosa were associated with the infiltration of both neutrophils and mast cells. Our biologic model represents a new model to further investigate the role of LL-37 in OE inflammation. PMID:26346056

  16. Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms

    PubMed Central

    Sparla, Richard; Hahnel, Maximilian; Bode, Johannes; Muckenthaler, Martina U.; Legewie, Stefan

    2017-01-01

    Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to ferroportin and triggers its degradation. The relative importance of individual ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular ferroportin transcription, and not by hepcidin-dependent ferroportin protein destabilization. In contrast, ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional

  17. IRF5 controls both acute and chronic inflammation.

    PubMed

    Weiss, Miriam; Byrne, Adam J; Blazek, Katrina; Saliba, David G; Pease, James E; Perocheau, Dany; Feldmann, Marc; Udalova, Irina A

    2015-09-01

    Whereas the importance of macrophages in chronic inflammatory diseases is well recognized, there is an increasing awareness that neutrophils may also play an important role. In addition to the well-documented heterogeneity of macrophage phenotypes and functions, neutrophils also show remarkable phenotypic diversity among tissues. Understanding the molecular pathways that control this heterogeneity should provide abundant scope for the generation of more specific and effective therapeutics. We have shown that the transcription factor IFN regulatory factor 5 (IRF5) polarizes macrophages toward an inflammatory phenotype. IRF5 is also expressed in other myeloid cells, including neutrophils, where it was linked to neutrophil function. In this study we explored the role of IRF5 in models of acute inflammation, including antigen-induced inflammatory arthritis and lung injury, both involving an extensive influx of neutrophils. Mice lacking IRF5 accumulate far fewer neutrophils at the site of inflammation due to the reduced levels of chemokines important for neutrophil recruitment, such as the chemokine (C-X-C motif) ligand 1. Furthermore we found that neutrophils express little IRF5 in the joints and that their migratory properties are not affected by the IRF5 deficiency. These studies extend prior ones suggesting that inhibiting IRF5 might be useful for chronic macrophage-induced inflammation and suggest that IRF5 blockade would ameliorate more acute forms of inflammation, including lung injury.

  18. The effect of purinergic signaling via the P2Y11 receptor on vascular function in a rat model of acute inflammation.

    PubMed

    Dănilă, Maria D; Privistirescu, Andreea; Duicu, Oana M; Rațiu, Corina D; Angoulvant, Denis; Muntean, Danina M; Sturza, Adrian

    2017-02-17

    There is a growing body of evidence pointing to the role of purinergic signaling in the development and progression of various conditions that have inflammation as a common pathogenetic denominator. The aim of the present study was to assess the involvement of P2Y11 purinergic receptors in the regulation of vascular function in aortic segments obtained using an experimental model of acute inflammation, the lipopolysaccharide (LPS, 8 mg/kg, i.p)-treated rats. Twelve hours after LPS administration, thoracic aortas were isolated and used for studies of vascular reactivity in the organ bath and for the measurement of reactive oxygen species (ROS) generation, respectively. LPS treatment significantly increased contractility to phenylephrine and attenuated the endothelium-dependent relaxation of the vascular segments in response to acetylcholine; an increased production of hydrogen peroxide (H2O2) was also recorded. The P2Y11 activator, NF546, decreased the LPS-induced aortic H2O2 release and partially normalized the vasomotor function, namely reduced contractility and improved relaxation. The effect was abolished by co-treatment with the P2Y11 inhibitor, NF340, and also after endothelium denudation. Importantly, NF546 did not elicit an antioxidant effect by acting as a H2O2 scavenger, suggesting that the beneficial outcome of this treatment on the vasculature is the consequence of P2Y11 stimulation. In conclusion, purinergic P2Y11 receptors stimulation improves vascular function and mitigates oxidative stress in the setting of acute systemic inflammation, revealing salutary effects and therapeutic potential in pathologies associated with endothelial dysfunction.

  19. The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells.

    PubMed

    Li, Ling; Fox, Bridget; Keeble, Julie; Salto-Tellez, Manuel; Winyard, Paul G; Wood, Mark E; Moore, Philip K; Whiteman, Matthew

    2013-03-01

    The role of hydrogen sulfide (H2 S) in inflammation remains unclear with both pro- and anti-inflammatory actions of this gas described. We have now assessed the effect of GYY4137 (a slow-releasing H2 S donor) on lipopolysaccharide (LPS)-evoked release of inflammatory mediators from human synoviocytes (HFLS) and articular chondrocytes (HAC) in vitro. We have also examined the effect of GYY4137 in a complete Freund's adjuvant (CFA) model of acute joint inflammation in the mouse. GYY4137 (0.1-0.5 mM) decreased LPS-induced production of nitrite (NO2 (-) ), PGE2 , TNF-α and IL-6 from HFLS and HAC, reduced the levels and catalytic activity of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reduced LPS-induced NF-κB activation in vitro. Using recombinant human enzymes, GYY4137 inhibited the activity of COX-2, iNOS and TNF-α converting enzyme (TACE). In the CFA-treated mouse, GYY4137 (50 mg/kg, i.p.) injected 1 hr prior to CFA increased knee joint swelling while an anti-inflammatory effect, as demonstrated by reduced synovial fluid myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAG) activity and decreased TNF-α, IL-1β, IL-6 and IL-8 concentration, was apparent when GYY4137 was injected 6 hrs after CFA. GYY4137 was also anti-inflammatory when given 18 hrs after CFA. Thus, although GYY4137 consistently reduced the generation of pro-inflammatory mediators from human joint cells in vitro, its effect on acute joint inflammation in vivo depended on the timing of administration.

  20. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

    PubMed

    Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

    2015-12-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak.

  1. G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling.

    PubMed

    Bajrami, Besnik; Zhu, Haiyan; Kwak, Hyun-Jeong; Mondal, Subhanjan; Hou, Qingming; Geng, Guangfeng; Karatepe, Kutay; Zhang, Yu C; Nombela-Arrieta, César; Park, Shin-Young; Loison, Fabien; Sakai, Jiro; Xu, Yuanfu; Silberstein, Leslie E; Luo, Hongbo R

    2016-09-19

    Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation.

  2. G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

    PubMed Central

    Bajrami, Besnik; Zhu, Haiyan; Zhang, Yu C.

    2016-01-01

    Cytokine-induced neutrophil mobilization from the bone marrow to circulation is a critical event in acute inflammation, but how it is accurately controlled remains poorly understood. In this study, we report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation. Nevertheless, although serum CXCR2 ligand concentrations increased during inflammation, neutrophil mobilization slowed after an initial acute fast phase, suggesting a suppression of neutrophil response to CXCR2 ligands after the acute phase. We demonstrate that granulocyte colony-stimulating factor (G-CSF), usually considered a prototypical neutrophil-mobilizing cytokine, was expressed later in the acute inflammatory response and unexpectedly impeded CXCR2-induced neutrophil mobilization by negatively regulating CXCR2-mediated intracellular signaling. Blocking G-CSF in vivo paradoxically elevated peripheral blood neutrophil counts in mice injected intraperitoneally with Escherichia coli and sequestered large numbers of neutrophils in the lungs, leading to sterile pulmonary inflammation. In a lipopolysaccharide-induced acute lung injury model, the homeostatic imbalance caused by G-CSF blockade enhanced neutrophil accumulation, edema, and inflammation in the lungs and ultimately led to significant lung damage. Thus, physiologically produced G-CSF not only acts as a neutrophil mobilizer at the relatively late stage of acute inflammation, but also prevents exaggerated neutrophil mobilization and the associated inflammation-induced tissue damage during early-phase infection and inflammation. PMID:27551153

  3. The Effects of Quercetin on Acute Lung Injury and Biomarkers of Inflammation and Oxidative Stress in the Rat Model of Sepsis.

    PubMed

    Gerin, Fethullah; Sener, Umit; Erman, Hayriye; Yilmaz, Ahsen; Aydin, Bayram; Armutcu, Ferah; Gurel, Ahmet

    2016-04-01

    Experimental studies indicate that sepsis causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative damage, and inflammation on lung injury, following sepsis model by cecal ligation and puncture, and the effects of quercetin, antioxidant, and anti-inflammatory flavonoid, in the lung tissue were investigated. In the present study, we found that administration of single-dose quercetin before cecal ligation and puncture procedure, while markedly diminishing the levels of YKL-40 and oxidant molecules (xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA)), increases the antioxidant enzymes levels. Quercetin is beneficial to acute lung injury by decreasing the levels of oxidative stress markers and increasing the antioxidant enzyme activities. Quercetin also causes a decrease in the serum levels of YKL-40 and periostin in the oxidative lung injury induced by the experimental sepsis model.

  4. Conserved gene regulation during acute inflammation between zebrafish and mammals.

    PubMed

    Forn-Cuní, G; Varela, M; Pereiro, P; Novoa, B; Figueras, A

    2017-02-03

    Zebrafish (Danio rerio), largely used as a model for studying developmental processes, has also emerged as a valuable system for modelling human inflammatory diseases. However, in a context where even mice have been questioned as a valid model for these analysis, a systematic study evaluating the reproducibility of human and mammalian inflammatory diseases in zebrafish is still lacking. In this report, we characterize the transcriptomic regulation to lipopolysaccharide in adult zebrafish kidney, liver, and muscle tissues using microarrays and demonstrate how the zebrafish genomic responses can effectively reproduce the mammalian inflammatory process induced by acute endotoxin stress. We provide evidence that immune signaling pathways and single gene expression is well conserved throughout evolution and that the zebrafish and mammal acute genomic responses after lipopolysaccharide stimulation are highly correlated despite the differential susceptibility between species to that compound. Therefore, we formally confirm that zebrafish inflammatory models are suited to study the basic mechanisms of inflammation in human inflammatory diseases, with great translational impact potential.

  5. Protective Effect of Baccharis trimera Extract on Acute Hepatic Injury in a Model of Inflammation Induced by Acetaminophen

    PubMed Central

    Pádua, Bruno da Cruz; Rossoni Júnior, Joamyr Victor; de Brito Magalhães, Cíntia Lopes; Chaves, Míriam Martins; Silva, Marcelo Eustáquio; Pedrosa, Maria Lucia; de Souza, Gustavo Henrique Bianco; Brandão, Geraldo Célio; Rodrigues, Ivanildes Vasconcelos; Lima, Wanderson Geraldo; Costa, Daniela Caldeira

    2014-01-01

    Background. Acetaminophen (APAP) is a commonly used analgesic and antipyretic. When administered in high doses, APAP is a clinical problem in the US and Europe, often resulting in severe liver injury and potentially acute liver failure. Studies have demonstrated that antioxidants and anti-inflammatory agents effectively protect against the acute hepatotoxicity induced by APAP overdose. Methods. The present study attempted to investigate the protective effect of B. trimera against APAP-induced hepatic damage in rats. The liver-function markers ALT and AST, biomarkers of oxidative stress, antioxidant parameters, and histopathological changes were examined. Results. The pretreatment with B. trimera attenuated serum activities of ALT and AST that were enhanced by administration of APAP. Furthermore, pretreatment with the extract decreases the activity of the enzyme SOD and increases the activity of catalase and the concentration of total glutathione. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by APAP. Conclusions. The hepatoprotective action of B. trimera extract may rely on its effect on reducing the oxidative stress caused by APAP-induced hepatic damage in a rat model. General Significance. These results make the extract of B. trimera a potential candidate drug capable of protecting the liver against damage caused by APAP overdose. PMID:25435714

  6. Models of Inflammation: Carrageenan Air Pouch.

    PubMed

    Duarte, Djane B; Vasko, Michael R; Fehrenbacher, Jill C

    2016-03-18

    The subcutaneous air pouch is an in vivo model that can be used to study the components of acute and chronic inflammation, the resolution of the inflammatory response, the oxidative stress response, and potential therapeutic targets for treating inflammation. Injection of irritants into an air pouch in rats or mice induces an inflammatory response that can be quantified by the volume of exudate produced, the infiltration of cells, and the release of inflammatory mediators. The model presented in this unit has been extensively used to identify potential anti-inflammatory drugs.

  7. Models of inflammation: carrageenan air pouch.

    PubMed

    Duarte, Djane B; Vasko, Michael R; Fehrenbacher, Jill C

    2012-03-01

    The subcutaneous air pouch is an in vivo model that can be used to study acute and chronic inflammation, the resolution of the inflammatory response, and the oxidative stress response. Injection of irritants into an air pouch in rats or mice induces an inflammatory response that can be quantified by the volume of exudate produced, the infiltration of cells, and the release of inflammatory mediators. The model presented in this unit has been extensively used to identify potential anti-inflammatory drugs.

  8. Trikatu, a herbal compound that suppresses monosodium urate crystal-induced inflammation in rats, an experimental model for acute gouty arthritis.

    PubMed

    Murunikkara, Vachana; Rasool, Mahaboobkhan

    2014-01-01

    Gout is an inflammatory joint disorder characterized by hyperuricaemia and precipitation of monosodium urate crystals in the joints. In the present study, we aimed to investigate the anti-inflammatory effect of trikatu, a herbal compound in monosodium urate crystal-induced inflammation in rats, an experimental model for acute gouty arthritis. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and histopathological examination of ankle joints were determined in control and monosodium urate crystal-induced rats. In addition, analgesic (acetic acid-induced writhing response), anti-pyretic (yeast-induced pyrexia) and gastric ulceration effects were tested. The levels of lysosomal enzymes, lipid peroxidation and paw volume were significantly increased, and anti-oxidant status was found to be reduced in monosodium urate crystal-induced rats, whereas the biochemical changes were reverted to near normal levels upon trikatu (1000 mg/kg b.wt) administration. The trikatu has also been found to exhibit significant analgesic and anti-pyretic effects with the absence of gastric damage. In conclusion, the present results clearly indicated that trikatu exert a potent anti-inflammatory effect against monosodium urate crystal-induced inflammation in rats in association with analgesic and anti-pyretic effects in the absence of gastrointestinal damage.

  9. The effects of Gamijinhae-tang on elastase/lipopolysaccharide-induced lung inflammation in an animal model of acute lung injury

    PubMed Central

    2013-01-01

    Background Gamijinhae-tang (GJHT) has long been used in Korea to treat respiratory diseases. The therapeutic effect of GJHT is likely associated with its anti-inflammatory activity. However, the precise mechanisms underlying its effects are unknown. This study was conducted to evaluate the protective effects of GJHT in a porcine pancreatic elastase (PPE) and lipopolysaccharide(LPS) induced animal model of acute lung injury (ALI). Methods In this study, mice were intranasally exposed to PPE and LPS for 4 weeks to induce chronic obstructive pulmonary disease (COPD)-like lung inflammation. Two hours prior to PPE and LPS administration, the treatment group was administered GJHT extracts via an oral injection. The numbers of neutrophils, lymphocytes, macrophages and total cells in the bronchoalveolar lavage (BAL) fluid were counted, and pro-inflammatory cytokines were also measured. For histologic analysis, hematoxylin and eosin (H&E) stains and periodic acid-Schiff (PAS) stains were evaluated. Results After inducing ALI by treating mice with PPE and LPS for 4 weeks, the numbers of neutrophils, lymphocytes and total cells were significantly lower in the GJHT group than in the ALI group. In addition, the IL-1β and IL-6 levels were significantly decreased in the GJHT group. The histological results also demonstrated the attenuation effect of GJHT on PPE- and LPS-induced lung inflammation. Conclusions The results of this study indicate that GJHT has significantly reduces PPE- and LPS-induced lung inflammation. The remarkable protective effects of GJHT suggest its therapeutic potential in COPD treatment. PMID:23866260

  10. Acute amygdaloid response to systemic inflammation.

    PubMed

    Engler, Harald; Doenlen, Raphael; Engler, Andrea; Riether, Carsten; Prager, Geraldine; Niemi, Maj-Britt; Pacheco-López, Gustavo; Krügel, Ute; Schedlowski, Manfred

    2011-10-01

    The amygdala, a group of nuclei located in the medial temporal lobe, is a key limbic structure involved in mood regulation, associative learning, and modulation of cognitive functions. Functional neuroanatomical studies suggest that this brain region plays also an important role in the central integration of afferent signals from the peripheral immune system. In the present study, intracerebral electroencephalography and microdialysis were employed to investigate the electrophysiological and neurochemical consequences of systemic immune activation in the amygdala of freely moving rats. Intraperitoneal administration of bacterial lipopolysaccharide (100 μg/kg) induced with a latency of about 2 h a significant increase in amygdaloid neuronal activity and a substantial rise in extracellular noradrenaline levels. Activated neurons in the amygdaloid complex, identified by c-Fos immunohistochemistry, were mainly located in the central nucleus and, to a lesser extent, in the basolateral nucleus of the amygdala. Gene expression analysis in micropunches of the amygdala revealed that endotoxin administration induced a strong time-dependent increase in IL-1β, IL-6, and TNF-α mRNA levels indicating that these cytokines are de novo synthesized in the amygdala in response to peripheral immune activation. The changes in amygdaloid activity were timely related to an increase in anxiety-like behavior and decreased locomotor activity and exploration in the open-field. Taken together, these data give novel insights into different features of the acute amygdaloid response during experimental inflammation and provides further evidence that the amygdala integrates immune-derived information to coordinate behavioral and autonomic responses.

  11. Inhibitory effect of anethole in nonimmune acute inflammation.

    PubMed

    Domiciano, Talita Perdigão; Dalalio, Márcia Machado de Oliveira; Silva, Expedito Leite; Ritter, Alessandra Mileni Versuti; Estevão-Silva, Camila Fernanda; Ramos, Fernando Seara; Caparroz-Assef, Silvana Martins; Cuman, Roberto Kenji Nakamura; Bersani-Amado, Ciomar Aparecida

    2013-04-01

    Anethole [1-methoxy-4-(1-propenyl)benzene] occurs naturally as a major component of the essential oil of star anise (Illicium verum Hook.f., family Illiciaceae), comprising more than 90 % of its volatile components. Studies showed that this substance has antioxidant, antibacterial, antifungal, and anesthetic properties. In this study, the anti-inflammatory properties of anethole in animal models of nonimmune acute inflammation such as croton oil-induced ear edema and carrageenan-induced pleurisy were investigated. The investigated parameters were edema formation, leukocyte migration, and inflammatory mediators involved. Oral administration of anethole at a dose of 250 and 500 mg/kg reduced both the volume of pleural exudates and the number of migrated leukocytes. Levels of nitric oxide (NO) and prostaglandins (PGE2) in the inflammatory exudate were reduced by treatment with anethole, but levels of tumor necrosis factor-α and interleukin-1β were not significantly altered. In ear edema, the oral treatment with anethole inhibited the formation of exudate and the activity of myeloperoxidase, but not after topical administration. These results suggest that the anethole may be effective in controlling some nonimmune acute inflammation-related disease, probably by an inhibitory action on production and/or release of PGE2 and NO.

  12. Necrotizing Enterocolitis in a mouse model leads to widespread renal inflammation, acute kidney injury and disruption of renal tight junction proteins

    PubMed Central

    Garg, Parvesh M; Tatum, Rodney; Ravisankar, Srikanth; Shekhawat, Prem S; Chen, Yan-Hua

    2015-01-01

    BACKGROUND Necrotizing enterocolitis (NEC) is a devastating condition affecting premature infants and leads to high mortality and chronic morbidity. Severe form of NEC is associated with acute renal failure, fluid imbalance, hyponatremia and acidosis. We investigated the effect of NEC on tight junction (TJ) proteins in kidneys using a NEC mouse model to investigate the basis for the observed renal dysfunction. METHODS NEC was induced in C57BL/6 mice by formula feeding and subjecting them to periods of hypoxia and cold stress. NEC was confirmed by gross and histological examination. We studied various markers of inflammation in kidneys and investigated changes in expression of several TJ proteins and AQP2 using immunofluorecent staining and Western blotting. RESULTS We found markedly increased expression of NFκB, TGFβ and ERK1/2 along with claudin-1, -2, -3, -4, -8 and AQP-2 in NEC kidneys. The membrane localization of claudin-2 was altered in the NEC kidneys and its immunostaining signal at TJ was disrupted. CONCLUSION NEC led to a severe inflammatory response not only in the gut but also the kidneys. NEC increased expression of several TJ proteins and caused disruption of claudin-2 in renal tubules. These observed changes can help explain some of the clinical findings observed in NEC. PMID:26270572

  13. Conserved gene regulation during acute inflammation between zebrafish and mammals

    PubMed Central

    Forn-Cuní, G.; Varela, M.; Pereiro, P.; Novoa, B.; Figueras, A.

    2017-01-01

    Zebrafish (Danio rerio), largely used as a model for studying developmental processes, has also emerged as a valuable system for modelling human inflammatory diseases. However, in a context where even mice have been questioned as a valid model for these analysis, a systematic study evaluating the reproducibility of human and mammalian inflammatory diseases in zebrafish is still lacking. In this report, we characterize the transcriptomic regulation to lipopolysaccharide in adult zebrafish kidney, liver, and muscle tissues using microarrays and demonstrate how the zebrafish genomic responses can effectively reproduce the mammalian inflammatory process induced by acute endotoxin stress. We provide evidence that immune signaling pathways and single gene expression is well conserved throughout evolution and that the zebrafish and mammal acute genomic responses after lipopolysaccharide stimulation are highly correlated despite the differential susceptibility between species to that compound. Therefore, we formally confirm that zebrafish inflammatory models are suited to study the basic mechanisms of inflammation in human inflammatory diseases, with great translational impact potential. PMID:28157230

  14. Myeloid ZFP36L1 Does Not Regulate Inflammation or Host Defense in Mouse Models of Acute Bacterial Infection

    PubMed Central

    Hyatt, Lynnae D.; Wasserman, Gregory A.; Rah, Yoon J.; Matsuura, Kori Y.; Coleman, Fadie T.; Hilliard, Kristie L.; Pepper-Cunningham, Zachary Ash; Ieong, Michael; Stumpo, Deborah J.; Blackshear, Perry J.; Quinton, Lee J.; Mizgerd, Joseph P.; Jones, Matthew R.

    2014-01-01

    Zinc finger protein 36, C3H type-like 1 (ZFP36L1) is one of several Zinc Finger Protein 36 (Zfp36) family members, which bind AU rich elements within 3′ untranslated regions (UTRs) to negatively regulate the post-transcriptional expression of targeted mRNAs. The prototypical member of the family, Tristetraprolin (TTP or ZFP36), has been well-studied in the context of inflammation and plays an important role in repressing pro-inflammatory transcripts such as TNF-α. Much less is known about the other family members, and none have been studied in the context of infection. Using macrophage cell lines and primary alveolar macrophages we demonstrated that, like ZFP36, ZFP36L1 is prominently induced by infection. To test our hypothesis that macrophage production of ZFP36L1 is necessary for regulation of the inflammatory response of the lung during pneumonia, we generated mice with a myeloid-specific deficiency of ZFP36L1. Surprisingly, we found that myeloid deficiency of ZFP36L1 did not result in alteration of lung cytokine production after infection, altered clearance of bacteria, or increased inflammatory lung injury. Although alveolar macrophages are critical components of the innate defense against respiratory pathogens, we concluded that myeloid ZFP36L1 is not essential for appropriate responses to bacteria in the lungs. Based on studies conducted with myeloid-deficient ZFP36 mice, our data indicate that, of the Zfp36 family, ZFP36 is the predominant negative regulator of cytokine expression in macrophages. In conclusion, these results imply that myeloid ZFP36 may fully compensate for loss of ZFP36L1 or that Zfp36l1-dependent mRNA expression does not play an integral role in the host defense against bacterial pneumonia. PMID:25299049

  15. Acute coronary disease Athero-Inflammation: Therapeutic approach.

    PubMed

    Altman, Raul

    2003-06-20

    Antithrombotic therapy is the cornerstone of the treatment of acute coronary syndromes, but there is now evidence which indicates that by blocking inflammation, thrombosis and thus, acute coronary events, could be lowered. The concept of athero-inflammation emerges as the meeting point of different morbidities; dyslipemia, diabetes, hypertension, obesity, immunity, infection, hyperhomocyteinemia, smoking, etc. usual named as risk factors. Thus, beside specific drugs, earliest treatment, in the stage of inflammation, using anti-inflammatory drugs, should be considered since in patients with increased risk of acute coronary process are likely to have many point of origen throughout the coronary arteries. There are a body of evidences for supporting the potential of anti-inflammatory therapy to the prevention of inflammation and atherosclerosis. COX-2 inhibition may decrease endothelial inflammation reducing monocytes infiltration improving vascular cells function, plaque stability and probably resulting in a decrease of coronary atherothrombotic events.Trials including large numbers of patients in prospective double-blind randomized studies worthwhile to confirm the efficacy of NSAID, mainly, COX-2 inhibitors, together with aspirin in the prevention of coronary events in patients with acute coronary disease.

  16. Acute coronary disease Athero-Inflammation: Therapeutic approach

    PubMed Central

    Altman, Raul

    2003-01-01

    Antithrombotic therapy is the cornerstone of the treatment of acute coronary syndromes, but there is now evidence which indicates that by blocking inflammation, thrombosis and thus, acute coronary events, could be lowered. The concept of athero-inflammation emerges as the meeting point of different morbidities; dyslipemia, diabetes, hypertension, obesity, immunity, infection, hyperhomocyteinemia, smoking, etc. usual named as risk factors. Thus, beside specific drugs, earliest treatment, in the stage of inflammation, using anti-inflammatory drugs, should be considered since in patients with increased risk of acute coronary process are likely to have many point of origen throughout the coronary arteries. There are a body of evidences for supporting the potential of anti-inflammatory therapy to the prevention of inflammation and atherosclerosis. COX-2 inhibition may decrease endothelial inflammation reducing monocytes infiltration improving vascular cells function, plaque stability and probably resulting in a decrease of coronary atherothrombotic events. Trials including large numbers of patients in prospective double-blind randomized studies worthwhile to confirm the efficacy of NSAID, mainly, COX-2 inhibitors, together with aspirin in the prevention of coronary events in patients with acute coronary disease. PMID:12904261

  17. An Anti-Interleukin-2 Receptor Drug Attenuates T- Helper 1 Lymphocytes-Mediated Inflammation in an Acute Model of Endotoxin-Induced Uveitis

    PubMed Central

    Navea, Amparo; Almansa, Inmaculada; Muriach, María; Bosch-Morell, Francisco

    2014-01-01

    The aim of the present study was to evaluate the anti-inflammatory efficacy of Daclizumab, an anti-interleukin-2 receptor drug, in an experimental uveitis model upon a subcutaneous injection of lipopolysaccharide into Lewis rats, a valuable model for ocular acute inflammatory processes. The integrity of the blood-aqueous barrier was assessed 24 h after endotoxin-induced uveitis by evaluating two parameters: cell count and protein concentration in aqueous humors. The histopathology of all the ocular structures (cornea, lens, sclera, choroid, retina, uvea, and anterior and posterior chambers) was also considered. Enzyme-linked immunosorbent assays of the aqueous humor samples were performed to quantify the levels of the different chemokine and cytokine proteins. Similarly, a biochemical analysis of oxidative stress-related markers was also assessed. The inflammation observed in the anterior chamber of the eyes when Daclizumab was administered with endotoxin was largely prevented since the aqueous humor protein concentration substantially lowered concomitantly with a significant reduction in the uveal and vitreous histopathological grading. Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon-γ, also significantly reduced with related anti-oxidant systems recovery. Daclizumab treatment in endotoxin-induced uveitis reduced Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon gamma, by about 60–70% and presented a preventive role in endotoxin-induced oxidative stress. This antioxidant protective effect of Daclizumab may be related to several of the observed Daclizumab effects in our study, including IL-6 cytokine regulatory properties and a substantial concomitant drop in INFγ. Concurrently, Daclizumab treatment triggered a significant reduction in both the uveal histopathological grading and protein concentration in aqueous humors, but not in cellular infiltration. PMID:24595020

  18. Dasatinib Reduces Lung Inflammation and Fibrosis in Acute Experimental Silicosis

    PubMed Central

    Cruz, Fernanda Ferreira; Horta, Lucas Felipe Bastos; Maia, Lígia de Albuquerque; Lopes-Pacheco, Miquéias; da Silva, André Benedito; Morales, Marcelo Marco; Gonçalves-de-Albuquerque, Cassiano Felippe; Takiya, Christina Maeda; de Castro-Faria-Neto, Hugo Caire; Rocco, Patricia Rieken Macedo

    2016-01-01

    Silicosis is an occupational lung disease with no effective treatment. We hypothesized that dasatinib, a tyrosine kinase inhibitor, might exhibit therapeutic efficacy in silica-induced pulmonary fibrosis. Silicosis was induced in C57BL/6 mice by a single intratracheal administration of silica particles, whereas the control group received saline. After 14 days, when the disease was already established, animals were randomly assigned to receive DMSO or dasatinib (1 mg/kg) by oral gavage, twice daily, for 14 days. On day 28, lung morphofunction, inflammation, and remodeling were investigated. RAW 264.7 cells (a macrophage cell line) were incubated with silica particles, followed by treatment or not with dasatinib, and evaluated for macrophage polarization. On day 28, dasatinib improved lung mechanics, increased M2 macrophage counts in lung parenchyma and granuloma, and was associated with reduction of fraction area of granuloma, fraction area of collapsed alveoli, protein levels of tumor necrosis factor-α, interleukin-1β, transforming growth factor-β, and reduced neutrophils, M1 macrophages, and collagen fiber content in lung tissue and granuloma in silicotic animals. Additionally, dasatinib reduced expression of iNOS and increased expression of arginase and metalloproteinase-9 in silicotic macrophages. Dasatinib was effective at inducing macrophage polarization toward the M2 phenotype and reducing lung inflammation and fibrosis, thus improving lung mechanics in a murine model of acute silicosis. PMID:26789403

  19. Chemically induced mouse models of intestinal inflammation.

    PubMed

    Wirtz, Stefan; Neufert, Clemens; Weigmann, Benno; Neurath, Markus F

    2007-01-01

    Animal models of intestinal inflammation are indispensable for our understanding of the pathogenesis of Crohn disease and ulcerative colitis, the two major forms of inflammatory bowel disease in humans. Here, we provide protocols for establishing murine 2,4,6-trinitro benzene sulfonic acid (TNBS)-, oxazolone- and both acute and chronic dextran sodium sulfate (DSS) colitis, the most widely used chemically induced models of intestinal inflammation. In the former two models, colitis is induced by intrarectal administration of the covalently reactive reagents TNBS/oxazolone, which are believed to induce a T-cell-mediated response against hapten-modified autologous proteins/luminal antigens. In the DSS model, mice are subjected several days to drinking water supplemented with DSS, which seems to be directly toxic to colonic epithelial cells of the basal crypts. The procedures for the hapten models of colitis and acute DSS colitis can be accomplished in about 2 weeks but the protocol for chronic DSS colitis takes about 2 months.

  20. Acute serum amyloid A induces migration, angiogenesis, and inflammation in synovial cells in vitro and in a human rheumatoid arthritis/SCID mouse chimera model.

    PubMed

    Connolly, Mary; Marrelli, Alessandra; Blades, Mark; McCormick, Jennifer; Maderna, Paola; Godson, Catherine; Mullan, Ronan; FitzGerald, Oliver; Bresnihan, Barry; Pitzalis, Costantino; Veale, Douglas J; Fearon, Ursula

    2010-06-01

    Serum amyloid A (A-SAA), an acute-phase protein with cytokine-like properties, is expressed at sites of inflammation. This study investigated the effects of A-SAA on chemokine-regulated migration and angiogenesis using rheumatoid arthritis (RA) cells and whole-tissue explants in vitro, ex vivo, and in vivo. A-SAA levels were measured by real-time PCR and ELISA. IL-8 and MCP-1 expression was examined in RA synovial fibroblasts, human microvascular endothelial cells, and RA synovial explants by ELISA. Neutrophil transendothelial cell migration, cell adhesion, invasion, and migration were examined using transwell leukocyte/monocyte migration assays, invasion assays, and adhesion assays with or without anti-MCP-1/anti-IL-8. NF-kappaB was examined using a specific inhibitor and Western blotting. An RA synovial/SCID mouse chimera model was used to examine the effects of A-SAA on cell migration, proliferation, and angiogenesis in vivo. High expression of A-SAA was demonstrated in RA patients (p < 0.05). A-SAA induced chemokine expression in a time- and dose-dependent manner (p < 0.05). Blockade with anti-scavenger receptor class B member 1 and lipoxin A4 (A-SAA receptors) significantly reduced chemokine expression in RA synovial tissue explants (p < 0.05). A-SAA induced cell invasion, neutrophil-transendothelial cell migration, monocyte migration, and adhesion (all p < 0.05), effects that were blocked by anti-IL-8 or anti-MCP-1. A-SAA-induced chemokine expression was mediated through NF-kappaB in RA explants (p < 0.05). Finally, in the RA synovial/SCID mouse chimera model, we demonstrated for the first time in vivo that A-SAA directly induces monocyte migration from the murine circulation into RA synovial grafts, synovial cell proliferation, and angiogenesis (p < 0.05). A-SAA promotes cell migrational mechanisms and angiogenesis critical to RA pathogenesis.

  1. Comparative study of flavonoids in experimental models of inflammation.

    PubMed

    Rotelli, Alejandra Ester; Guardia, Teresita; Juárez, Américo Osvaldo; de la Rocha, Nadir Ernesto; Pelzer, Lilian Eugenia

    2003-12-01

    The anti-inflammatory activities of flavonols (quercetin, rutin and morin) and flavanones (hesperetin and hesperidin) were investigated in animal models of acute and chronic inflammation. Rutin was only effective in the chronic process, principally in adjuvant arthritis. On neurogenic inflammation induced by xylene, only the flavanones were effective; besides, these compounds were the most effective on subchronic process. The most important compound in reducing paw oedema induced by carrageenan was quercetin.

  2. Circulating histones exacerbate inflammation in mice with acute liver failure.

    PubMed

    Wen, Zongmei; Liu, Yan; Li, Feng; Ren, Feng; Chen, Dexi; Li, Xiuhui; Wen, Tao

    2013-10-01

    Circulating histones are a newly recognized mediator implicated in various inflammatory diseases. It is likely that the release of histones, from dying hepatocytes or inflammatory leukocytes, into the circulation initiates and amplifies inflammation during the course of acute liver failure (ALF). In this study, we investigated a putative pathogenic role of circulating histones in a murine model of ALF induced by D-galactosamine (GalN) plus lipopolysaccharide (LPS). Hepatic function and histological indexes, myeloperoxidase (MPO) activity, hepatocyte apoptosis and the levels of circulating histone were measured in GalN/LPS-treated mice. GalN/LPS caused severe liver damage and a notable increase in plasma concentration of circulating histones. To further assess the role of circulating histones in our model, we administered exogenous histones and anti-histone H4 antibody. Notably, exogenous histones aggravated GalN/LPS-induced hepatotoxicity, whereas anti-histone antibody significantly protected mice. Circulating histones may serve as both a functional marker of ALF activity and as an inflammatory mediator contributing to the progression of ALF. Blockade of circulating histones shows potent protective effects, suggesting a potential therapeutic strategy for ALF.

  3. Role of inflammation and its mediators in acute ischemic stroke

    PubMed Central

    Jin, Rong; Liu, Lin; Zhang, Shihao; Nanda, Anil; Li, Guohong

    2013-01-01

    Inflammation plays an important role in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. Increasing evidence suggests that inflammatory response is a double-edged sword, as it not only exacerbates secondary brain injury in the acute stage of stroke but also beneficially contributes to brain recovery after stroke. In this article, we provide an overview on the role of inflammation and its mediators in acute ischemic stroke. We discuss various pro-inflammatory and anti-inflammatory responses in different phases after ischemic stroke and the possible reasons for their failures in clinical trials. Undoubtedly, there is still much to be done in order to translate promising pre-clinical findings into clinical practice. A better understanding of the dynamic balance between pro- and anti-inflammatory responses and identifying the discrepancies between pre-clinical studies and clinical trials may serve as a basis for designing effective therapies. PMID:24006091

  4. [Acute-phase proteins in inflammation].

    PubMed

    Engler, R

    1995-01-01

    The acute phase proteins (APPs) have been empirically defined as those whose plasma concentration changes following inflammatory reaction. Those proteins whose concentrations increase are referred to as positive APP, while those whose levels decline are termed negative APP. In man, positive APP are: alpha 1 acid glycoprotein, alpha 1 protease inhibitor, alpha 1 antichymotrypsin, haptoglobin, ceruloplasmin, fibrinogen, C-reactive protein, serum amyloid A. Great variability in the APP response between different species is observed. The principal functions of APP, result from the interaction of these proteins with ligands of various origins which give "protein-ligands" complexes. These complexes are cleared by the RES or by the hepatocyte. The results are protease inhibition, neutralization of toxic molecules such as hemoglobin or the superoxide anion, clearance of cell membranes and chromatin. The drop of the plasma concentration of negative APP during an inflammatory reaction carries a rise of free ligands (fatty acids, hormones, vitamins, trace elements). IL6 has been recognized as the principal regulator of most APP genes. The response of the hepatic cell to IL6 is characterized by the enhanced production of type 2 or IL6 specific APPs. The biochemical process of signal transduction is IL6--JAK2--APRF The set of APP genes regulated by IL1 type cytokines (type 1 APPs) is distinct from that regulated by IL6 type cytokine. IL1 and TNF alpha mediated stimulation of type 1 APP genes is synergistically enhanced by IL6 type cytokines. The biochemical process of signal transduction is IL1, IL6--Ras--MAP kinase--NFIL6 The targeted inflammatory proteic profile including the assay of C-reactive protein, haptoglobin and alpha 1 acid glycoprotein produces a "biological tool" to the clinician in order to manage an inflammatory response. IL6, a proteic marker for the future, connected with CRP, will be assayed during early inflammatory reaction.

  5. Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation

    PubMed Central

    Serhan, Charles N.

    2010-01-01

    Because inflammation is appreciated as a unifying basis of many widely occurring diseases, the mechanisms involved in its natural resolution are of considerable interest. Using contained, self-limited inflammatory exudates and a systems approach, novel lipid-derived mediators and pathways were uncovered in the resolution of inflammatory exudates. These new families of local mediators control both the duration and magnitude of acute inflammation as well as the return of the site to homeostasis in the process of catabasis. This new genus of specialized proresolving mediators (SPM) includes essential fatty acid–derived lipoxins, resolvins, protectins, and, most recently, maresins. These families were named based on their unique structures and potent stereoselective actions. The temporally initiated biosynthesis of SPM and their direct impact on leukocyte trafficking and macrophage-directed clearance mechanisms provide clear evidence that resolution is an active, programmed response at the tissue level. Moreover, SPM that possess anti-inflammatory (ie, limiting PMN infiltration) and proresolving (enhance macrophage uptake and clearance of apoptotic PMN and microbial particles) actions as well as stimulating mucosal antimicrobial responses demonstrate that anti-inflammation and proresolution are different responses of the host and novel defining properties of these molecules. The mapping of new resolution circuits has opened the possibility for understanding mechanisms that lead from acute to chronic inflammation, or to the resolution thereof, as well as to potential, resolution-based immunopharmacological therapies. PMID:20813960

  6. Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor.

    PubMed

    Ribeiro, Alison; Ferraz-de-Paula, Viviane; Pinheiro, Milena L; Vitoretti, Luana B; Mariano-Souza, Domenica P; Quinteiro-Filho, Wanderley M; Akamine, Adriana T; Almeida, Vinícius I; Quevedo, João; Dal-Pizzol, Felipe; Hallak, Jaime E; Zuardi, Antônio W; Crippa, José A; Palermo-Neto, João

    2012-03-05

    Acute lung injury is an inflammatory condition for which treatment is mainly supportive because effective therapies have not been developed. Cannabidiol, a non-psychotropic cannabinoid component of marijuana (Cannabis sativa), has potent immunosuppressive and anti-inflammatory properties. Therefore, we investigated the possible anti-inflammatory effect of cannabidiol in a murine model of acute lung injury. Analysis of total inflammatory cells and differential in bronchoalveolar lavage fluid was used to characterize leukocyte migration into the lungs; myeloperoxidase activity of lung tissue and albumin concentration in the bronchoalveolar lavage fluid were analyzed by colorimetric assays; cytokine/chemokine production in the bronchoalveolar lavage fluid was also analyzed by Cytometric Bead Arrays and Enzyme-Linked Immunosorbent Assay (ELISA). A single dose of cannabidiol (20mg/kg) administered prior to the induction of LPS (lipopolysaccharide)-induced acute lung injury decreases leukocyte (specifically neutrophil) migration into the lungs, albumin concentration in the bronchoalveolar lavage fluid, myeloperoxidase activity in the lung tissue, and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) 1, 2, and 4days after the induction of LPS-induced acute lung injury. Additionally, adenosine A(2A) receptor is involved in the anti-inflammatory effects of cannabidiol on LPS-induced acute lung injury because ZM241385 (4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol) (a highly selective antagonist of adenosine A(2A) receptor) abrogated all of the anti-inflammatory effects of cannabidiol previously described. Thus, we show that cannabidiol has anti-inflammatory effects in a murine model of acute lung injury and that this effect is most likely associated with an increase in the extracellular adenosine offer and signaling through adenosine A(2A) receptor.

  7. Vocal exercise may attenuate acute vocal fold inflammation

    PubMed Central

    Abbott, Katherine Verdolini; Li, Nicole Y.K.; Branski, Ryan C.; Rosen, Clark A.; Grillo, Elizabeth; Steinhauer, Kimberly; Hebda, Patricia A.

    2012-01-01

    Objectives/Hypotheses The objective was to assess the utility of selected “resonant voice” exercises for the reduction of acute vocal fold inflammation. The hypothesis was that relatively large-amplitude, low-impact exercises associated with resonant voice would reduce inflammation more than spontaneous speech and possibly more than voice rest. Study Design The study design was prospective, randomized, double-blind. Methods Nine vocally healthy adults underwent a 1-hr vocal loading procedure, followed by randomization to (a) a spontaneous speech condition, (b) a vocal rest condition, or (c) a resonant voice exercise condition. Treatments were monitored in clinic for 4 hr, and continued extra-clinically until the next morning. At baseline, immediately following loading, after the 4-hr in-clinic treatment, and 24 hr post baseline, secretions were suctioned from the vocal folds bilaterally and submitted to enzyme-linked immunosorbent assay (ELISA) to estimate concentrations of key markers of tissue injury and inflammation: IL-1β, IL-6, IL-8, TNF-α, MMP-8, and IL-10. Results Complete data sets were obtained for 3 markers -- IL-1β, IL-6, and MMP-8 -- for one subject in each treatment condition. For those markers, results were poorest at 24-hr follow-up in the spontaneous speech condition, sharply improved in the voice rest condition, and best in the resonant voice condition. Average results for all markers, for all responsive subjects with normal baseline mediator concentrations, revealed an almost identical pattern. Conclusions Some forms of tissue mobilization may be useful to attenuate acute vocal fold inflammation. PMID:23177745

  8. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis.

    PubMed

    Cronstein, Bruce N; Sunkureddi, Prashanth

    2013-01-01

    It has been recently demonstrated that interleukin 1β (IL-1β) plays a central role in monosodium urate crystal-induced inflammation and that the NALP3 inflammasome plays a major role in IL-1β production. These discoveries have offered new insights into the pathogenesis of acute gouty arthritis. In this review, we discuss the molecular mechanisms by which monosodium urate crystals induce acute inflammation and examine the mechanisms of action (MOAs) of traditional anti-inflammatory drugs (e.g., nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids) and biologic agents (e.g., the IL-1β antagonists anakinra, rilonacept, and canakinumab) to understand how their MOAs contribute to their safety profiles. Traditional anti-inflammatory agents may act on the IL-1β pathway at some level; however, their MOAs are broad-ranging, unspecific, and biologically complex. This lack of specificity may explain the range of systemic adverse effects associated with them. The therapeutic margins of nonsteroidal anti-inflammatory drugs, colchicine, and glucocorticoids are particularly low in elderly patients and in patients with cardiovascular, metabolic, or renal comorbidities that are frequently associated with gouty arthritis. In contrast, the IL-1β antagonists act on very specific targets of inflammation, which may decrease the potential for systemic adverse effects, although infrequent but serious adverse events (including infection and administration reactions) have been reported. Because these IL-1β antagonists target an early event immediately downstream from NALP3 inflammasome activation, they may provide effective alternatives to traditional agents with minimal systemic adverse effects. Results of ongoing trials of IL-1β antagonists will likely provide clarification of their potential role in the management of acute gouty arthritis.

  9. 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.

  10. Novel endogenous N-acyl amides activate TRPV1-4 receptors, BV-2 microglia, and are regulated in brain in an acute model of inflammation

    PubMed Central

    Raboune, Siham; Stuart, Jordyn M.; Leishman, Emma; Takacs, Sara M.; Rhodes, Brandon; Basnet, Arjun; Jameyfield, Evan; McHugh, Douglas; Widlanski, Theodore; Bradshaw, Heather B.

    2014-01-01

    A family of endogenous lipids, structurally analogous to the endogenous cannabinoid, N-arachidonoyl ethanolamine (Anandamide), and called N-acyl amides have emerged as a family of biologically active compounds at TRP receptors. N-acyl amides are constructed from an acyl group and an amine via an amide bond. This same structure can be modified by changing either the fatty acid or the amide to form potentially hundreds of lipids. More than 70 N-acyl amides have been identified in nature. We have ongoing studies aimed at isolating and characterizing additional members of the family of N-acyl amides in both central and peripheral tissues in mammalian systems. Here, using a unique in-house library of over 70 N-acyl amides we tested the following three hypotheses: (1) Additional N-acyl amides will have activity at TRPV1-4, (2) Acute peripheral injury will drive changes in CNS levels of N-acyl amides, and (3) N-acyl amides will regulate calcium in CNS-derived microglia. Through these studies, we have identified 20 novel N-acyl amides that collectively activate (stimulating or inhibiting) TRPV1-4. Using lipid extraction and HPLC coupled to tandem mass spectrometry we showed that levels of at least 10 of these N-acyl amides that activate TRPVs are regulated in brain after intraplantar carrageenan injection. We then screened the BV2 microglial cell line for activity with this N-acyl amide library and found overlap with TRPV receptor activity as well as additional activators of calcium mobilization from these lipids. Together these data provide new insight into the family of N-acyl amides and their roles as signaling molecules at ion channels, in microglia, and in the brain in the context of inflammation. PMID:25136293

  11. Changes of early post-traumatic osteoarthritis in an ovine model of simulated ACL reconstruction are associated with transient acute post-injury synovial inflammation and tissue catabolism.

    PubMed

    Heard, B J; Solbak, N M; Achari, Y; Chung, M; Hart, D A; Shrive, N G; Frank, C B

    2013-12-01

    The study described here tested the hypothesis that early intra-articular inflammation is associated with the development of post-traumatic osteoarthritis (PTOA) in a sheep model. We extended previously published work in which we investigated joint gross morphology and synovial mRNA expression of inflammatory and catabolic molecules 2 weeks after anatomic Anterior cruciate ligament (ACL) autograft reconstructive surgery (ACL-R). The same variables have been analyzed at 20 weeks post surgery together with new experimental variables at both time points. Animals were sacrificed at 20 weeks post ACL-R surgery and their joints graded for signs of PTOA. Synovial samples were harvested for histological grading plus mRNA and protein analysis for a panel of inflammatory and catabolic molecules. The mRNA expression levels for this panel plus connective tissue matrix turnover molecules were also investigated in cartilage samples. Results of gross morphological assessments at 20 weeks post surgery showed some changes consistent with early OA, but indicated little progression of damage from the 2 week time point. While significant alterations in mRNA levels for synovial inflammatory and catabolic molecules were detected at 2 weeks, values had normalized by 20 weeks. Similarly, all mRNA expression levels for inflammatory and catabolic molecules in articular cartilage had returned to normal levels by 20 weeks post ACL-R surgery. We conclude that synovial inflammatory processes are initiated very early after ACL-R surgery and may instigate events that lead to the gross cartilage and joint abnormalities observed as early as 2 weeks. However, the absence of sustained inflammation and joint instability may prevent OA progression.

  12. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

    PubMed

    Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

    2015-02-01

    We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

  13. Tinea corporis with acute inflammation caused by Trichophyton tonsurans.

    PubMed

    Ohno, Sayoko; Tanabe, Hiroshi; Kawasaki, Masako; Horiguchi, Yuji

    2008-09-01

    A 13-year-old Japanese boy presented with acute skin inflammation on the extremities. He belonged to a judo club of a junior high school in which club tinea capitis and tinea corporis seemed to be prevalent. Vesicles and pustules appeared on his right forearm and right leg. They increased in numbers and formed annular lesions. Pruritic erythema appeared surrounding these lesions. Direct microscopic examination of the lesions detected hyphae, and culture for the fungi yielded yellowish colonies. The result of culture from pustules revealed Staphylococcus aureus. At first, a topical antifungal drug and systemic antibiotics seemed to cure annular lesions, but pustules arose again. A large surrounding erythema was cured by topical treatment with a steroid agent. A biopsy specimen from a pustule showed hyphae of fungi within a hair shaft and in the bulb. The restriction fragment length polymorphism in the internal transcribed spacer regions of the ribosomal gene (polymerase chain reaction restriction fragment length polymorphism) revealed a banding pattern compatible with Trichophyton tonsurans. Treatment with systemic itraconazole was begun and lesions disappeared immediately. Systemic antifungal therapy was needed in our case. Tinea corporis with inflammation necessitates systemic antifungal therapy.

  14. Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves' orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation.

    PubMed

    Moshkelgosha, Sajad; So, Po-Wah; Deasy, Neil; Diaz-Cano, Salvador; Banga, J Paul

    2013-09-01

    Graves' orbitopathy (GO) is a complication in Graves' disease (GD) but mechanistic insights into pathogenesis remain unresolved, hampered by lack of animal model. The TSH receptor (TSHR) and perhaps IGF-1 receptor (IGF-1R) are considered relevant antigens. We show that genetic immunization of human TSHR (hTSHR) A-subunit plasmid leads to extensive remodeling of orbital tissue, recapitulating GO. Female BALB/c mice immunized with hTSHR A-subunit or control plasmids by in vivo muscle electroporation were evaluated for orbital remodeling by histopathology and magnetic resonance imaging (MRI). Antibodies to TSHR and IGF-1R were present in animals challenged with hTSHR A-subunit plasmid, with predominantly TSH blocking antibodies and were profoundly hypothyroid. Orbital pathology was characterized by interstitial inflammation of extraocular muscles with CD3+ T cells, F4/80+ macrophages, and mast cells, accompanied by glycosaminoglycan deposition with resultant separation of individual muscle fibers. Some animals showed heterogeneity in orbital pathology with 1) large infiltrate surrounding the optic nerve or 2) extensive adipogenesis with expansion of retrobulbar adipose tissue. A striking finding that underpins the new model were the in vivo MRI scans of mouse orbital region that provided clear and quantifiable evidence of orbital muscle hypertrophy with protrusion (proptosis) of the eye. Additionally, eyelid manifestations of chemosis, including dilated and congested orbital blood vessels, were visually apparent. Immunization with control plasmids failed to show any orbital pathology. Overall, these findings support TSHR as the pathogenic antigen in GO. Development of a new preclinical model will facilitate molecular investigations on GO and evaluation of new therapeutic interventions.

  15. Mouse models of intestinal inflammation and cancer.

    PubMed

    Westbrook, Aya M; Szakmary, Akos; Schiestl, Robert H

    2016-09-01

    Chronic inflammation is strongly associated with approximately one-fifth of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here, we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With

  16. Salivary Markers of Inflammation in Response to Acute Stress

    PubMed Central

    Slavish, Danica C.; Graham-Engeland, Jennifer E.; Smyth, Joshua M.; Engeland, Christopher G.

    2014-01-01

    There is burgeoning interest in the ability to detect inflammatory markers in response to stress within naturally occurring social contexts and/or across multiple time points per day within individuals. Salivary collection is a less invasive process than current methods of blood collection and enables intensive naturalistic methodologies, such as those involving extensive repeated measures per day over time. Yet the reliability and validity of saliva-based to blood-based inflammatory biomarkers in response to stress remains unclear. We review and synthesize the published studies that have examined salivary markers of inflammation following exposure to an acute laboratory stressor. Results from each study are reviewed by analyte (IL-1β, TNF-α, IL-6, IL-2, IL-4, IL-10, IL-12, CRP) and stress type (social-cognitive and exercise-physical), after which methodological issues and limitations are addressed. Although the literature is limited, several inflammatory markers (including IL-1β, TNF-α, and IL-6) have been reliably determined from saliva and have increased significantly in response to stress across multiple studies, with effect sizes ranging from very small to very large. Although CRP from saliva has been associated with CRP in circulating blood more consistently than other biomarkers have been associated with their counterparts in blood, evidence demonstrating it reliably responds to acute stress is absent. Although the current literature is presently too limited to allow broad assertion that inflammatory biomarkers determined from saliva are valuable for examining acute stress responses, this review suggests that specific targets may be valid and highlights specific areas of need for future research. PMID:25205395

  17. Acute Respiratory Distress Syndrome: Role of Oleic Acid-Triggered Lung Injury and Inflammation

    PubMed Central

    Gonçalves-de-Albuquerque, Cassiano Felippe; Silva, Adriana Ribeiro; Burth, Patrícia; Castro-Faria, Mauro Velho; Castro-Faria-Neto, Hugo Caire

    2015-01-01

    Lung injury especially acute respiratory distress syndrome (ARDS) can be triggered by diverse stimuli, including fatty acids and microbes. ARDS affects thousands of people worldwide each year, presenting high mortality rate and having an economic impact. One of the hallmarks of lung injury is edema formation with alveoli flooding. Animal models are used to study lung injury. Oleic acid-induced lung injury is a widely used model resembling the human disease. The oleic acid has been linked to metabolic and inflammatory diseases; here we focus on lung injury. Firstly, we briefly discuss ARDS and secondly we address the mechanisms by which oleic acid triggers lung injury and inflammation. PMID:26640323

  18. Galectin-3–null mice display defective neutrophil clearance during acute inflammation

    PubMed Central

    Wright, Rachael D; Souza, Patricia R.; Flak, Magdalena B.; Thedchanamoorthy, Prasheetha; Norling, Lucy V.; Cooper, Dianne

    2017-01-01

    Galectin-3 has been associated with a plethora of proinflammatory functions because of its ability, among others, to promote neutrophil activation and because of the reduction in neutrophil recruitment in models of infection in Gal-3-null mice. Conversely, it has also been linked to resolution of inflammation through its actions as an opsonin and its ability to promote efferocytosis of apoptotic neutrophils. Using a self-resolving model of peritonitis, we have addressed the modulation and role of Gal-3 in acute inflammation. We have shown that Gal-3 expression is increased in neutrophils that travel to the inflamed peritoneum and that cellular localization of this lectin is modulated during the course of the inflammatory response. Furthermore, neutrophil recruitment to the inflamed peritoneum is increased in Gal-3–null mice during the course of the response, and that correlates with reduced numbers of monocytes/macrophages in the cavities of those mice, as well as reduced apoptosis and efferocytosis of Gal-3–null neutrophils. These data indicate a role for endogenous Gal-3 in neutrophil clearance during acute inflammation. PMID:27733579

  19. Phagocyte respiratory burst activates macrophage erythropoietin signalling to promote acute inflammation resolution

    PubMed Central

    Luo, Bangwei; Wang, Jinsong; Liu, Zongwei; Shen, Zigang; Shi, Rongchen; Liu, Yu-Qi; Liu, Yu; Jiang, Man; Wu, Yuzhang; Zhang, Zhiren

    2016-01-01

    Inflammation resolution is an active process, the failure of which causes uncontrolled inflammation which underlies many chronic diseases. Therefore, endogenous pathways that regulate inflammation resolution are fundamental and of wide interest. Here, we demonstrate that phagocyte respiratory burst-induced hypoxia activates macrophage erythropoietin signalling to promote acute inflammation resolution. This signalling is activated following acute but not chronic inflammation. Pharmacological or genetical inhibition of the respiratory burst suppresses hypoxia and macrophage erythropoietin signalling. Macrophage-specific erythropoietin receptor-deficient mice and chronic granulomatous disease (CGD) mice, which lack the capacity for respiratory burst, display impaired inflammation resolution, and exogenous erythropoietin enhances this resolution in WT and CGD mice. Mechanistically, erythropoietin increases macrophage engulfment of apoptotic neutrophils via PPARγ, promotes macrophage removal of debris and enhances macrophage migration to draining lymph nodes. Together, our results provide evidences of an endogenous pathway that regulates inflammation resolution, with important implications for treating inflammatory conditions. PMID:27397585

  20. Elimination Half-Lives of Acute Phase Proteins in Rats and Beagle Dogs During Acute Inflammation.

    PubMed

    Kuribayashi, Takashi; Seita, Tetsuro; Momotani, Eiichi; Yamazaki, Shunsuke; Hagimori, Kohei; Yamamoto, Shizuo

    2015-08-01

    The half-lives of typical acute phase proteins in rats and beagle dogs during acute inflammation were investigated. Acute inflammation was induced by injection of turpentine oil in rats and administration of indomethacin in beagle dogs. Serum concentrations of α2-macroglobulin (α2M) and C-reactive protein (CRP) were measured by enzyme-linked immunosorbent assay and α1-acid glycoprotein (AAG) was measured by single radial immunodiffusion. Half-life was calculated as 0.693/elimination rate constant (K). The mean half-lives in the terminal elimination phase of α2M and AAG were 68.1 and 164.8 h, respectively. The half-life of AAG was significantly longer than that of α2M. Mean half-lives in the terminal elimination phase of CRP and AAG were 161.9 and 304.4 h, respectively. The half-life of AAG was significantly longer than that of CRP in beagle dogs. No significant differences in the half-life of AAG were observed between rats and beagle dogs. Furthermore, serum concentrations in the terminal elimination phase could be simulated with the K data acquired in this study.

  1. Anti-Inflammation Property of Syzygium cumini (L.) Skeels on Indomethacin-Induced Acute Gastric Ulceration

    PubMed Central

    Chanudom, Lanchakon; Tangpong, Jitbanjong

    2015-01-01

    Indomethacin, nonsteroidal anti-inflammatory drug (NSAIDs), induced gastric damage and perforation through the excess generation of reactive oxygen species (ROS). Syzygium cumini (L.) Skeels is commonly used as a medicinal plant and is claimed to have antioxidant activities. The effects of Syzygium cumini (L.) Skeels aqueous extract (SCC) on antifree radical, anti-inflammation, and antiulcer of SCC on indomethacin induced acute gastric ulceration were determined in our study. Scavenging activity at 50% of SCC is higher than ascorbic acid in in vitro study. Mice treated with indomethacin revealed mucosal hemorrhagic lesion and inhibited mucus content. Pretreatment with SCC caused discernible decrease in indomethacin induced gastric lesion and lipid peroxide content. In addition, oxidized glutathione (GSSG), glutathione peroxidase (GPx), nitric oxide (NO) levels, and gastric wall mucus were restored on acute treated mice model. Indomethacin induced inflammation by activated inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) proinflammatory cytokines to release large amount of ROS/RNS which were ameliorated in mice pretreatment with SCC. SCC showed restoration of the imbalance of oxidative damage leading to amelioration of cyclooxygenase enzyme (COX). In conclusion, SCC acts as an antioxidant, anti-inflammation, and antiulcer against indomethacin. PMID:26633969

  2. Anti-Inflammation Property of Syzygium cumini (L.) Skeels on Indomethacin-Induced Acute Gastric Ulceration.

    PubMed

    Chanudom, Lanchakon; Tangpong, Jitbanjong

    2015-01-01

    Indomethacin, nonsteroidal anti-inflammatory drug (NSAIDs), induced gastric damage and perforation through the excess generation of reactive oxygen species (ROS). Syzygium cumini (L.) Skeels is commonly used as a medicinal plant and is claimed to have antioxidant activities. The effects of Syzygium cumini (L.) Skeels aqueous extract (SCC) on antifree radical, anti-inflammation, and antiulcer of SCC on indomethacin induced acute gastric ulceration were determined in our study. Scavenging activity at 50% of SCC is higher than ascorbic acid in in vitro study. Mice treated with indomethacin revealed mucosal hemorrhagic lesion and inhibited mucus content. Pretreatment with SCC caused discernible decrease in indomethacin induced gastric lesion and lipid peroxide content. In addition, oxidized glutathione (GSSG), glutathione peroxidase (GPx), nitric oxide (NO) levels, and gastric wall mucus were restored on acute treated mice model. Indomethacin induced inflammation by activated inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) proinflammatory cytokines to release large amount of ROS/RNS which were ameliorated in mice pretreatment with SCC. SCC showed restoration of the imbalance of oxidative damage leading to amelioration of cyclooxygenase enzyme (COX). In conclusion, SCC acts as an antioxidant, anti-inflammation, and antiulcer against indomethacin.

  3. The therapeutic effects of tuberostemonine against cigarette smoke-induced acute lung inflammation in mice.

    PubMed

    Jung, Kyung-Hwa; Beak, Hyunjung; Park, Soojin; Shin, Dasom; Jung, Jaehoon; Park, Sangwon; Kim, Jinju; Bae, Hyunsu

    2016-03-05

    Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking and is characterized by the destruction of lung parenchyma, structural alterations of the small airways, and systemic inflammation. Tuberostemonine (TS) is an alkaloid-type phytochemical from Stemona tuberosa. In the present study, we evaluated the anti-inflammatory effect of TS in a cigarette smoke (CS)-induced mouse model of acute lung inflammation. The mice were whole-body exposed to CS or fresh air for 7 days. TS was administered by an intraperitoneal (i.p.) injection 1h before exposure to CS. To test the effects of TS, the numbers of total cells, neutrophils, macrophages and lymphocytes in the bronchoalveolar lavage (BAL) fluid were counted. Furthermore, we measured the levels of several chemokines, such as GCP-2, MIP-3α, MCP-1 and KC, in the lung tissue. The cellular profiles and histopathological analysis demonstrated that the infiltration of peribronchial and perivascular inflammatory cells significantly decreased in the TS-treated groups compared with the CS-exposure group. The TS treatment significantly ameliorated the airway epithelial thickness induced by CS exposure and caused a significant decrement in the production of chemokines in the lung. These results suggest that TS has anti-inflammatory effects against CS-induced acute lung inflammation.

  4. Computational Modeling of Inflammation and Wound Healing

    PubMed Central

    Ziraldo, Cordelia; Mi, Qi; An, Gary; Vodovotz, Yoram

    2013-01-01

    Objective Inflammation is both central to proper wound healing and a key driver of chronic tissue injury via a positive-feedback loop incited by incidental cell damage. We seek to derive actionable insights into the role of inflammation in wound healing in order to improve outcomes for individual patients. Approach To date, dynamic computational models have been used to study the time evolution of inflammation in wound healing. Emerging clinical data on histo-pathological and macroscopic images of evolving wounds, as well as noninvasive measures of blood flow, suggested the need for tissue-realistic, agent-based, and hybrid mechanistic computational simulations of inflammation and wound healing. Innovation We developed a computational modeling system, Simple Platform for Agent-based Representation of Knowledge, to facilitate the construction of tissue-realistic models. Results A hybrid equation–agent-based model (ABM) of pressure ulcer formation in both spinal cord-injured and -uninjured patients was used to identify control points that reduce stress caused by tissue ischemia/reperfusion. An ABM of arterial restenosis revealed new dynamics of cell migration during neointimal hyperplasia that match histological features, but contradict the currently prevailing mechanistic hypothesis. ABMs of vocal fold inflammation were used to predict inflammatory trajectories in individuals, possibly allowing for personalized treatment. Conclusions The intertwined inflammatory and wound healing responses can be modeled computationally to make predictions in individuals, simulate therapies, and gain mechanistic insights. PMID:24527362

  5. Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia.

    PubMed

    Gomes, Rachel Novaes; Castro-Faria-Neto, Hugo C; Bozza, Patricia T; Soares, Milena B P; Shoemaker, Charles B; David, John R; Bozza, Marcelo T

    2005-12-01

    Calcitonin gene-related peptide (CGRP), a potent vasodilatory peptide present in central and peripheral neurons, is released at inflammatory sites and inhibits several macrophage, dendritic cell, and lymphocyte functions. In the present study, we investigated the role of CGRP in models of local and systemic acute inflammation and on macrophage activation induced by lipopolysaccharide (LPS). Intraperitoneal pretreatment with synthetic CGRP reduces in approximately 50% the number of neutrophils in the blood and into the peritoneal cavity 4 h after LPS injection. CGRP failed to inhibit neutrophil recruitment induced by the direct chemoattractant platelet-activating factor, whereas it significantly inhibited LPS-induced KC generation, suggesting that the effect of CGRP on neutrophil recruitment is indirect, acting on chemokine production by resident cells. Pretreatment of mice with 1 mug of CGRP protects against a lethal dose of LPS. The CGRP-induced protection is receptor mediated because it is completely reverted by the CGRP receptor antagonist, CGRP 8-37. The protective effect of CGRP correlates with an inhibition of TNF-alpha and an induction of IL-6 and IL-10 in mice sera 90 min after LPS challenge. Finally, CGRP significantly inhibits LPS-induced TNF-alpha released from mouse peritoneal macrophages. These results suggest that activation of the CGRP receptor on macrophages during acute inflammation could be part of the negative feedback mechanism controlling the extension of acute inflammatory responses.

  6. Asialoerythropoietin ameliorates bleomycin-induced acute lung injury in rabbits by reducing inflammation

    PubMed Central

    SONODA, AKINAGA; NITTA, NORIHISA; TSUCHIYA, KEIKO; OTANI, HIDEJI; WATANABE, SHOBU; MUKAISHO, KENICHI; TOMOZAWA, YUKI; NAGATANI, YUKIHIRO; OHTA, SHINICHI; TAKAHASHI, MASASHI; MURATA, KIYOSHI

    2014-01-01

    Acute lung injury, a critical illness characterized by acute respiratory failure with bilateral pulmonary infiltrates, remains unresponsive to current treatments. The condition involves injury to the alveolar capillary barrier, neutrophil accumulation and the induction of proinflammatory cytokines followed by lung fibrosis. In the present study, a rabbit model of bleomycin-induced acute lung injury was established to examine the effects of asialoerythropoietin (AEP), an agent with tissue-protective activities, on pulmonary inflammation. Six Japanese white rabbits were randomly divided into two equal groups. Acute lung injury was induced in all rabbits by intratracheally injecting bleomycin. The control group was injected with bleomycin only; the experimental (AEP) group was injected intravenously with AEP (80 μg/kg) prior to the bleomycin injection. Computed tomography (CT) studies were performed seven days later. The CT inflammatory scores of areas exhibiting abnormal density and the pathological inflammatory scores were recorded as a ratio on a 7×7 mm grid. The CT and pathological inflammatory scores were significantly different between the control and AEP groups [122±10 and 16.3±1.5 (controls) vs. 71±8.5 and 9.7±1.4 (AEP), respectively; P<0.01]. Thus, the present study revealed that AEP prevents bleomycin-induced acute lung injury in rabbits. PMID:25289037

  7. Morin, a dietary bioflavonol suppresses monosodium urate crystal-induced inflammation in an animal model of acute gouty arthritis with reference to NLRP3 inflammasome, hypo-xanthine phospho-ribosyl transferase, and inflammatory mediators.

    PubMed

    Dhanasekar, Chitra; Rasool, Mahaboobkhan

    2016-09-05

    The anti-inflammatory effect of morin, a dietary bioflavanol was explored on monosodium urate (MSU) crystal-induced inflammation in rats, an experimental model for acute gouty arthritis. Morin treatment (30mg/kg b.wt) significantly attenuated the ankle swelling and the levels of lipid peroxidation, nitric oxide, serum pro-inflammatory cytokines (tumor necrosis factor (TNF) -α, interleukin (IL)-1β, and IL-6), monocyte chemoattractant protein (MCP)-1, vascular endothelial growth factor (VEGF), prostaglandin E2 (PGE2), and articular elastase along with an increased anti-oxidant status (catalase (CAT) and superoxide dismutase (SOD)) in the joint homogenate of MSU crystal-induced rats. Histological assessment revealed that morin limited the diffusion of joint space, synovial hyperplasia, and inflammatory cell infiltrations. The mRNA expression of NLRP3 (nucleotide oligomerization domain (NOD)-like receptor family, pyrin domain containing 3) inflammasome, caspase-1, pro-inflammatory cytokines, MCP-1, inflammatory enzymes (inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)), and nuclear factor-kappa B (NF-κB) p65 was found downregulated and HPRT (hypo-xanthine phospho-ribosyl transferase) mRNA expression was upregulated in morin treated MSU crystal-induced rats. In addition, morin treatment reduced the protein expression of NF-κB p65, p-NF-κB p65, iNOS, COX-2, and TNF-α. The results clearly demonstrated that morin exert a potent anti-inflammatory effect on MSU crystal-induced inflammation in rats.

  8. Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation?

    PubMed Central

    Fox, Lisa; Hegde, Subramanya

    2010-01-01

    Natural killer T cells are an innate population of T lymphocytes that recognize antigens derived from host lipids and glycolipids. In this review, we focus on how these unique T cells are positioned to influence both acute and chronic inflammatory processes through their early recruitment to sites of inflammation, interactions with myeloid antigen presenting cells, and recognition of lipids associated with inflammation. PMID:20850561

  9. Acute radiation risk models

    NASA Astrophysics Data System (ADS)

    Smirnova, Olga

    Biologically motivated mathematical models, which describe the dynamics of the major hematopoietic lineages (the thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems) in acutely/chronically irradiated humans are developed. These models are implemented as systems of nonlinear differential equations, which variables and constant parameters have clear biological meaning. It is shown that the developed models are capable of reproducing clinical data on the dynamics of these systems in humans exposed to acute radiation in the result of incidents and accidents, as well as in humans exposed to low-level chronic radiation. Moreover, the averaged value of the "lethal" dose rates of chronic irradiation evaluated within models of these four major hematopoietic lineages coincides with the real minimal dose rate of lethal chronic irradiation. The demonstrated ability of the models of the human thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems to predict the dynamical response of these systems to acute/chronic irradiation in wide ranges of doses and dose rates implies that these mathematical models form an universal tool for the investigation and prediction of the dynamics of the major human hematopoietic lineages for a vast pattern of irradiation scenarios. In particular, these models could be applied for the radiation risk assessment for health of astronauts exposed to space radiation during long-term space missions, such as voyages to Mars or Lunar colonies, as well as for health of people exposed to acute/chronic irradiation due to environmental radiological events.

  10. Inflammation Activation Contributes to Adipokine Imbalance in Patients with Acute Coronary Syndrome.

    PubMed

    Li, Rong; Chen, Lu-zhu; Zhao, Shui-ping; Huang, Xian-sheng

    2016-01-01

    Inflammation can be activated as a defensive response by the attack of acute coronary syndrome (ACS) for ischemic tissue injury. The aim of the present study was to investigate the impact of ACS-activated inflammation on adipokine imbalance and the effects of statins on the crosstalk between inflammation and adipokine imbalance during ACS. In this study, 586 subjects were categorized into: (1) control group; (2) SA (stable angina) group; and (3) ACS group. Circulating levels of hs-CRP, adiponectin and resistin were measured by ELISA. Furthermore, forty C57BL/6 mice were randomized into: sham, AMI, low-statin (atorvastatin, 2 mg/kg/day) and high-statin (atorvastatin, 20 mg/kg/day) group. After 3 weeks, AMI models were established by surgical coronary artery ligation. Circulating levels and adipose expressions of adiponectin and resistin were assessed in animals. Besides, we investigate the effects of atorvastatin on ox-LDL-induced adipokine imbalance in vitro. As a result, we found that ACS patients had higher hs-CRP and resistin levels and lower adiponectin levels. Our correlation analysis demonstrated hs-CRP concentrations were positively correlated with resistin but negatively with adiponectin levels in humans. Our animal findings indicated higher circulating hs-CRP and resistin levels and lower adiponectin levels in AMI mice. Atorvastatin pre-treatment dose-dependently decreased hs-CRP and resistin levels but increased adiponectin levels in mice. The consistent findings were observed about the adipose expressions of resistin and adiponectin in mice. In study in vitro, ox-LDL increased cellular resistin expressions and otherwise for adiponectin expressions, which dose-dependently reversed by the addition of atorvastatin. Therefore, our study indicates that the ACS attack activates inflammation leading to adipokine imbalance that can be ameliorated by anti-inflammation of atorvastatin.

  11. Protective effect of proteins derived from Calotropis procera latex against acute inflammation in rat.

    PubMed

    Kumar, V L; Guruprasad, B; Chaudhary, P; Fatmi, S M A; Oliveira, R S B; Ramos, M V

    2015-07-01

    The non-dialysable proteins present in the latex of plant Calotropis procera possess anti-inflammatory and analgesic properties. The aim of this study was to evaluate the effect of latex proteins (LP) on the level of inflammatory mediators, oxidative stress markers and tissue histology in the rat model of carrageenan-induced acute inflammation. This study also aimed at evaluating the anti-inflammatory efficacy of LP against different mediators and comparing it with their respective antagonists. Paw inflammation was induced by subplantar injection of carrageenan, and the effect of LP was evaluated on oedema volume, level of TNF-α, PGE(2), myeloperoxidase, nitric oxide, reduced glutathione, thiobarbituric acid-reactive substances and tissue histology at the time of peak inflammation. Paw inflammation was also induced by histamine, serotonin, bradykinin and PGE(2), and the inhibitory effect of LP against these mediators was compared with their respective antagonists at the time of peak effect. Treatment with LP produced a dose-dependent inhibition of oedema formation, and its anti-inflammatory effect against carrageenan-induced paw inflammation was accompanied by reduction in the levels of inflammatory mediators, oxidative stress markers and normalization of tissue architecture. LP also produced a dose-dependent inhibition of oedema formation induced by different inflammatory mediators, and its efficacy was comparable to their respective antagonists and more pronounced than that of diclofenac. Thus, our study shows that LP has a potential to be used for the treatment of various inflammatory conditions where the role of these mediators is well established.

  12. Pharmacokinetic/Pharmacodynamic Modeling in Inflammation

    PubMed Central

    Lon, Hoi-Kei; Liu, Dongyang; Jusko, William J.

    2012-01-01

    Inflammation is an array of immune responses to infection and injury. It results from a complex immune cascade and is the basis of many chronic diseases such as arthritis, diabetes, and cancer. Numerous mathematical models have been developed to describe the disease progression and effects of anti-inflammatory drugs. This review illustrates the state of the art in modeling the effects of diverse drugs for treating inflammation, describes relevant biomarkers amenable to modeling, and summarizes major advantages and limitations of the published pharmacokinetic/ pharmacodynamic (PK/PD) models. Simple direct inhibitory models are often used to describe in vitro effects of anti-inflammatory drugs. Indirect response models are more mechanism based and have been widely applied to the turnover of symptoms and biomarkers. These, along with target-mediated and transduction models, have been successfully applied to capture the PK/PD of many anti-inflammatory drugs and describe disease progression of inflammation. Biologics have offered opportunities to address specific mechanisms of action, and evolve small systems models to quantitatively capture the underlying physiological processes. More advanced mechanistic models should allow evaluation of the roles of some key mediators in disease progression, assess drug interactions, and better translate drug properties from in vitro and animal data to patients. PMID:23140121

  13. Dioscin relieves endotoxemia induced acute neuro-inflammation and protect neurogenesis via improving 5-HT metabolism

    PubMed Central

    Yang, Rui; Chen, Wei; Lu, Ye; Li, Yingke; Du, Hongli; Gao, Songyan; Dong, Xin; Yuan, Hongbin

    2017-01-01

    Sepsis, in addition to causing fatality, is an independent risk factor for cognitive impairment among sepsis survivors. The pathologic mechanism of endotoxemia induced acute neuro-inflammation still has not been fully understood. For the first time, we found the disruption of neurotransmitters 5-HT, impaired neurogenesis and activation of astrocytes coupled with concomitant neuro-inflammation were the potential pathogenesis of endotoxemia induced acute neuro-inflammation in sepsis survivors. In addition, dioscin a natural steroidal saponin isolated from Chinese medicinal herbs, enhanced the serotonergic system and produced anti-depressant effect by enhancing 5-HT levels in hippocampus. What is more, this finding was verified by metabolic analyses of hippocampus, indicating 5-HT related metabolic pathway was involved in the pathogenesis of endotoxemia induced acute neuro-inflammation. Moreover, neuro-inflammation and neurogenesis within hippocampus were indexed using quantitative immunofluorescence analysis of GFAP DCX and Ki67, as well as real-time RT-PCR analysis of some gene expression levels in hippocampus. Our in vivo and in vitro studies show dioscin protects hippocampus from endotoxemia induced cascade neuro-inflammation through neurotransmitter 5-HT and HMGB-1/TLR4 signaling pathway, which accounts for the dioscin therapeutic effect in behavioral tests. Therefore, the current findings suggest that dioscin could be a potential approach for the therapy of endotoxemia induced acute neuro-inflammation. PMID:28059131

  14. Resolution of Acute Inflammation and the Role of Resolvins in Immunity, Thrombosis, and Vascular Biology.

    PubMed

    Sansbury, Brian E; Spite, Matthew

    2016-06-24

    Acute inflammation is a host-protective response that is mounted in response to tissue injury and infection. Initiated and perpetuated by exogenous and endogenous mediators, acute inflammation must be resolved for tissue repair to proceed and for homeostasis to be restored. Resolution of inflammation is an actively regulated process governed by an array of mediators as diverse as those that initiate inflammation. Among these, resolvins have emerged as a genus of evolutionarily conserved proresolving mediators that act on specific cellular receptors to regulate leukocyte trafficking and blunt production of inflammatory mediators, while also promoting clearance of dead cells and tissue repair. Given that chronic unresolved inflammation is emerging as a central causative factor in the development of cardiovascular diseases, an understanding of the endogenous processes that govern normal resolution of acute inflammation is critical for determining why sterile maladaptive cardiovascular inflammation perpetuates. Here, we provide an overview of the process of resolution with a focus on the enzymatic biosynthesis and receptor-dependent actions of resolvins and related proresolving mediators in immunity, thrombosis, and vascular biology. We discuss how nutritional and current therapeutic approaches modulate resolution and propose that harnessing resolution concepts could potentially lead to the development of new approaches for treating chronic cardiovascular inflammation in a manner that is not host disruptive.

  15. Effects of Liver × receptor agonist treatment on signal transduction pathways in acute lung inflammation

    PubMed Central

    2010-01-01

    Background Liver × receptor α (LXRα) and β (LXRβ) are members of the nuclear receptor super family of ligand-activated transcription factors, a super family which includes the perhaps better known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. There is limited evidence that LXL activation may reduces acute lung inflammation. The aim of this study was to investigate the effects of T0901317, a potent LXR receptor ligand, in a mouse model of carrageenan-induced pleurisy. Methods Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), tumor necrosis factor-α, (TNF-α) and interleukin-1β (IL-1β). Furthermore, carrageenan induced the expression of iNOS, nitrotyrosine and PARP, as well as induced apoptosis (TUNEL staining and Bax and Bcl-2 expression) in the lung tissues. Results Administration of T0901317, 30 min after the challenge with carrageenan, caused a significant reduction in a dose dependent manner of all the parameters of inflammation measured. Conclusions Thus, based on these findings we propose that LXR ligand such as T0901317, may be useful in the treatment of various inflammatory diseases. PMID:20175894

  16. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis.

    PubMed

    Lin, Wei-Chieh; Chen, Chang-Wen; Huang, Yu-Wen; Chao, Lee; Chao, Julie; Lin, Yee-Shin; Lin, Chiou-Feng

    2015-07-22

    Kallistatin, an endogenous plasma protein, exhibits pleiotropic properties in inhibiting inflammation, oxidative stress and apoptosis, as evidenced in various animal models and cultured cells. Here, we demonstrate that kallistatin levels were positively correlated with the concentration of total protein in bronchoalveolar lavage fluids (BALF) from patients with sepsis-related acute respiratory distress syndrome (ARDS), indicating a compensatory mechanism. Lower ratio of kallistatin to total protein in BALF showed a significant trend toward elevated neutrophil counts (P = 0.002) in BALF and increased mortality (P = 0.046). In lipopolysaccharide (LPS)-treated mice, expression of human kallistatin in lung by gene transfer with human kallistatin-encoding plasmid ameliorated acute lung injury (ALI) and reduced cytokine/chemokine levels in BALF. These mice exhibited attenuated lung epithelial apoptosis and decreased Fas/FasL expression compared to the control mice. Mouse survival was improved by kallistatin gene transfer or recombinant human kallistatin treatment after LPS challenge. In LPS-stimulated A549 human lung epithelial cells, kallistatin attenuated apoptosis, down-regulated Fas/FasL signaling, suppressed intracellular reactive oxygen species (ROS) and inhibited ROS-mediated NF-κB activation and inflammation. Furthermore, LPS-induced apoptosis was blocked by antioxidant N-acetylcysteine or NF-κB inhibitor via down-regulating Fas expression. These findings suggest the therapeutic potential of kallistatin for sepsis-related ALI/ARDS.

  17. MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

    PubMed Central

    Van Hove, Inge; Lefevere, Evy; De Groef, Lies; Sergeys, Jurgen; Salinas-Navarro, Manuel; Libert, Claude; Vandenbroucke, Roosmarijn; Moons, Lieve

    2016-01-01

    Matrix metalloproteinase-3 (MMP-3) is known to mediate neuroinflammatory processes by activating microglia, disrupting blood–central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE) and the blood–retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU) model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1), interleukin 6 (Il6), cytokine-inducible nitrogen oxide synthase (Nos2) and tumor necrosis factor α (Tnfα), which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP)-1 and (C-X-C motif) ligand 1 (CXCL1). These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation. PMID:27809288

  18. Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury.

    PubMed

    Altmann, Chris; Ahuja, Nilesh; Kiekhaefer, Carol M; Andres Hernando, Ana; Okamura, Kayo; Bhargava, Rhea; Duplantis, Jane; Kirkbride-Romeo, Lara A; Huckles, Jill; Fox, Benjamin M; Kahn, Kashfi; Soranno, Danielle; Gil, Hyo-Wook; Teitelbaum, Isaac; Faubel, Sarah

    2017-03-16

    Although dialysis has been used in the care of patients with acute kidney injury (AKI) for over 50 years, very little is known about the potential benefits of uremic control on systemic complications of AKI. Since the mortality of AKI requiring renal replacement therapy (RRT) is greater than half in the intensive care unit, a better understanding of the potential of RRT to improve outcomes is urgently needed. Therefore, we sought to develop a technically feasible and reproducible model of RRT in a mouse model of AKI. Models of low- and high-dose peritoneal dialysis (PD) were developed and their effect on AKI, systemic inflammation, and lung injury after ischemic AKI was examined. High-dose PD had no effect on AKI, but effectively cleared serum IL-6, and dramatically reduced lung inflammation, while low-dose PD had no effect on any of these three outcomes. Both models of RRT using PD in AKI in mice reliably lowered urea in a dose-dependent fashion. Thus, use of these models of PD in mice with AKI has great potential to unravel the mechanisms by which RRT may improve the systemic complications that have led to increased mortality in AKI. In light of recent data demonstrating reduced serum IL-6 and improved outcomes with prophylactic PD in children, we believe that our results are highly clinically relevant.

  19. Smoking Is Associated with Acute and Chronic Prostatic Inflammation: Results from the REDUCE Study.

    PubMed

    Moreira, Daniel M; Nickel, J Curtis; Gerber, Leah; Muller, Roberto L; Andriole, Gerald L; Castro-Santamaria, Ramiro; Freedland, Stephen J

    2015-04-01

    Both anti- and proinflammatory effects of cigarette smoking have been described. As prostate inflammation is common, we hypothesized smoking could contribute to prostate inflammation. Thus, we evaluated the association of smoking status with acute and chronic inflammation within the prostate of men undergoing prostate biopsy. We retrospectively analyzed 8,190 men ages 50 to 75 years with PSA levels between 2.5 and 10 ng/mL enrolled in the Reduction by Dutasteride of Prostate Cancer Events study. Smoking status was self-defined as never, former, or current. Prostate inflammation was assessed by systematic central review blinded to smoking status. The association of smoking with inflammation in the baseline, 2-year, and 4-year biopsies was evaluated with univariable and multivariable logistic regressions. At study enrollment, 1,233 (15%), 3,203 (39%), and 3,754 (46%) men were current, former, and never smokers, respectively. Current smokers were significantly younger and had smaller prostates than former and never smokers (all P < 0.05). Former smokers were significantly heavier than current and never smokers (P < 0.001). Acute and chronic prostate inflammations were identified in 1,261 (15%) and 6,352 (78%) baseline biopsies, respectively. In univariable analysis, current smokers were more likely to have acute inflammation than former (OR, 1.35; P, 0.001) and never smokers (OR, 1.36; P, 0.001). The results were unchanged at 2- and 4-year biopsies. In contrast, current smoking was linked with chronic inflammation in the baseline biopsy, but not at 2- and 4-year biopsies. In conclusion, among men undergoing prostate biopsy, current smoking was independently associated with acute and possibly chronic prostate inflammations.

  20. [Experimental models of acute pancreatitis].

    PubMed

    Ceranowicz, Piotr; Cieszkowski, Jakub; Warzecha, Zygmunt; Dembiński, Artur

    2015-02-21

    Acute pancreatitis is a severe disease with high mortality. Clinical studies can bring some data about etiology, pathogenesis and the course of acute pancreatitis. However, studies concerning early events of this disease and the new concepts of treatment cannot be performed on humans, due to ethical reasons. Animal models of acute pancreatitis have been developed to solve this problem. This review presents currently used experimental models of acute pancreatitis, their properties and clinical relevance. Experimental models of acute pancreatitis can be divided into in vivo (non-invasive and invasive) and ex vivo models. The onset, development, severity and extent of acute pancreatitis, as well as the mortality, vary considerably between these different models. Animal models reproducibly produce mild, moderate or severe acute pancreatitis. One of the most commonly used models of acute pancreatitis is created by administration of supramaximal doses of cerulein, an analog of cholecystokinin. This model produces acute mild edematous pancreatitis in rats, whereas administration of cerulein in mice leads to the development of acute necrotizing pancreatitis. Acute pancreatitis evoked by retrograde administration of sodium taurocholate into the pancreatic duct is the most often used model of acute severe necrotizing pancreatitis in rats. Ex vivo models allow to eliminate the influence of hormonal and nervous factors on the development of acute pancreatitis.

  1. Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure.

    PubMed

    Shannahan, Jonathan H; Alzate, Oscar; Winnik, Witold M; Andrews, Debora; Schladweiler, Mette C; Ghio, Andrew J; Gavett, Stephen H; Kodavanti, Urmila P

    2012-04-15

    Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA.

  2. Anti-inflammatory activity of Ajmodadi Churna extract against acute inflammation in rats

    PubMed Central

    Ram, H. N. Aswatha; Sriwastava, Neeraj K.; Makhija, Inder K.; Shreedhara, C. S.

    2012-01-01

    Background: Ayurvedic polyherbal formulations are widely prescribed for a wide range of inflammatory conditions, yet, despite widespread use, there has been no systematic documentation of their safety and efficacy. Objective: The present study was undertaken to evaluate the anti-inflammatory activity of aqueous extracts of Ajmodadi churna (AJM) in rats. Materials and Methods: Carrageenan-induced hind paw edema and air pouch inflammation models were used for the study. Results: The extracts showed significant antiinflammatory activity, reducing paw edema volume by 0.417 ± 0.097 and 0.379 ± 0.049, respectively. In the carrageenan-induced air pouch model, AJM reduced total leukocyte count by 73.09 ± 7.13 and 62.17 ± 10.53, granulocyte count by 69.48 ± 5.44 and 63.33 ± 4.13, and myeloperoxidase activity by 14.84 ± 0.91 and 18.44 ± 3.18, respectively, compared to controls. Discussion and Conclusion: AJM significantly reduced paw edema, during the second phase of edema development. In the carrageenan-induced air pouch model, AJM inhibited cellular infiltration into the air pouch fluid. We conclude that AJM is an effective candidate for prevention or treatment of acute inflammation PMID:22529678

  3. Allergic airway inflammation decreases lung bacterial burden following acute Klebsiella pneumoniae infection in a neutrophil- and CCL8-dependent manner.

    PubMed

    Dulek, Daniel E; Newcomb, Dawn C; Goleniewska, Kasia; Cephus, Jaqueline; Zhou, Weisong; Reiss, Sara; Toki, Shinji; Ye, Fei; Zaynagetdinov, Rinat; Sherrill, Taylor P; Blackwell, Timothy S; Moore, Martin L; Boyd, Kelli L; Kolls, Jay K; Peebles, R Stokes

    2014-09-01

    The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.

  4. Pharmacologic modulation of acute ocular inflammation with quercetin.

    PubMed

    Romero, J; Marak, G E; Rao, N A

    1989-01-01

    Anti-inflammatory potentials of a safe, common dietary component, quercetin, were investigated in suppression of intraocular inflammation induced by retinal S antigen. Lewis rats sensitized to S antigen were treated daily with intraperitoneal injections of quercetin. Control rats with S-antigen-induced uveitis were similarly treated with diluent. When compared with controls the treated group showed marked reduction in uveal and retinal inflammation and in vasculitis and perivasculitis. Morphometric analysis revealed a significant reduction (p less than 0.005) in choroidal thickness when compared with that of control animals. These results clearly show the antiphlogistic effects of quercetin in experimental uveitis.

  5. Effects of an acute bout of moderate-intensity exercise on postprandial lipemia and airway inflammation.

    PubMed

    Johnson, Ariel M; Kurti, Stephanie P; Smith, Joshua R; Rosenkranz, Sara K; Harms, Craig A

    2016-03-01

    A high-fat meal (HFM) induces an increase in blood lipids (postprandial lipemia; PPL), systemic inflammation, and acute airway inflammation. While acute exercise has been shown to have anti-inflammatory and lipid-lowering effects, it is unknown whether exercise prior to an HFM will translate to reduced airway inflammation post-HFM. Our purpose was to determine the effects of an acute bout of exercise on airway inflammation post-HFM and to identify whether any protective effect of exercise on airway inflammation was associated with a reduction in PPL or systemic inflammation. In a randomized cross-over study, 12 healthy, 18- to 29-year-old men (age, 23.0 ± 3.2 years; height, 178.9 ± 5.5 cm; weight, 78.5 ± 11.7 kg) consumed an HFM (1 g fat/1 kg body weight) 12 h following exercise (EX; 60 min at 60% maximal oxygen uptake) or without exercise (CON). Fractional exhaled nitric oxide (FENO; measure of airway inflammation), triglycerides (TG), and inflammatory markers (high-sensitivity C-reactive protein, tumor-necrosis factor-alpha, and interleukin-6) were measured while fasted at 2 h and 4 h post-HFM. FENO increased over time (2 h: CON, p = 0.001; EX, p = 0.002, but not by condition (p = 0.991). TG significantly increased 2 and 4 h post-HFM (p < 0.001), but was not significant between conditions (p = 0.256). Inflammatory markers did not significantly increase by time or condition (p > 0.05). There were no relationships between FENO and TG or systemic inflammatory markers for any time point or condition (p > 0.05). In summary, an acute bout of moderate-intensity exercise performed 12 h prior to an HFM did not change postprandial airway inflammation or lipemia in healthy, 18- to 29-year-old men.

  6. Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure

    SciTech Connect

    Shannahan, Jonathan H.; Alzate, Oscar; Winnik, Witold M.; Andrews, Debora; Schladweiler, Mette C.; Ghio, Andrew J.; Gavett, Stephen H.; Kodavanti, Urmila P.

    2012-04-15

    Identification of biomarkers assists in the diagnosis of disease and the assessment of health risks from environmental exposures. We hypothesized that rats exposed to Libby amphibole (LA) would present with a unique serum proteomic profile which could help elucidate epidemiologically-relevant biomarkers. In four experiments spanning varied protocols and temporality, healthy (Wistar Kyoto, WKY; and F344) and cardiovascular compromised (CVD) rat models (spontaneously hypertensive, SH; and SH heart failure, SHHF) were intratracheally instilled with saline (control) or LA. Serum biomarkers of cancer, inflammation, metabolic syndrome (MetS), and the acute phase response (APR) were analyzed. All rat strains exhibited acute increases in α-2-macroglobulin, and α1-acid glycoprotein. Among markers of inflammation, lipocalin-2 was induced in WKY, SH and SHHF and osteopontin only in WKY after LA exposure. While rat strain- and age-related changes were apparent in MetS biomarkers, no LA effects were evident. The cancer marker mesothelin was increased only slightly at 1 month in WKY in one of the studies. Quantitative Intact Proteomic profiling of WKY serum at 1 day or 4 weeks after 4 weekly LA instillations indicated no oxidative protein modifications, however APR proteins were significantly increased. Those included serine protease inhibitor, apolipoprotein E, α-2-HS-glycoprotein, t-kininogen 1 and 2, ceruloplasmin, vitamin D binding protein, serum amyloid P, and more 1 day after last LA exposure. All changes were reversible after a short recovery regardless of the acute or long-term exposures. Thus, LA exposure induces an APR and systemic inflammatory biomarkers that could have implications in systemic and pulmonary disease in individuals exposed to LA. -- Highlights: ► Biomarkers of asbestos exposure are required for disease diagnosis. ► Libby amphibole exposure is associated with increased human mortality. ► Libby amphibole increases circulating proteins involved

  7. Animal models of gastrointestinal inflammation and cancer.

    PubMed

    Lu, L; Chan, Ruby L Y; Luo, X M; Wu, William K K; Shin, Vivian Y; Cho, C H

    2014-07-11

    Inflammation and cancer are the two major disorders in the gastrointestinal tract. They are causally related in their pathogenesis. It is important to study animal models' causal relationship and, in particular, to discover new therapeutic agents for such diseases. There are several criteria for these models in order to make them useful in better understanding the etiology and treatment of the said diseases in humans. In this regard, animal models should be similar as possible to human diseases and also be easy to produce and reproducible and also economic to allow a continuous replication in different laboratories. In this review, we summarize the various animal models for inflammatory and cancerous disorders in the upper and lower gastrointestinal tract. Experimental approaches are as simple as by giving a single oral dose of alcohol or other noxious agents or by injections of multiple dosages of ulcer inducing agents or by parenteral administration or in drinking water of carcinogens or by modifying the genetic makeups of animals to produce relatively long-term pathological changes in particular organs. With these methods they could induce consistent inflammatory responses or tumorigenesis in the gastrointestinal mucosa. These animal models are widely used in laboratories in understanding the pathogenesis as well as the mechanisms of action for therapeutic agents in the treatment of gastrointestinal inflammation and cancer.

  8. Adaptations in responsiveness of brainstem pain-modulating neurons in acute compared with chronic inflammation.

    PubMed

    Cleary, Daniel R; Heinricher, Mary M

    2013-06-01

    Despite similar behavioral hypersensitivity, acute and chronic pain have distinct neural bases. We used intraplantar injection of complete Freund's adjuvant to directly compare activity of pain-modulating neurons in the rostral ventromedial medulla (RVM) in acute vs chronic inflammation. Heat-evoked and von Frey-evoked withdrawal reflexes and corresponding RVM neuronal activity were recorded in lightly anesthetized animals either during the first hour after complete Freund's adjuvant injection (acute) or 3 to 10 days later (chronic). Thermal and modest mechanical hyperalgesia during acute inflammation were associated with increases in the spontaneous activity of pain-facilitating ON-cells and suppression of pain-inhibiting OFF-cells. Acute hyperalgesia was reversed by RVM block, showing that the increased activity of RVM ON-cells is necessary for acute behavioral hypersensitivity. In chronic inflammation, thermal hyperalgesia had resolved but mechanical hyperalgesia had become pronounced. The spontaneous discharges of ON- and OFF-cells were not different from those in control subjects, but the mechanical response thresholds for both cell classes were reduced into the innocuous range. RVM block in the chronic condition worsened mechanical hyperalgesia. These studies identify distinct contributions of RVM ON- and OFF-cells to acute and chronic inflammatory hyperalgesia. During early immune-mediated inflammation, ON-cell spontaneous activity promotes hyperalgesia. After inflammation is established, the antinociceptive influence of OFF-cells is dominant, yet the lowered threshold for the OFF-cell pause allows behavioral responses to stimuli that would normally be considered innocuous. The efficacy of OFF-cells in counteracting sensitization of ascending transmission pathways could therefore be an important determining factor in development of chronic inflammatory pain.

  9. Melatonin attenuates inflammation of acute pulpitis subjected to dental pulp injury

    PubMed Central

    Li, Ji-Guo; Lin, Jia-Ji; Wang, Zhao-Ling; Cai, Wen-Ke; Wang, Pei-Na; Jia, Qian; Zhang, An-Sheng; Wu, Gao-Yi; Zhu, Guo-Xiong; Ni, Long-Xing

    2015-01-01

    Acute pulpitis (AP), one of the most common diseases in the endodontics, usually causes severe pain to the patients, which makes the search for therapeutic target of AP essential in clinic. Toll-like receptor 4 (TLR4) signaling is widely involved in the mechanism of pulp inflammation, while melatonin has been reported to have an inhibition for a various kinds of inflammation. We hereby studied whether melatonin can regulate the expression of TLR4/NF-ĸB signaling in the pulp tissue of AP and in human dental pulp cells (HDPCs). Two left dental pulps of the adult rat were drilled open to establish the AP model, and the serum levels of melatonin and pro-inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 18 (IL-18) and tumor necrosis factor α (TNF-α), were assessed at 1, 3 and 5 d post injury. At the same time points, the expression of TLR4 signaling in the pulp was explored by quantitative real-time PCR and immunohistochemistry. The AP rats were administered an abdominal injection of melatonin to assess whether melatonin rescued AP and TLR4/NF-ĸB signaling. Dental pulp injury led to an approximately five-day period acute pulp inflammation and necrosis in the pulp and a significant up-regulation of IL-1β, IL-18 and TNF-α in the serum. ELISA results showed that the level of melatonin in the serum decreased due to AP, while an abdominal injection of melatonin suppressed the increase in serum cytokines and the percentage of necrosis at the 5 d of the injured pulp. Consistent with the inflammation in AP rats, TLR4, NF-ĸB, TNF-α and IL-1β in the pulp were increased post AP compared with the baseline expression. And melatonin showed an inhibition on TLR4/NF-ĸB signaling as well as IL-1β and TNF-α production in the pulp of AP rats. Furthermore, melatonin could also regulate the expression of TLR4/NF-ĸB signaling in LPS-stimulated HDPCs. These data suggested that dental pulp injury induced AP and reduced the serum level of melatonin and that

  10. Short-term effect of acute and repeated urinary bladder inflammation on thigmotactic behaviour in the laboratory rat

    PubMed Central

    Morland, Rosemary H; Novejarque, Amparo; Huang, Wenlong; Wodarski, Rachel; Denk, Franziska; Dawes, John D; Pheby, Tim; McMahon, Stephen B; Rice, Andrew SC

    2015-01-01

    Understanding the non-sensory components of the pain experience is crucial to developing effective treatments for pain conditions. Chronic pain is associated with increased incidence of anxio-depressive disorders, and patients often report feelings of vulnerability which can decrease quality of life. In animal models of pain, observation of behaviours such as thigmotaxis can be used to detect such affective disturbances by exploiting the influence of nociceptive stimuli on the innate behavioural conflict between exploration of a novel space and predator avoidance behaviour. This study investigates whether acute and repeated bladder inflammation in adult female Wistar rats increases thigmotactic behaviour in the open field paradigm, and aims to determine whether this correlates with activation in the central amygdala, as measured by c-Fos immunoreactivity. Additionally, up-regulation of inflammatory mediators in the urinary bladder was measured using RT-qPCR array featuring 92 transcripts to examine how local mediators change under experimental conditions. We found acute but not repeated turpentine inflammation of the bladder increased thigmotactic behaviour (decreased frequency of entry to the inner zone) in the open field paradigm, a result that was also observed in the catheter-only instrumentation group. Decreases in locomotor activity were also observed in both models in turpentine and instrumentation groups. No differences were observed in c-Fos activation, although a general increased in activation along the rostro-caudal axis was seen. Inflammatory mediator up-regulation was greatest following acute inflammation, with CCL12, CCL7, and IL-1β significantly up-regulated in both conditions when compared to naïve tissue. These results suggest that acute catheterisation, with or without turpentine inflammation, induces affective alterations detectable in the open field paradigm accompanied by up-regulation of multiple inflammatory mediators. PMID:27158443

  11. Fish oil supplementation alters levels of lipid mediators of inflammation in microenvironment of acute human wounds

    PubMed Central

    McDaniel, Jodi C.; Massey, Karen; Nicolaou, Anna

    2013-01-01

    Chronic wounds often result from prolonged inflammation involving excessive polymorphonuclear leukocyte activity. Studies show that the ω-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oils generate bioactive lipid mediators that reduce inflammation and polymorphonuclear leukocyte recruitment in numerous inflammatory disease models. This study’s purpose was to test the hypotheses that boosting plasma levels of EPA and DHA with oral supplementation would alter lipid mediator levels in acute wound microenvironments and reduce polymorphonuclear leukocyte levels. Eighteen individuals were randomized to 28 days of either EPA + DHA supplementation (Active Group) or placebo. After 28 days, the Active Group had significantly higher plasma levels of EPA (p < 0.001) and DHA (p < 0.001) than the Placebo Group and significantly lower wound fluid levels of two 15-lipoxygenase products of ω-6 polyunsaturated fatty acids (9-hydroxyoctadecadienoic acid [p=0.033] and 15-hydroxyeicosatrienoic acid [p=0.006]), at 24 hours postwounding. The Active Group also had lower mean levels of myeloperoxidase, a leukocyte marker, at 12 hours and significantly more reepithelialization on Day 5 postwounding. We suggest that lipid mediator profiles can be manipulated by altering polyunsaturated fatty acid intake to create a wound microenvironment more conducive to healing. PMID:21362086

  12. Dietary flaxseed intake exacerbates acute colonic mucosal injury and inflammation induced by dextran sodium sulfate.

    PubMed

    Zarepoor, Leila; Lu, Jenifer T; Zhang, Claire; Wu, Wenqing; Lepp, Dion; Robinson, Lindsay; Wanasundara, Janitha; Cui, Steve; Villeneuve, Sébastien; Fofana, Bourlaye; Tsao, Rong; Wood, Geoffrey A; Power, Krista A

    2014-06-15

    Flaxseed (FS), a dietary oilseed, contains a variety of anti-inflammatory bioactives, including fermentable fiber, phenolic compounds (lignans), and the n-3 polyunsaturated fatty acid (PUFA) α-linolenic acid. The objective of this study was to determine the effects of FS and its n-3 PUFA-rich kernel or lignan- and soluble fiber-rich hull on colitis severity in a mouse model of acute colonic inflammation. C57BL/6 male mice were fed a basal diet (negative control) or a basal diet supplemented with 10% FS, 6% kernel, or 4% hull for 3 wk prior to and during colitis induction via 5 days of 2% (wt/vol) dextran sodium sulfate (DSS) in their drinking water (n = 12/group). An increase in anti-inflammatory metabolites (hepatic n-3 PUFAs, serum mammalian lignans, and cecal short-chain fatty acids) was associated with consumption of all FS-based diets, but not with anti-inflammatory effects in DSS-exposed mice. Dietary FS exacerbated DSS-induced acute colitis, as indicated by a heightened disease activity index and an increase in colonic injury and inflammatory biomarkers [histological damage, apoptosis, myeloperoxidase, inflammatory cytokines (IL-6 and IL-1β), and NF-κB signaling-related genes (Nfkb1, Ccl5, Bcl2a1a, Egfr, Relb, Birc3, and Atf1)]. Additionally, the adverse effect of the FS diet was extended systemically, as serum cytokines (IL-6, IFNγ, and IL-1β) and hepatic cholesterol levels were increased. The adverse effects of FS were not associated with alterations in fecal microbial load or systemic bacterial translocation (endotoxemia). Collectively, this study demonstrates that although consumption of a 10% FS diet enhanced the levels of n-3 PUFAs, short-chain polyunsaturated fatty acids, and lignans in mice, it exacerbated DSS-induced colonic injury and inflammation.

  13. CO and CO-releasing molecules (CO-RMs) in acute gastrointestinal inflammation

    PubMed Central

    Babu, D; Motterlini, R; Lefebvre, R A

    2015-01-01

    Carbon monoxide (CO) is enzymatically generated in mammalian cells alongside the liberation of iron and the production of biliverdin and bilirubin. This occurs during the degradation of haem by haem oxygenase (HO) enzymes, a class of ubiquitous proteins consisting of constitutive and inducible isoforms. The constitutive HO2 is present in the gastrointestinal tract in neurons and interstitial cells of Cajal and CO released from these cells might contribute to intestinal inhibitory neurotransmission and/or to the control of intestinal smooth muscle cell membrane potential. On the other hand, increased expression of the inducible HO1 is now recognized as a beneficial response to oxidative stress and inflammation. Among the products of haem metabolism, CO appears to contribute primarily to the antioxidant and anti-inflammatory effects of the HO1 pathway explaining the studies conducted to exploit CO as a possible therapeutic agent. This article reviews the effects and, as far as known today, the mechanism(s) of action of CO administered either as CO gas or via CO-releasing molecules in acute gastrointestinal inflammation. We provide here a comprehensive overview on the effect of CO in experimental in vivo models of post-operative ileus, intestinal injury during sepsis and necrotizing enterocolitis. In addition, we will analyse the in vitro data obtained so far on the effect of CO on intestinal epithelial cell lines exposed to cytokines, considering the important role of the intestinal mucosa in the pathology of gastrointestinal inflammation. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24641722

  14. Neovestitol, an isoflavonoid isolated from Brazilian red propolis, reduces acute and chronic inflammation: involvement of nitric oxide and IL-6

    PubMed Central

    Franchin, Marcelo; Colón, David F.; da Cunha, Marcos G.; Castanheira, Fernanda V. S.; Saraiva, André L. L.; Bueno-Silva, Bruno; Alencar, Severino M.; Cunha, Thiago M.; Rosalen, Pedro L.

    2016-01-01

    Isoflavonoids have been largely studied due to their distinct biological activities identified thus far. Herein, we evaluated the activity of neovestitol, an isoflavonoid isolated from Brazilian red propolis, in acute and chronic inflammation. As for acute inflammation, we found that neovestitol reduced neutrophil migration, leukocyte rolling and adhesion, as well as expression of ICAM-1 in the mesenteric microcirculation during lipopolysaccharide-induced acute peritonitis. No changes were observed in the levels of TNF-α, CXCL1/KC and CXCL2/MIP-2 upon pretreatment with neovestitol. The administration of an inducible nitric oxide synthase (iNOS) inhibitor abolished the inhibitory effects of neovestitol in neutrophil migration and ICAM-1 expression. Nitrite levels increased upon treatment with neovestitol. No effects of neovestitol were observed on the chemotaxis of neutrophils in vitro. As for chronic inflammation, neovestitol also reduced the clinical score and joint damage in a collagen-induced arthritis model. There was no change in the frequency of IL-17-producing TCD4+ cells. In addition, pretreatment with neovestitol reduced the levels of IL-6. These results demonstrate a potential anti-inflammatory activity of neovestitol, which may be useful for therapeutic purposes and/or as a nutraceutical. PMID:27819273

  15. Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation

    PubMed Central

    Barthel, Lea; Bednarek, Joseph M.; Yunt, Zulma X.; Henson, Peter M.; Janssen, William J.

    2014-01-01

    Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1−/−) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasL-dependent manner. Specifically, FasL-expressing CD8+ T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8+ T lymphocytes in the resolution of acute pulmonary inflammation. PMID:24838751

  16. The role of CD69 in acute neutrophil-mediated inflammation.

    PubMed

    Lamana, Amalia; Sancho, David; Cruz-Adalia, Aránzazu; del Hoyo, Gloria Martínez; Herrera, Ada María; Feria, Manuel; Díaz-González, Federico; Gómez, Manuel; Sánchez-Madrid, Francisco

    2006-10-01

    The leukocyte activation marker CD69 functions as a negative regulator of the immune response, both in NK-dependent tumor rejection and in the inflammation associated with lymphocyte-dependent collagen-induced arthritis. In contrast, it has been reported that CD69-deficient mice are refractory to the neutrophil-dependent acute inflammatory response associated with anti-type II collagen antibody-induced arthritis (CAIA), suggesting a positive regulatory role for CD69 in neutrophil function during arthritis induction. To clarify this discrepancy, the CAIA response was independently analyzed in our CD69-deficient mice. In these experiments, the inflammatory response was unaffected by CD69 deficiency. Additionally, the in vivo down-regulation of CD69 expression by treatment of wild-type mice with the anti-CD69 mAb 2.2, which mimics the CD69-deficient phenotype, did not affect the course of arthritis in this model. Moreover, down-regulation of CD69 expression increased expression in arthritic joints of key inflammatory mediators, including IL-1beta, IL-6 and the chemokine MCP-1. Neutrophil accumulation in zymosan-treated air pouches and in thioglycolate-treated peritoneal cavities was also unaffected in CD69-deficient mice. In addition, CD69 expression was absent in activated neutrophils. Taken together, these results rule out a significant stimulatory role for CD69 in acute inflammatory responses mediated by neutrophils.

  17. Neutrophil-derived JAML Inhibits Repair of Intestinal Epithelial Injury During Acute Inflammation

    PubMed Central

    Weber, Dominique A.; Sumagin, Ronen; McCall, Ingrid C.; Leoni, Giovanna; Neumann, Philipp A.; Andargachew, Rakieb; Brazil, Jennifer C.; Medina-Contreras, Oscar; Denning, Timothy L.; Nusrat, Asma; Parkos, Charles A.

    2014-01-01

    Neutrophil transepithelial migration (TEM) during acute inflammation is associated with mucosal injury. Using models of acute mucosal injury in-vitro and in-vivo, we describe a new mechanism by which neutrophils infiltrating the intestinal mucosa disrupt epithelial homeostasis. We report that junctional adhesion molecule-like protein (JAML) is cleaved from neutrophil surface by zinc-metalloproteases during TEM. Neutrophil-derived soluble JAML bound to the epithelial tight junction protein coxsackie-adenovirus receptor (CAR) resulting in compromised barrier and inhibition of wound repair, through decreased epithelial proliferation. The deleterious effects of JAML on barrier and wound repair were reversed with an anti-JAML mAb that inhibits JAML-CAR binding. Thus, JAML released from transmigrating neutrophils across inflamed epithelia can promote recruitment of leukocytes and aid in clearance of invading microorganisms. However, sustained release of JAML under pathologic conditions associated with persistence of large numbers of infiltrated neutrophil would compromise intestinal barrier and inhibit mucosal healing. Targeting JAML-CAR interactions may thus improve mucosal healing responses under conditions of dysregulated neutrophil recruitment. PMID:24621992

  18. Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma.

    PubMed

    Ha, Y; Liu, H; Xu, Z; Yokota, H; Narayanan, S P; Lemtalsi, T; Smith, S B; Caldwell, R W; Caldwell, R B; Zhang, W

    2015-10-08

    Acute glaucoma is a leading cause of irreversible blindness in East Asia. The mechanisms underlying retinal neuronal injury induced by a sudden rise in intraocular pressure (IOP) remain obscure. Here we demonstrate that the activation of CXCL10/CXCR3 axis, which mediates the recruitment and activation of inflammatory cells, has a critical role in a mouse model of acute glaucoma. The mRNA and protein expression levels of CXCL10 and CXCR3 were significantly increased after IOP-induced retinal ischemia. Blockade of the CXCR3 pathway by deleting CXCR3 gene significantly attenuated ischemic injury-induced upregulation of inflammatory molecules (interleukin-1β and E-selectin), inhibited the recruitment of microglia/monocyte to the superficial retina, reduced peroxynitrite formation, and prevented the loss of neurons within the ganglion cell layer. In contrast, intravitreal delivery of CXCL10 increased leukocyte recruitment and retinal cell apoptosis. Inhibition of endoplasmic reticulum (ER) stress with chemical chaperones partially blocked ischemic injury-induced CXCL10 upregulation, whereas induction of ER stress with tunicamycin enhanced CXCL10 expression in retina and primary retinal ganglion cells. Interestingly, deleting CXCR3 attenuated ER stress-induced retinal cell death. In conclusion, these results indicate that ER stress-medicated activation of CXCL10/CXCR3 pathway has an important role in retinal inflammation and neuronal injury after high IOP-induced ischemia.

  19. Flow cytometric gating for spleen monocyte and DC subsets: differences in autoimmune NOD mice and with acute inflammation.

    PubMed

    Dong, Matthew B; Rahman, M Jubayer; Tarbell, Kristin V

    2016-05-01

    The role of antigen presenting cells (APCs) in the pathogenesis of autoimmune and other inflammatory diseases is now better understood due to advances in multicolor flow cytometry, gene expression analysis of APC populations, and functional correlation of mouse to human APC populations. A simple but informative nomenclature of conventional and plasmacytoid dendritic cell subsets (cDC1, cDC2, pDC) and monocyte-derived populations incorporates these advances, but accurate subset identification is critical. Ambiguous gating schemes and alterations of cell surface markers in inflammatory condition can make comparing results between studies difficult. Both acute inflammation, such as TLR-ligand stimulation, and chronic inflammation as found in mouse models of autoimmunity can alter DC subset gating. Here, we address these issues using in vivo CpG stimulation as an example of acute inflammation and the non-obese diabetic (NOD) mouse as a model of chronic inflammation.We provide a flow cytometric antibody panel and gating scheme that differentiate 2 monocytic and 3DC subsets in the spleen both at steady state and after CpG stimulation. Using this method, we observed differences in the composition of NOD DCs that have been previously reported, and newly identified increases in the number of NOD monocyte-derived DCs. Finally, we established a protocol for DC phosphoflow to measure the phosphorylation state of intracellular proteins, and use it to confirm functional differences in the identified subsets. Therefore, we present optimized methods for distinguishing monocytic and DC populations with and without inflammation and/or autoimmunity associated with NOD mice.

  20. Spred-2 Deficiency Exacerbates Lipopolysaccharide-Induced Acute Lung Inflammation in Mice

    PubMed Central

    Xu, Yang; Ito, Toshihiro; Fushimi, Soichiro; Takahashi, Sakuma; Itakura, Junya; Kimura, Ryojiro; Sato, Miwa; Mino, Megumi; Yoshimura, Akihiko; Matsukawa, Akihiro

    2014-01-01

    Background Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation. Methods Wild-type (WT) mice and Spred-2−/− mice were exposed to intratracheal LPS (50 µg in 50 µL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2−/− mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. Results LPS-induced acute lung inflammation was significantly exacerbated in Spred-2−/− mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2−/− mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. Conclusions The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the

  1. CD137 Facilitates the Resolution of Acute DSS-Induced Colonic Inflammation in Mice

    PubMed Central

    Martínez Gómez, Julia M.; Chen, Lieping; Schwarz, Herbert; Karrasch, Thomas

    2013-01-01

    Background CD137 and its ligand (CD137L) are potent immunoregulatory molecules that influence activation, proliferation, differentiation and cell death of leukocytes. Expression of CD137 is upregulated in the lamina propria cells of Crohn’s disease patients. Here, the role of CD137 in acute Dextran-Sodium-Sulfate (DSS)-induced colitis in mice was examined. Methods We induced acute large bowel inflammation (colitis) via DSS administration in CD137−/− and wild-type (WT) mice. Colitis severity was evaluated by clinical parameters (weight loss), cytokine secretion in colon segment cultures, and scoring of histological inflammatory parameters. Additionally, populations of lamina propria mononuclear cells (LPMNC) and intraepithelial lymphocytes (IEL) were characterized by flow cytometry. In a subset of mice, resolution of intestinal inflammation was evaluated 3 and 7 days after withdrawal of DSS. Results We found that both CD137−/− and WT mice demonstrated a similar degree of inflammation after 5 days of DSS exposure. However, the resolution of colonic inflammation was impaired in the absence of CD137. This was accompanied by a higher histological score of inflammation, and increased release of the pro-inflammatory mediators granulocyte macrophage colony-stimulating factor (GM-CSF), CXCL1, IL-17 and IFN-γ. Further, there were significantly more neutrophils among the LPMNC of CD137−/− mice, and reduced numbers of macrophages among the IEL. Conclusion We conclude that CD137 plays an essential role in the resolution of acute DSS-induced intestinal inflammation in mice. PMID:24023849

  2. CRTH2 antagonism significantly ameliorates airway hyperreactivity and downregulates inflammation-induced genes in a mouse model of airway inflammation.

    PubMed

    Lukacs, Nicholas W; Berlin, Aaron A; Franz-Bacon, Karin; Sásik, Roman; Sprague, L James; Ly, Tai Wei; Hardiman, Gary; Boehme, Stefen A; Bacon, Kevin B

    2008-11-01

    Prostaglandin D(2), the ligand for the G protein-coupled receptors DP1 and CRTH2, has been implicated in the pathogenesis of the allergic response in diseases such as asthma, rhinitis, and atopic dermatitis. This prostanoid also fulfills a number of physiological, anti-inflammatory roles through its receptor DP1. We investigated the role of PGD(2) and CRTH2 in allergic pulmonary inflammation by using a highly potent and specific antagonist of CRTH2. Administration of this antagonist ameliorated inflammation caused by either acute or subchronic sensitization using the cockroach egg antigen. Gene expression and ELISA analysis revealed that there was reduced proinflammatory cytokine mRNA or protein produced, as well as a wide array of genes associated with the Th2-type proinflammatory response. Importantly, the CRTH2 antagonist reduced antigen-specific IgE, IgG1, and IgG2a antibody levels as well as decreased mucus deposition and leukocyte infiltration in the large airways. Collectively, these findings suggest that the PGD(2)-CRTH2 activation axis has a pivotal role in mediating the inflammation and the underlying immune response in a T cell-driven model of allergic airway inflammation.

  3. Endothelial Semaphorin 7A Promotes Inflammation in Seawater Aspiration-Induced Acute Lung Injury

    PubMed Central

    Zhang, Minlong; Wang, Li; Dong, Mingqing; Li, Zhichao; Jin, Faguang

    2014-01-01

    Inflammation is involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have shown that Semaphorin 7A (SEMA7A) promotes inflammation, there are limited reports regarding immunological function of SEMA7A in seawater aspiration-induced ALI. Therefore, we investigated the role of SEMA7A during seawater aspiration-induced ALI. Male Sprague–Dawley rats were underwent seawater instillation. Then, lung samples were collected at an indicated time for analysis. In addition, rat pulmonary microvascular endothelial cells (RPMVECs) were cultured and then stimulated with 25% seawater for indicated time point. After these treatments, cells samples were collected for analysis. In vivo, seawater instillation induced lung histopathologic changes, pro-inflammation cytokines release and increased expression of SEMA7A. In vitro, seawater stimulation led to pro-inflammation cytokine release, cytoskeleton remodeling and increased monolayer permeability in pulmonary microvascular endothelial cells. In addition, knockdown of hypoxia-inducible factor (HIF)-1α inhibited the seawater induced increase expression of SEMA7A. Meanwhile, knockdown of SEMA7A by specific siRNA inhibited the seawater induced aberrant inflammation, endothelial cytoskeleton remodeling and endothelial permeability. These results suggest that SEMA7A is critical in the development of lung inflammation and pulmonary edema in seawater aspiration-induced ALI, and may be a therapeutic target for this disease. PMID:25353180

  4. Anti-inflammatory activity of aqueous fruit pulp extract of Hunteria umbellata K. Schum in acute and chronic inflammation.

    PubMed

    Igbe, Ighodaro; Ching, Fidelis P; Eromon, Aigbe

    2010-01-01

    The anti-inflammatory effect of the aqueous fruit pulp extract of Hunteria umbellata K. Schum (Apocynaceae) was evaluated using the carrageenan- and dextran-induced rat paw edema, xylene-induced ear edema and formalin-induced arthritis inflammation tests. Oral administration of the extract produced significant (p < 0.05) antiedematogenic effect with a dose of 500 mg/kg throughout the period of the experiment in the dextran induced paw edema and at the 3 h in the carrageenan model. The extract (250 and 500 mg/kg) exhibited a dose-related and significant (p < 0.01) inhibition of xylene induced ear edema and the effect was similar to that produced by dexamethasone (1 mg/kg). In the chronic inflammation (formalin induced arthritis) the extract did not show any significant anti-inflammatory activity. Oral acute toxicity assays did not show any mortality at 15 g/kg of the plant extract. The results indicate that the aqueous extract of H. umbellata possesses acute inflammatory activity which may be mediated by either inhibition or by blocking the release of prostaglandins and histamine, thus supporting the usage of the plant in traditional medicine treatment of inflammation.

  5. Models of acute and chronic pancreatitis.

    PubMed

    Lerch, Markus M; Gorelick, Fred S

    2013-06-01

    Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include.

  6. Antihyperalgesic effects of δ opioid agonists in a rat model of chronic inflammation

    PubMed Central

    Fraser, Graeme L; Gaudreau, Geneviève-Anne; Clarke, Paul B S; Ménard, Daniel P; Perkins, Martin N

    2000-01-01

    Opioid receptors in the brain activate descending pain pathways to inhibit the nociceptive response to acute noxious stimuli. The aim of the present study was to clarify the role of supraspinal opioid receptors in modulating the nociceptive response to persistent inflammation in rats.Subcutaneous administration of 50 μl of complete Freund's Adjuvant (CFA) into the plantar surface of the hindpaw induced a significant decrease in paw withdrawal latency to thermal stimuli (P<0.01) at 24 h post-injection.Intracerebroventricular (i.c.v.) administration of the μ opioid receptor agonists, DAMGO and morphine, and the δ opioid receptor agonists, deltorphin II and SNC80, significantly reversed the hyperalgesic response associated with peripheral inflammation in a dose-dependent manner (P<0.0001).The μ and δ agonists also significantly attenuated the antinociceptive response to acute thermal stimulation in rats (P<0.001). However, deltorphin II and SNC80 were less potent, and in the case of SNC80 less efficacious, in modulating the response to acute thermal nociception in comparison to hyperalgesia associated with persistent inflammation.These results indicate that μ and δ opioid receptors in the brain modulate descending pain pathways to attenuate the nociceptive response to acute thermal stimuli in both normal and inflamed tissues. The heightened response to δ agonists in the hyperalgesia model suggests that δ opioid receptors in the brain are promising targets for the treatment of pain arising from chronic inflammation. PMID:10780972

  7. The acute airway inflammation induced by PM2.5 exposure and the treatment of essential oils in Balb/c mice

    PubMed Central

    Wang, Hetong; Song, Laiyu; Ju, Wenhui; Wang, Xuguang; Dong, Lu; Zhang, Yining; Ya, Ping; Yang, Chun; Li, Fasheng

    2017-01-01

    PM2.5 is the main particulate air pollutant whose aerodynamic diameter is less than 2.5 micron. The inflammation of various respiratory diseases are associated with PM2.5 inhalation. Pro-inflammatory cytokine IL-1β generated from effected cells usually plays a crucial role in many kinds of lung inflammatory reactions. The exacerbation of Th immune responses are identified in some PM2.5 related diseases. To elucidate the underlying mechanism of PM2.5-induced acute lung inflammation, we exposed Balb/c mice to PM2.5 intratracheally and established a mice model. Acute lung inflammation and increased IL-1β expression was observed after PM2.5 instillation. Regulatory factors of IL-1β (TLR4/MyD88 signaling pathway and NLRP3 inflammasome) participated in this lung inflammatory response as well. Treatment with compound essential oils (CEOs) substantially attenuated PM2.5-induced acute lung inflammation. The decreased IL-1β and Th immune responses after CEOs treatment were significant. PM2.5 may increase the secretion of IL-1β through TLR4/MyD88 and NLRP3 pathway resulting in murine airway inflammation. CEOs could attenuate the lung inflammation by reducing IL-1β and Th immune responses in this model. This study describes a potentially important mechanism of PM2.5-induced acute lung inflammation and that may bring about novel therapies for the inflammatory diseases associated with PM2.5 inhalation. PMID:28276511

  8. Central autonomic network mediates cardiovascular responses to acute inflammation: Relevance to increased cardiovascular risk in depression?

    PubMed Central

    Harrison, Neil A.; Cooper, Ella; Voon, Valerie; Miles, Ken; Critchley, Hugo D.

    2013-01-01

    Inflammation is a risk factor for both depression and cardiovascular disease. Depressed mood is also a cardiovascular risk factor. To date, research into mechanisms through which inflammation impacts cardiovascular health rarely takes into account central effects on autonomic cardiovascular control, instead emphasizing direct effects of peripheral inflammatory responses on endothelial reactivity and myocardial function. However, brain responses to inflammation engage neural systems for motivational and homeostatic control and are expressed through depressed mood state and changes in autonomic cardiovascular regulation. Here we combined an inflammatory challenge, known to evoke an acute reduction in mood, with neuroimaging to identify the functional brain substrates underlying potentially detrimental changes in autonomic cardiovascular control. We first demonstrated that alterations in the balance of low to high frequency (LF/HF) changes in heart rate variability (a measure of baroreflex sensitivity) could account for some of the inflammation-evoked changes in diastolic blood pressure, indicating a central (rather than solely local endothelial) origin. Accompanying alterations in regional brain metabolism (measured using 18FDG-PET) were analysed to localise central mechanisms of inflammation-induced changes in cardiovascular state: three discrete regions previously implicated in stressor-evoked blood pressure reactivity, the dorsal anterior and posterior cingulate and pons, strongly mediated the relationship between inflammation and blood pressure. Moreover, activity changes within each region predicted the inflammation-induced shift in LF/HF balance. These data are consistent with a centrally-driven component originating within brain areas supporting stressor evoked blood pressure reactivity. Together our findings highlight mechanisms binding psychological and physiological well-being and their perturbation by peripheral inflammation. PMID:23416033

  9. CD97 antibody depletes granulocytes in mice under conditions of acute inflammation via a Fc receptor-dependent mechanism.

    PubMed

    Veninga, Henrike; de Groot, Dorien M; McCloskey, Natalie; Owens, Bronwyn M; Dessing, Mark C; Verbeek, J Sjef; Nourshargh, Sussan; van Eenennaam, Hans; Boots, Annemieke M; Hamann, Jörg

    2011-03-01

    Antibodies to the pan-leukocyte adhesion-GPCR CD97 efficiently block neutrophil recruitment in mice, thereby reducing antibacterial host defense, inflammatory disease, and hematopoietic stem cell mobilization. Here, we investigated the working mechanism of the CD97 antibody 1B2. Applying sterile models of inflammation, intravital microscopy, and mice deficient for the CD97L CD55, the complement component C3, or the FcR common γ-chain, we show that 1B2 acts in vivo independent of ligand-binding interference by depleting PMN granulocytes in bone marrow and blood. Granulocyte depletion with 1B2 involved FcR but not complement activation and was associated with increased serum levels of TNF and other proinflammatory cytokines. Notably, depletion of granulocytes by CD97 antibody required acute inflammation, suggesting a mechanism of conditional, antibody-mediated granulocytopenia.

  10. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins.

    PubMed

    Meseguer, Victor; Alpizar, Yeranddy A; Luis, Enoch; Tajada, Sendoa; Denlinger, Bristol; Fajardo, Otto; Manenschijn, Jan-Albert; Fernández-Peña, Carlos; Talavera, Arturo; Kichko, Tatiana; Navia, Belén; Sánchez, Alicia; Señarís, Rosa; Reeh, Peter; Pérez-García, María Teresa; López-López, José Ramón; Voets, Thomas; Belmonte, Carlos; Talavera, Karel; Viana, Félix

    2014-01-01

    Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.

  11. TRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins

    NASA Astrophysics Data System (ADS)

    Meseguer, Victor; Alpizar, Yeranddy A.; Luis, Enoch; Tajada, Sendoa; Denlinger, Bristol; Fajardo, Otto; Manenschijn, Jan-Albert; Fernández-Peña, Carlos; Talavera, Arturo; Kichko, Tatiana; Navia, Belén; Sánchez, Alicia; Señarís, Rosa; Reeh, Peter; Pérez-García, María Teresa; López-López, José Ramón; Voets, Thomas; Belmonte, Carlos; Talavera, Karel; Viana, Félix

    2014-01-01

    Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.

  12. Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice

    PubMed Central

    Pietrofesa, Ralph A.; Velalopoulou, Anastasia; Arguiri, Evguenia; Menges, Craig W.; Testa, Joseph R.; Hwang, Wei-Ting; Albelda, Steven M.

    2016-01-01

    Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2+/mu mice. Mice (n = 16–17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM. PMID:26678224

  13. Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice.

    PubMed

    Pietrofesa, Ralph A; Velalopoulou, Anastasia; Arguiri, Evguenia; Menges, Craig W; Testa, Joseph R; Hwang, Wei-Ting; Albelda, Steven M; Christofidou-Solomidou, Melpo

    2016-02-01

    Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2(+/mu) mice. Mice (n = 16-17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM.

  14. Role of hepcidin in the setting of hypoferremia during acute inflammation.

    PubMed

    Deschemin, Jean-Christophe; Vaulont, Sophie

    2013-01-01

    The anemia of chronic disease (also called anemia of inflammation) is an acquired disorder of iron homeostasis associated with infection, malignancy, organ failure, trauma, or other causes of inflammation. It is now widely accepted that induction of hepcidin expression in response to inflammation might explain the characteristic hypoferremia associated with this condition. To determine the role of hepcidin in acute inflammation and the regulation of its receptor, the iron exporter, ferroportin, wild-type, heterozygote and hepcidin knockout mice (Hepc-/-) were challenged with sublethal doses of lipopolysaccharide (LPS). Six hours after injection, ferroportin mRNA and protein levels were assessed in the duodenum and the spleen and plasma iron was determined. Our results demonstrate that hepcidin is crucial, though not the sole mediator of LPS-mediated acute hypoferremia, and also that hepcidin major contribution relies on decreased ferroportin protein levels found in the spleen. Furthermore, we establish that LPS-mediated repression of the membrane iron transporter DMT1 and oxidoreductase Dcytb in the duodenum is independent of hepcidin. Finally, our results in the hepc+/- mice indicate that elevated hepcidin gene expression is not a prerequisite for the setting of hypoferremia during early inflammatory response, and they highlight the intimate crosstalk between inflammatory and iron-responsive pathways for the control of hepcidin.

  15. Analgesic and anti-inflammatory actions of robenacoxib in acute joint inflammation in dog.

    PubMed

    Schmid, V B; Spreng, D E; Seewald, W; Jung, M; Lees, P; King, J N

    2010-04-01

    The objectives of this study were to establish dose-response and blood concentration-response relationships for robenacoxib, a novel nonsteroidal anti-inflammatory drug with selectivity for inhibition of the cyclooxygenase (COX)-2 isoenzyme, in a canine model of synovitis. Acute synovitis of the stifle joint was induced by intra-articular injection of sodium urate crystals. Robenacoxib (0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg), placebo and meloxicam (0.2 mg/kg) were administered subcutaneously (s.c.) 3 h after the urate crystals. Pharmacodynamic endpoints included data from forceplate analyses, clinical orthopaedic examinations and time course of inhibition of COX-1 and COX-2 in ex vivo whole blood assays. Blood was collected for pharmacokinetics. Robenacoxib produced dose-related improvement in weight-bearing, pain and swelling as assessed objectively by forceplate analysis (estimated ED(50) was 1.23 mg/kg for z peak force) and subjectively by clinical orthopaedic assessments. The analgesic and anti-inflammatory effects of robenacoxib were significantly superior to placebo (0.25-4 mg/kg robenacoxib) and were non-inferior to meloxicam (0.5-4 mg/kg robenacoxib). All dosages of robenacoxib produced significant dose-related inhibition of COX-2 (estimated ED(50) was 0.52 mg/kg) but no inhibition of COX-1. At a dosage of 1-2 mg/kg administered s.c., robenacoxib should be at least as effective as 0.2 mg/kg of meloxicam in suppressing acute joint pain and inflammation in dogs.

  16. Cryotherapy suppresses tendon inflammation in an animal model

    PubMed Central

    Zhang, Jianying; Pan, Tiffany; Wang, James H.-C.

    2015-01-01

    Summary Cryotherapy (or cold treatment) has been a popular treatment to relieve pain caused by injuries to tissues such as tendons. However, the exact mechanisms behind the beneficial effects of cryotherapy in tendons remain largely unclear. As prostaglandin E2 (PGE2) is known to be a major mediator of acute inflammation in tissues, which is related to tissue pain, we hypothesized that the beneficial effects of cryotherapy in tendons are mediated by downregulation of PGE2 levels. To test this hypothesis, we applied cold treatment to mouse patellar and Achilles tendons using two animal models: exhaustive mouse treadmill running and acute mouse tendon injury by needle penetration. We then measured the levels of PGE2 and protein expression levels of COX-2, an enzyme responsible for PGE2 production in tissues, under both experimental conditions. We found that treadmill running increased PGE2 levels in both patellar and Achilles tendons compared to control mice without running. Cold treatment for 30 min after treadmill running was sufficient to reduce PGE2 levels to near baseline control levels in both tendons. An extension of cold treatment to 60 min resulted only in a marginal decrease in patellar tendons, but a marked decrease in Achilles tendons. Moreover, COX-2 protein levels in both tendons were also lowered by cold treatment, suggesting that the reduction of PGE2 levels in tendons by cold treatment is at least in part due to the decreased COX-2 expression. Similarly, in the acutely injured tendons, 30 min of cold treatment after needle penetration reduced PGE2 levels when compared to the controls at room temperature (22°C). This decrease was sustained up to at least 3 h after the administration of cryotherapy. Given that PGE2 is a known pain sensitiser, the results of this study suggest that the ability of cold treatment to reduce pain may be attributable to its ability to decrease PGE2 production in tendons. PMID:26594634

  17. In Vivo Bioluminescence Imaging for Longitudinal Monitoring of Inflammation in Animal Models of Uveitis

    PubMed Central

    Gutowski, Michal B.; Wilson, Leslie; Van Gelder, Russell N.; Pepple, Kathryn L.

    2017-01-01

    Purpose We develop a quantitative bioluminescence assay for in vivo longitudinal monitoring of inflammation in animal models of uveitis. Methods Three models of experimental uveitis were induced in C57BL/6 albino mice: primed mycobacterial uveitis (PMU), endotoxin-induced uveitis (EIU), and experimental autoimmune uveitis (EAU). Intraperitoneal injection of luminol sodium salt, which emits light when oxidized, provided the bioluminescence substrate. Bioluminescence images were captured by a PerkinElmer In Vivo Imaging System (IVIS) Spectrum and total bioluminescence was analyzed using Living Image software. Bioluminescence on day zero was compared to bioluminescence on the day of peak inflammation for each model. Longitudinal bioluminescence imaging was performed in EIU and EAU. Results In the presence of luminol, intraocular inflammation generates detectable bioluminescence in three mouse models of uveitis. Peak bioluminescence in inflamed PMU eyes (1.46 × 105 photons/second [p/s]) was significantly increased over baseline (1.47 × 104 p/s, P = 0.01). Peak bioluminescence in inflamed EIU eyes (3.18 × 104 p/s) also was significantly increased over baseline (1.09 × 104 p/s, P = 0.04), and returned to near baseline levels by 48 hours. In EAU, there was a nonsignificant increase in bioluminescence at peak inflammation. Conclusions In vivo bioluminescence may be used as a noninvasive, quantitative measure of intraocular inflammation in animal models of uveitis. Primed mycobacterial uveitis and EIU are both acute models with robust anterior inflammation and demonstrated significant changes in bioluminescence corresponding with peak inflammation. Experimental autoimmune uveitis is a more indolent posterior uveitis and generated a more modest bioluminescent signal. In vivo imaging system bioluminescence is a nonlethal, quantifiable assay that can be used for monitoring inflammation in animal models of uveitis. PMID:28278321

  18. Vitamin C fails to protect amino acids and lipids from oxidation during acute inflammation.

    PubMed

    Gaut, Joseph P; Belaaouaj, Abderrazzaq; Byun, Jaeman; Roberts, L Jackson; Maeda, Nobuyo; Frei, Balz; Heinecke, Jay W

    2006-05-01

    The observation that antioxidant vitamins fail to confer protective benefits in large, well-designed randomized clinical trials has led many to question the role of oxidative stress in the pathogenesis of disease. However, there is little evidence that proposed antioxidants actually scavenge reactive intermediates in vivo. Ascorbate reacts rapidly with oxidants produced by activated neutrophils in vitro, and neutrophils markedly increase their oxidant production when mice are infected intraperitoneally with the gram-negative bacterium Klebsiella pneumoniae. To explore the antioxidant properties of ascorbate in vivo, we therefore used K. pneumoniae infection as a model of oxidative stress. When mice deficient in L-gulono-gamma-lactone oxidase (Gulo(-/-)), the rate-limiting enzyme in ascorbate synthesis, were depleted of ascorbate and infected with K. pneumoniae, they were three times as likely as ascorbate-replete Gulo(-/-)mice to die from infection. Mass spectrometric analysis of peritoneal lavage fluid revealed a marked increase in the levels of oxidized amino acids and of F2-isoprostanes (sensitive and specific markers of lipid oxidation) in infected animals. Surprisingly, there were no significant differences in the levels of the oxidation products in the ascorbate-deficient and -replete Gulo(-/-)mice. Our observations suggest that ascorbate plays a previously unappreciated role in host defense mechanisms against invading pathogens but that the vitamin does not protect amino acids and lipids from oxidative damage during acute inflammation. To examine the oxidation hypothesis of disease, optimal antioxidant regimens that block oxidative reactions in animals and humans need to be identified.

  19. Cross-Sectional Detection of Acute HIV Infection: Timing of Transmission, Inflammation and Antiretroviral Therapy

    PubMed Central

    Gay, Cynthia; Dibben, Oliver; Anderson, Jeffrey A.; Stacey, Andrea; Mayo, Ashley J.; Norris, Philip J.; Kuruc, JoAnn D.; Salazar-Gonzalez, Jesus F.; Li, Hui; Keele, Brandon F.; Hicks, Charles; Margolis, David; Ferrari, Guido; Haynes, Barton; Swanstrom, Ronald; Shaw, George M.; Hahn, Beatrice H.; Eron, Joseph J.; Borrow, Persephone; Cohen, Myron S.

    2011-01-01

    Background Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions. Methods Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24. Results Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment. Discussion The results emphasize the difficulty in recruiting subjects early in AHI. Viral sequence diversity proved accurate in estimating time of infection. Regardless of aggressive screening, peak viremia and inflammation occurred before enrollment and potential intervention. Given the personal and public health importance, improved AHI detection is urgently needed. PMID:21573003

  20. Tamoxifen Attenuates Lipopolysaccharide/Galactosamine-induced Acute Liver Failure by Antagonizing Hepatic Inflammation and Apoptosis.

    PubMed

    Zhang, Peng; Zhang, Meisheng; Wan, Mengqi; Huang, Xiaoliu; Jiang, Yan; Xu, Siying; Luo, Mansheng

    2017-04-01

    Bacterial lipopolysaccharide (LPS)-induced acute liver failure (ALF) is a common severe clinical syndrome in intensive care unit. No other methods are available for its prevention apart from supportive treatment and liver transplantation. Tamoxifen (TAM) was reported to attenuate ALF induced by excessive acetaminophen, while its effect on LPS-induced ALF remained unknown. For this, in the present study, we comprehensively assessed whether TAM can attenuate ALF induced by LPS/galactosamine (GaIN). Mice were given TAM once a day for three times. Twelve hours after the last treatment, mice were given LPS/GaIN (intraperitoneally [i.p.]). Survival, plasma transaminases, and histopathology were examined. Serum TNF-α and IL-1β were analyzed by ELISA. Hepatic apoptosis was analyzed by TUNEL and caspase-3 Western blotting, respectively. Compared to the model group, ALF induced by LPS/GaIN was alleviated remarkably following TAM administration, as evidenced by the improvement of survival (87.5% vs. 37.5%), hepatic swell, moderate transaminases, slightly increased serum TNF-α, IL-1β (P < 0.05), and moderate histopathology. In respect of apoptosis, severe hepatocellular apoptosis was reduced notably by TAM treatment confirmed by less TUNEL-positive hepatocytes and decreased caspase-3 cleavage. The results demonstrated that TAM could attenuate LPS/GaIN-induced ALF effectively, probably due to hepatic inflammation and apoptosis antagonism. Furthermore, it was the first report about the effect of TAM on LPS/GaIN-induced ALF.

  1. Serum biomarkers and source of inflammation in acute coronary syndromes and percutaneous coronary interventions.

    PubMed

    Centurión, Osmar Antonio

    2016-03-01

    There is robust information that confirms the enormous contribution of inflammation to plaque development, progression and vulnerability. The presence of plaques with inflammatory components associates with a greater likelihood of future cardiovascular events. The inflammatory cascade has been implicated during the entire plaque formation, from the early stages of endothelial dysfunction to the development of acute coronary syndromes (ACS). The presence of macrophages, T lymphocytes, dendritic cells, and mast cells in atherosclerotic lesions; the detection of HLA class II antigen expression; and the finding of secretion of several cytokines point to the involvement of immune inflammatory mechanisms in the pathogenesis of atherosclerosis. Serum biomarkers reflecting the activity of biological processes involved in plaque growth or destabilization may provide great help in establishing the appropriate clinical management, and therapeutic interventions. Evidence for a role of inflammation in plaque rupture has been demonstrated by localization of inflammation at plaque rupture sites. However, the focus of inflammation may not precisely reside within the coronary vessel itself but rather in the injured myocardium distal to the disrupted plaque. These observations outline the potential benefits of therapies targeting inflammation in the arterial wall and cardiovascular system. Emerging anti-inflammatory approaches to vascular protection have the potential to benefit patients by marked reductions in serum biomarkers of inflammation and reduce vascular events. With ongoing technical advances, percutaneous coronary interventions (PCI) will continue to play a critical role in the evaluation of novel compounds designed to modulate inflammation. The constant refinements in the different therapeutic strategies, the combination of scientific understanding in the adequate utilization of novel inflammatory markers, the new pharmacologic agents, and the new techniques in PCI will

  2. Quantification of structural changes in acute inflammation by fractal dimension, angular second moment and correlation.

    PubMed

    Stankovic, Marija; Pantic, Igor; De Luka, Silvio R; Puskas, Nela; Zaletel, Ivan; Milutinovic-Smiljanic, Sanja; Pantic, Senka; Trbovich, Alexander M

    2016-03-01

    The aim of the study was to examine alteration and possible application of fractal dimension, angular second moment, and correlation for quantification of structural changes in acutely inflamed tissue. Acute inflammation was induced by injection of turpentine oil into the right and left hind limb muscles of mice, whereas control animals received intramuscular saline injection. After 12 h, animals were anesthetised and treated muscles collected. The tissue was stained by hematoxylin and eosin, digital micrographs produced, enabling determination of fractal dimension of the cells, angular second moment and correlation of studied tissue. Histopathological analysis showed presence of inflammatory infiltrate and tissue damage in inflammatory group, whereas tissue structure in control group was preserved, devoid of inflammatory infiltrate. Fractal dimension of the cells, angular second moment and correlation of treated tissue in inflammatory group decreased in comparison to the control group. In this study, we were first to observe and report that fractal dimension of the cells, angular second moment, and correlation were reduced in acutely inflamed tissue, indicating loss of overall complexity of the cells in the tissue, the tissue uniformity and structure regularity. Fractal dimension, angular second moment and correlation could be useful methods for quantification of structural changes in acute inflammation.

  3. Inhibitory Effect of Helicteres gardneriana Ethanol Extract on Acute Inflammation

    PubMed Central

    de Melo, Juliana Oliveira; de Arruda, Laura Lícia Milani; Baroni, Silmara; Truiti, Maria da Conceição Torrado; Caparroz-Assef, Silvana Martins; Cuman, Roberto Kenji Nakamura; Bersani-Amado, Ciomar Aparecida

    2012-01-01

    The anti-inflammatory effect of an ethanol extract of Helicteres gardneriana (Nees) Castiglioni was assayed in experimental models of pleurisy and microcirculation in situ. Treatment of animals with 500 mg/kg body weight reduced the exudate volume (35% reduction) induced by intrapleural injection of carrageenan and the migration of polymorphonuclear cells into the inflamed pleural cavity of rats (40%). Additionally, rolling and adhesion of leukocytes and the number of leukocytes that migrated toward the perivascular space in response to the carrageenan injection were decreased by the extract (500 mg/kg). These data demonstrate the anti-inflammatory effect of the ethanol extract of Helicteres gardneriana and imply that inhibition of leukocyte-endothelial interactions is important in the extract's mechanism of action. PMID:22028731

  4. Increased taurine in pre-weaned juvenile mdx mice greatly reduces the acute onset of myofibre necrosis and dystropathology and prevents inflammation

    PubMed Central

    Terrill, Jessica R.; Grounds, Miranda D; Arthur, Peter G.

    2016-01-01

    Background: The mdx mouse model for the fatal muscle wasting disease Duchenne Muscular Dystrophy (DMD) shows a very mild pathology once growth has ceased, with low levels of myofibre necrosis in adults. However, from about 3 weeks of post-natal age, muscles of juvenile mdx mice undergo an acute bout of severe necrosis and inflammation: this subsequently decreases and stabilises to lower adult levels by about 6 weeks of age. Prior to the onset of this severe dystropathology, we have shown that mdx mice are deficient in the amino acid taurine (potentially due to weaning), and we propose that this exacerbates myofibre necrosis and inflammation in juvenile mdx mice. Objectives: The purpose of this study was to increase taurine availability to pre-weaned juvenile mdx mice (from 14 days of age), to evaluate the impact on levels of myofibre necrosis and inflammation (at 22 days) during the acute period of severe dystropathology. Results: Untreated 22 day old mdx muscle was not deficient in taurine, with similar levels to normal C57 control muscle. However taurine treatment, which increased the taurine content of young dystrophic muscle (by 40%), greatly reduced myofibre necrosis (by 75%) and prevented significant increases in 3 markers of inflammation. Conclusion: Taurine was very effective at preventing the acute phase of muscle damage that normally results in myofibre necrosis and inflammation in juvenile mdx mice, supporting continued research into the use of taurine as a therapeutic intervention for protecting growing muscles of young DMD boys PMID:27679740

  5. Inflammation and Rupture of a Congenital Pericardial Cyst Manifesting Itself as an Acute Chest Pain Syndrome

    PubMed Central

    Cheong, Benjamin Y.C.; Lufschanowski, Roberto

    2016-01-01

    We present the case of a 63-year-old woman with a remote history of supraventricular tachycardia and hyperlipidemia, who presented with recurrent episodes of acute-onset chest pain. An electrocardiogram showed no evidence of acute coronary syndrome. A chest radiograph revealed a prominent right-sided heart border. A suspected congenital pericardial cyst was identified on a computed tomographic chest scan, and stranding was noted around the cyst. The patient was treated with nonsteroidal anti-inflammatory drugs, and the pain initially abated. Another flare-up was treated similarly. Cardiac magnetic resonance imaging was then performed after symptoms had resolved, and no evidence of the cyst was seen. The suspected cause of the patient's chest pain was acute inflammation of a congenital pericardial cyst with subsequent rupture and resolution of symptoms. PMID:28100978

  6. Role of interleukin-1 and tumour necrosis factor in leukocyte recruitment to acute dermal inflammation

    PubMed Central

    Lopes, Nancy; Issekutz, Thomas B.

    1992-01-01

    The cytokines IL-1 and TNF-α are involved in inflammation and their production is stimulated by various agents, especially endotoxin (LPS). Here, using the human IL-1 receptor antagonist (IL-1RA) and a new monoclonal antibody (mAb 7F11) to rabbit TNF, the role of endogenous IL-l and TNF production in acute (3h) leukocyte (PMNL) recruitment to dermal inflammation in rabbits has been studied. IL-1RA inhibited by 27% the PMNL accumulation in reactions induced by killed Escherichia coli (p < 0.05) but not by LPS. The monoclonal antibody to TNF inhibited by 27% and 38% (p < 0.002) the PMNL accumulation in LPS and E. coli reactions respectively, but a combination of the mAb with IL-1RA was not more effective. Treatment of human umbilical vein endothelium with LPS for 3 h activated endothelium to induce PMNL transendothelial migration in vitro, which was not inhibited by IL-1RA, antibody to TNF-α, IL-1 or to IL-8. In conclusion, TNF and IL-1 may partially mediate acute PMNL infiltration in vivo to LPS and Gram negative bacteria, but there is a major IL-1/TNF independent mechanism, at least in dermal inflammation, which may be due to direct LPS activation of the microvasculature or perhaps the generation of cytokines other than IL-1 and TNF. PMID:18475483

  7. Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation.

    PubMed

    Sunil, Vasanthi R; Vayas, Kinal N; Cervelli, Jessica A; Malaviya, Rama; Hall, LeRoy; Massa, Christopher B; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2014-08-01

    Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (150-174 g; 8-10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histopathological changes in the lung within 3d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2(+) and MMP-9(+)), and anti-inflammatory/wound repair (CD163+ and Gal-3(+)) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3(+) macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants.

  8. Acute Joint Pathology and Synovial Inflammation is Associated with Increased Intra-Articular Fracture Severity in the Mouse Knee

    PubMed Central

    Lewis, John S.; Hembree, W. Chad; Furman, Bridgette D.; Tippets, Lauren; Cattel, Dennis; Huebner, Janet L.; Little, Dianne; DeFrate, Louis E.; Kraus, Virginia B.; Guilak, Farshid; Olson, Steven A.

    2012-01-01

    OBJECTIVE Post-traumatic arthritis is a frequent cause of disability and occurs most commonly and predictably after articular fracture. The objective of this investigation was to examine the effect of fracture severity on acute joint pathology in a novel murine model of intra-articular fracture. DESIGN Low and high energy articular fractures (n=25 per group) of the tibial plateau were created in adult male C57BL/6 mice. The acute effect of articular fracture severity on synovial inflammation, bone morphology, liberated fracture area, cartilage pathology, chondrocyte viability, and systemic cytokines and biomarkers levels was assessed at 0, 1, 3, 5, and 7 days post-fracture. RESULTS Increasing intra-articular fracture severity was associated with greater acute pathology in the synovium and bone compared to control limbs, including increased global synovitis and reduced periarticular bone density and thickness. Applied fracture energy was significantly correlated with degree of liberated cortical bone surface area, indicating greater comminution. Serum concentrations of hyaluronic acid (HA) were significantly increased one day post-fracture. While articular fracture significantly reduced chondrocyte viability, there was no relationship between fracture severity and chondrocyte viability, cartilage degeneration, or systemic levels of cytokines and biomarkers. CONCLUSIONS This study demonstrates that articular fracture is associated with a loss of chondrocyte viability and increased levels of systemic biomarkers, and that increased intra-articular fracture severity is associated with increased acute joint pathology in a variety of joint tissues, including synovial inflammation, cortical comminution, and bone morphology. Further characterization of the early events following articular fracture could aid in the treatment of post-traumatic arthritis. PMID:21619936

  9. Acute Inflammation

    MedlinePlus

    ... foot and ankle surgeons. All Fellows of the College are board certified by the American Board of Foot and Ankle Surgery. Copyright © 2017 American College of Foot and Ankle Surgeons (ACFAS), All Rights ...

  10. Steroidogenic acute regulatory protein (StAR) overexpression reduces inflammation and insulin resistance in obese mice.

    PubMed

    Qiu, Yanyan; Sui, Xianxian; Cao, Shengxuan; Li, Xiaobo; Ning, Yanxia; Wang, Songmei; Yin, Lianhua; Zhi, Xiuling

    2017-04-12

    Steroidogenic acute regulatory protein (StAR), a mitochondrial cholesterol delivery protein, plays a beneficial role in hyperlipidemia, NAFLD and endothelial inflammation. Elevated circulating fatty acids and low grade inflammation are known as key risk factors of insulin resistance and type 2 diabetes. In the present study, C57BL/6J mice were fed with a HFD and infected with recombinant adenovirus expressing StAR by tail-vein injection. Intraperitoneal glucose/insulin tolerance test was performed to assess the insulin sensitivity. Morphological analysis and intramuscular lipid determination were used to illustrate the adipose hypertrophy and ectopic fat accumulation in skeletal muscle. The levels of inflammatory factor and nitric oxide were determined by ELISA and classic Griess reagent methods respectively. The fatty acids composition was analysis using gas chromatography -mass spectrometry (GC-MS). The expression of genes associated with inflammation and insulin resistance were determined by Western blotting and qPCR to elucidate the underlying mechanism.We demonstrated that StAR overexpression ameliorated insulin resistance and systemic inflammatory response with the reduction of adipose hypertrophy and intramuscular lipid in HFD fed mice. In addition, StAR overexpression increased serum unsaturated fatty acids and PPARγ expression in muscle and adipose tissue of obese mice. In conclusion, StAR may activate PPARγ by increasing unsaturated fatty acids, which leads to a protective role in systemic inflammation and insulin resistance in obese mice. This article is protected by copyright. All rights reserved.

  11. Mast cells and histamine are triggering the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation

    PubMed Central

    Nizamutdinova, Irina Tsoy; Dusio, Giuseppina F.; Gasheva, Olga Yu.; Skoog, Hunter; Tobin, Richard; Peddaboina, Chander; Meininger, Cynthia J.; Zawieja, David C.; Newell-Rogers, M. Karen; Gashev, Anatoliy A.

    2016-01-01

    This study aimed to establish mechanistic links between the aging-associated changes in the functional status of mast cells and the altered responses of mesenteric tissue and mesenteric lymphatic vessels (MLVs) to acute inflammation. We used an in vivo model of acute peritoneal inflammation induced by lipopolysaccharide treatment of adult (9-month) and aged (24-month) F-344 rats. We analyzed contractility of isolated MLVs, mast cell activation, activation of nuclear factor-κB (NF-κB) without and with stabilization of mast cells by cromolyn or blockade of all types of histamine receptors and production of 27 major pro-inflammatory cytokines in adult and aged perilymphatic mesenteric tissues and blood. We found that the reactivity of aged contracting lymphatic vessels to LPS-induced acute inflammation was abolished and that activated mast cells trigger NF-κB signaling in the mesentery through release of histamine. The aging-associated basal activation of mesenteric mast cells limits acute inflammatory NF-κB activation in aged mesentery. We conclude that proper functioning of the mast cell/histamine/NF-κB axis is necessary for reactions of the lymphatic vessels to acute inflammatory stimuli as well as for interaction and trafficking of immune cells near and within the collecting lymphatics. PMID:27875806

  12. Dioscin alleviates dimethylnitrosamine-induced acute liver injury through regulating apoptosis, oxidative stress and inflammation.

    PubMed

    Zhang, Weixin; Yin, Lianhong; Tao, Xufeng; Xu, Lina; Zheng, Lingli; Han, Xu; Xu, Youwei; Wang, Changyuan; Peng, Jinyong

    2016-07-01

    In our previous study, the effects of dioscin against alcohol-, carbon tetrachloride- and acetaminophen-induced liver damage have been found. However, the activity of it against dimethylnitrosamine (DMN)-induced acute liver injury remained unknown. In the present study, dioscin markedly decreased serum ALT and AST levels, significantly increased the levels of SOD, GSH-Px, GSH, and decreased the levels of MDA, iNOS and NO. Mechanism study showed that dioscin significantly decreased the expression levels of IL-1β, IL-6, TNF-α, IκBα, p50 and p65 through regulating TLR4/MyD88 pathway to rehabilitate inflammation. In addition, dioscin markedly up-regulated the expression levels of SIRT1, HO-1, NQO1, GST and GCLM through increasing nuclear translocation of Nrf2 against oxidative stress. Furthermore, dioscin significantly decreased the expression levels of FasL, Fas, p53, Bak, Caspase-3/9, and upregulated Bcl-2 level through decreasing IRF9 level against apoptosis. In conclusion, dioscin showed protective effect against DMN-induced acute liver injury via ameliorating apoptosis, oxidative stress and inflammation, which should be developed as a new candidate for the treatment of acute liver injury in the future.

  13. Caerulein-induced acute pancreatitis results in mild lung inflammation and altered respiratory mechanics.

    PubMed

    Elder, Alison S F; Saccone, Gino T P; Bersten, Andrew D; Dixon, Dani-Louise

    2011-03-01

    Acute lung injury is a common complication of acute pancreatitis (AP) and contributes to the majority of AP-associated deaths. Although some aspects of AP-induced lung inflammation have been demonstrated, investigation of resultant changes in lung function is limited. The aim of this study was to characterize lung injury in caerulein-induced AP. Male Sprague Dawley rats (n = 7-8/group) received 7 injections of caerulein (50 μg/kg) at 12, 24, 48, 72, 96, or 120 hours before measurement of lung impedance mechanics. Bronchoalveolar lavage (BAL), plasma, pancreatic, and lung tissue were collected to determine pancreatic and lung measures of acute inflammation. AP developed between 12 and 24 hours, as indicated by increased plasma amylase activity and pancreatic myeloperoxidase (MPO) activity, edema, and abnormal acinar cells, before beginning to resolve by 48 hours. In the lung, MPO activity peaked at 12 and 96 hours, with BAL cytokine concentrations peaking at 12 hours, followed by lung edema at 24 hours, and BAL cell count at 48 hours. Importantly, no significant changes in BAL protein concentration or arterial blood gas-pH levels were evident over the same period, and only modest changes were observed in respiratory mechanics. Caerulein-induced AP results in minor lung injury, which is not sufficient to allow protein permeability and substantially alter respiratory mechanics.

  14. Use of Metal Oxide Nanoparticle Band Gap to Develop a Predictive Paradigm for Oxidative Stress and Acute Pulmonary Inflammation

    PubMed Central

    Zhang, Haiyuan; Ji, Zhaoxia; Xia, Tian; Meng, Huan; Low-Kam, Cecile; Liu, Rong; Pokhrel, Suman; Lin, Sijie; Wang, Xiang; Liao, Yu-Pei; Wang, Meiying; Li, Linjiang; Rallo, Robert; Damoiseaux, Robert; Telesca, Donatello; Mädler, Lutz; Cohen, Yoram; Zink, Jeffrey I.; Nel, Andre E.

    2014-01-01

    We demonstrate for 24 metal oxide (MOx) nanoparticles that it is possible to use conduction band energy levels to delineate their toxicological potential at cellular and whole animal levels. Among the materials, the overlap of conduction band energy (Ec) levels with the cellular redox potential (−4.12 to −4.84 eV) was strongly correlated to the ability of Co3O4, Cr2O3, Ni2O3, Mn2O3 and CoO nanoparticles to induce oxygen radicals, oxidative stress and inflammation. This outcome is premised on permissible electron transfers from the biological redox couples that maintain the cellular redox equilibrium to the conduction band of the semiconductor particles. Both single parameter cytotoxic as well as multi-parameter oxidative stress assays in cells showed excellent correlation to the generation of acute neutrophilic inflammation and cytokine responses in the lungs of CB57 Bl/6 mice. Co3O4, Ni2O3, Mn2O3 and CoO nanoparticles could also oxidize cytochrome c as a representative redox couple involved in redox homeostasis. While CuO and ZnO generated oxidative stress and acute pulmonary inflammation that is not predicted by Ec levels, the adverse biological effects of these materials could be explained by their solubility, as demonstrated by ICP-MS analysis. Taken together, these results demonstrate, for the first time, that it is possible to predict the toxicity of a large series of MOx nanoparticles in the lung premised on semiconductor properties and an integrated in vitro/in vivo hazard ranking model premised on oxidative stress. This establishes a robust platform for modeling of MOx structure-activity relationships based on band gap energy levels and particle dissolution. This predictive toxicological paradigm is also of considerable importance for regulatory decision-making about this important class of engineered nanomaterials. PMID:22502734

  15. The Resolution Code of Acute Inflammation: Novel Pro-Resolving Lipid Mediators in Resolution

    PubMed Central

    Serhan, Charles N.; Chiang, Nan; Dalli, Jesmond

    2015-01-01

    Studies into the mechanisms in resolution of self-limited inflammation and acute reperfusion injury have uncovered a new genus of pro-resolving lipid mediators coined specialized pro-resolving mediators (SPM) including lipoxins, resolvins, protectins and maresins that are each temporally produced by resolving-exudates with distinct actions for return to homeostasis. SPM evoke potent anti-inflammatory and novel pro-resolving mechanisms as well as enhance microbial clearance. While born in inflammation-resolution, SPM are conserved structures with functions discovered in microbial defense, pain, organ protection and tissue regeneration, wound healing, cancer, reproduction, and neurobiology-cognition. This review covers these SPM mechanisms and other new omega-3 PUFA pathways that open their path for functions in resolution physiology. PMID:25857211

  16. Novel translational model of resolving inflammation triggered by UV‐killed E. coli

    PubMed Central

    Motwani, Madhur P; Flint, Julia D; De Maeyer, Roel PH; Fullerton, James N; Smith, Andrew M; Marks, Daniel JB

    2016-01-01

    Abstract Whilst numerous studies investigating the aetiology of inflammatory diseases have been performed in rodents, the applicability of these data to human pathophysiology is frequently debated. Regardless of the strengths and weaknesses of rodent models in biomedical research, there is a need to develop models of experimental inflammation in humans. Here, we describe a self‐resolving acute inflammatory response triggered by the intradermal injection of UV‐killed Escherichia coli into the forearm of healthy volunteers. Cells and exudates were harvested from onset to resolution by applying negative pressure over the inflamed site. Onset was characterized by high blood flow, neutrophilia and peak levels of pro‐inflammatory cytokines, whilst resolution showed a decline in blood blow, reduction in neutrophils, increase in monocytes/macrophages and waning of classic pro‐inflammatory cytokine levels. An anti‐inflammatory effect, defined as suppression of onset phase events, was demonstrated by administering naproxen, a conventional non‐steroidal anti‐inflammatory drug. In summary, this model of resolving acute inflammation is minimally invasive, highly tractable and allows simultaneous investigation of the vascular response, cellular trafficking and chemical mediator profile of onset and resolution phases of acute inflammation in humans. It can serve as a translational platform to provide mechanistic insights and to test the clinical efficacy of novel anti‐inflammatory and pro‐resolving drugs, and also as a tool in patients to explore inherent defects in resolution pathways. PMID:27499924

  17. Introduction of an agent-based multi-scale modular architecture for dynamic knowledge representation of acute inflammation

    PubMed Central

    An, Gary

    2008-01-01

    Background One of the greatest challenges facing biomedical research is the integration and sharing of vast amounts of information, not only for individual researchers, but also for the community at large. Agent Based Modeling (ABM) can provide a means of addressing this challenge via a unifying translational architecture for dynamic knowledge representation. This paper presents a series of linked ABMs representing multiple levels of biological organization. They are intended to translate the knowledge derived from in vitro models of acute inflammation to clinically relevant phenomenon such as multiple organ failure. Results and Discussion ABM development followed a sequence starting with relatively direct translation from in-vitro derived rules into a cell-as-agent level ABM, leading on to concatenated ABMs into multi-tissue models, eventually resulting in topologically linked aggregate multi-tissue ABMs modeling organ-organ crosstalk. As an underlying design principle organs were considered to be functionally composed of an epithelial surface, which determined organ integrity, and an endothelial/blood interface, representing the reaction surface for the initiation and propagation of inflammation. The development of the epithelial ABM derived from an in-vitro model of gut epithelial permeability is described. Next, the epithelial ABM was concatenated with the endothelial/inflammatory cell ABM to produce an organ model of the gut. This model was validated against in-vivo models of the inflammatory response of the gut to ischemia. Finally, the gut ABM was linked to a similarly constructed pulmonary ABM to simulate the gut-pulmonary axis in the pathogenesis of multiple organ failure. The behavior of this model was validated against in-vivo and clinical observations on the cross-talk between these two organ systems Conclusion A series of ABMs are presented extending from the level of intracellular mechanism to clinically observed behavior in the intensive care setting

  18. Intratendinous Injection of Hyaluronate Induces Acute Inflammation: A Possible Detrimental Effect

    PubMed Central

    Wu, Po-Ting; Jou, I-Ming; Kuo, Li-Chieh; Su, Fong-Chin

    2016-01-01

    Hyaluronate (HA) is therapeutic for tendinopathy, but an intratendinous HA injection is usually painful; thus, it is not suggested for clinical practice. However, there are no studies on the histopathological changes after an intratendinous HA injection. We hypothesized that an HA injection would induce more-acute inflammation than that induced by an injection of phosphate buffered saline (PBS). Thirty-two rats were randomly divided into 4 post-injection groups (n = 8): day 3, day 7, day 28, and day 42. HA (0.1 c.c.) was, using ultrasound guidance, intratendinously injected into each left Achilles tendon, and PBS (0.1 c.c.) into each right one. For each group, both Achilles tendons of 3 control-group rats (n = 6) were given only needle punctures. The histopathological score, ED1+ and ED2+ macrophage densities, interleukin (IL)-1β expression, and the extent of neovascularization were evaluated. In both experimental groups, each Achilles tendon showed significant histopathological changes and inflammation compatible with acute tendon injury until day 42. The HA group showed more-significant (p < 0.05) histopathological changes, higher ED1+ and ED2+ macrophage density, and higher IL-1β expression than did the PBS group. The neovascularization area was also significantly (p < 0.05) greater in the HA group, except on day 3. Both HA and PBS induced acute tendon injury and inflammation, sequential histopathological changes, ED1+ and ED2+ macrophage accumulation, IL-1β expression, and neovascularization until post-injection day 42.HA induced more-severe injury than did PBS. Therefore, an intratendinous HA injection should be avoided. PMID:27176485

  19. Exosomes from Human Dental Pulp Stem Cells Suppress Carrageenan-Induced Acute Inflammation in Mice.

    PubMed

    Pivoraitė, Ugnė; Jarmalavičiūtė, Akvilė; Tunaitis, Virginijus; Ramanauskaitė, Giedrė; Vaitkuvienė, Aida; Kašėta, Vytautas; Biziulevičienė, Genė; Venalis, Algirdas; Pivoriūnas, Augustas

    2015-10-01

    The primary goal of this study was to examine the effects of human dental pulp stem cell-derived exosomes on the carrageenan-induced acute inflammation in mice. Exosomes were purified by differential ultracentrifugation from the supernatants of stem cells derived from the dental pulp of human exfoliated deciduous teeth (SHEDs) cultivated in serum-free medium. At 1 h post-carrageenan injection, exosomes derived from supernatants of 2 × 10(6) SHEDs were administered by intraplantar injection to BALB/c mice; 30 mg/kg of prednisolone and phosphate-buffered saline (PBS) were used as positive and negative controls, respectively. Edema was measured at 6, 24, and 48 h after carrageenan injection. For the in vivo imaging experiments, AngioSPARK750, Cat B 750 FAST, and MMPSense 750 FAST were administered into the mouse tail vein 2 h post-carrageenan injection. Fluorescence images were acquired at 6, 24, and 48 h after edema induction by IVIS Spectrum in vivo imaging system. Exosomes significantly reduced the carrageenan-induced edema at all the time points studied (by 39.5, 41.6, and 25.6% at 6, 24, and 48 h after injection, respectively), to similar levels seen with the positive control (prednisolone). In vivo imaging experiments revealed that, both exosomes and prednisolone suppress activities of cathepsin B and matrix metalloproteinases (MMPs) at the site of carrageenan-induced acute inflammation, showing more prominent effects of prednisolone at the early stages, while exosomes exerted their suppressive effects gradually and at later time points. Our study demonstrates for the first time that exosomes derived from human dental pulp stem cells suppress carrageenan-induced acute inflammation in mice.

  20. Pattern of airway inflammation and its determinants in children with acute severe asthma.

    PubMed

    Gibson, P G; Norzila, M Z; Fakes, K; Simpson, J; Henry, R L

    1999-10-01

    The aim of this study was to examine the relationship between sputum cell counts and clinical variables in children with an acute exacerbation of asthma. Sputum was successfully obtained from 37 of 42 children presenting to the Emergency Department with acute asthma, using ultrasonically nebulized normal saline (n = 19) or spontaneous expectoration (n = 18). Sputum portions were selected and dispersed, and total and differential cell counts were performed. Sputum supernatant was assessed for eosinophil cationic protein (ECP), interleukin (IL)-5, and IL-8. The exacerbations were of 3 inflammatory cell patterns: eosinophilic (n = 16 or 43% of total), combined eosinophilic/neutrophilic (E/N; n = 13.3 or 35% of total), or noneosinophilic (n = 8 or 22% of total). IL-5 was highest in eosinophilic exacerbations. Combined E/N exacerbations had increased mast cells (77%) and higher sputum ECP levels than eosinophilic exacerbations: 2,146 ng/mL vs. 666 ng/mL (P = 0.04). The speed of onset of the exacerbation was not related to the inflammatory cell profile. Logistic regression identified maintenance asthma treatment (odds ratio (OR), 5.9; 95% confidence interval (CI), 1.3-26.8) and lung function during the acute episode (OR, 4.0; 95% CI, 1.7-93) as significantly associated with the intensity of sputum eosinophilia. Eosinophils were lowest in children who received maintenance treatment with oral corticosteroids compared to those with no background asthma preventer therapy (P = 0.001). In conclusion, we identified three distinct patterns of airway inflammation in children with acute asthma; they included increased eosinophils, combined eosinophilic-neutrophilic infiltration, and a noneosinophilic pattern. Eosinophil degranulation was greatest with the combined eosinophilic/neutrophilic pattern of airway inflammation. Sputum eosinophils were associated with clinical severity, and background asthma therapy, but not with outcome, nor with speed of onset of exacerbations. These

  1. Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure

    PubMed Central

    Wen, Zongmei; Lei, Zhen; Yao, Lu; Jiang, Ping; Gu, Tao; Ren, Feng; Liu, Yan; Gou, Chunyan; Li, Xiuhui; Wen, Tao

    2016-01-01

    Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients' sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use. PMID:27685635

  2. Eupafolin nanoparticle improves acute renal injury induced by LPS through inhibiting ROS and inflammation.

    PubMed

    Zhang, Hao; Chen, Ming-Kun; Li, Ke; Hu, Cheng; Lu, Min-Hua; Situ, Jie

    2017-01-01

    Acute renal injury is a common severe clinical syndrome, occurring in many clinical situations. It is necessary to explore effective drugs to treat it. Eupafolin is a flavonoid compound, derived from Phyla nodiflora, which has been previously reported to possess a variety of pharmacological activities, including anti-inflammatory and antioxidant effects. However, it is known little about how it works in acute renal injury. Also, eupafolin is characterized by skin penetration and poor water solubility, limiting its clinical applications. Thus, we synthesized an eupafolin nanoparticle delivery system. We found that eupafolin nanoparticle could address the physicochemical defects of raw eupafolin and increase water solubility without any toxicity to normal renal cells via reducing particle size. Eupafolin nanoparticle attenuated LPS-induced acute renal injury in mice through inhibiting oxidative stress and inflammation accompanied with up-regulated SOD activity and down-regulated pro-inflammatory cytokines. Additionally, inactivation of NF-κB and MAPKs of p38, ERK1/2 and JNK signaling pathways was a main molecular mechanism by which eupafolin nanoparticle improved renal injury. Together, eupafolin nanoparticle exhibits effective anti-oxidant and anti-inflammatory activities, which could be used as a potential drug to ameliorate acute renal injury clinically.

  3. Immunomodulatory effects of high-protein diet with resveratrol supplementation on radiation-induced acute-phase inflammation in rats.

    PubMed

    Kim, Kyoung-Ok; Park, HyunJin; Chun, Mison; Kim, Hyun-Sook

    2014-09-01

    We hypothesized that a high-protein diet and/or resveratrol supplementation will improve acute inflammatory responses in rats after receiving experimental abdominal radiation treatment (ART). Based on our previous study, the period of 10 days after ART was used as an acute inflammation model. Rats were exposed to a radiation dose of 17.5 Gy and were supplied with a control (C), 30% high-protein diet (HP), resveratrol supplementation (RES), or HP with RES diet ([HP+RES]). At day 10 after ART, we measured profiles of lipids, proteins, and immune cells in blood. The levels of clusters of differentiating 4(+) (CD4(+)) cells and regulatory T cells, serum proinflammatory cytokines, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine were also measured. ART caused significant disturbances of lipid profiles by increasing triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C), and decreasing high-density lipoprotein cholesterol. The proinflammatroy cytokine levels were also increased by ART. All the experimental diets (HP, RES, and [HP+RES]) significantly decreased levels of TG, monocytes, proinflammatory cytokines, and 8-OHdG, whereas the platelet counts were increased. In addition, the HP and [HP+RES] diets decreased the concentrations of plasma LDL-C and total cholesterol. Also, the HP and RES diets decreased regulatory T cells compared with those of the control diet in ART group. Further, the HP diet led to a significant recovery of white blood cell counts, as well as increased percentages of lymphocyte and decreased percentages of neutrophils. In summary, RES appeared to be significantly effective in minimizing radiation-induced damage to lipid metabolism and immune responses. Our study also demonstrated the importance of dietary protein intake in recovering from acute inflammation by radiation.

  4. Acute Respiratory Inflammation in Children and Black Carbon in Ambient Air before and during the 2008 Beijing Olympics

    PubMed Central

    Lin, Weiwei; Huang, Wei; Hu, Min; Brunekreef, Bert; Zhang, Yuanhang; Liu, Xingang; Cheng, Hong; Gehring, Ulrike; Li, Chengcai; Tang, Xiaoyan

    2011-01-01

    Background: Epidemiologic evidence for a causative association between black carbon (BC) and health outcomes is limited. Objectives: We estimated associations and exposure–response relationships between acute respiratory inflammation in schoolchildren and concentrations of BC and particulate matter with an aerodynamic diameter of ≤ 2.5 μm (PM2.5) in ambient air before and during the air pollution intervention for the 2008 Beijing Olympics. Methods: We measured exhaled nitric oxide (eNO) as an acute respiratory inflammation biomarker and hourly mean air pollutant concentrations to estimate BC and PM2.5 exposure. We used 1,581 valid observations of 36 subjects over five visits in 2 years to estimate associations of eNO with BC and PM2.5 according to generalized estimating equations with polynomial distributed-lag models, controlling for body mass index, asthma, temperature, and relative humidity. We also assessed the relative importance of BC and PM2.5 with two-pollutant models. Results: Air pollution concentrations and eNO were clearly lower during the 2008 Olympics. BC and PM2.5 concentrations averaged over 0–24 hr were strongly associated with eNO, which increased by 16.6% [95% confidence interval (CI), 14.1–19.2%] and 18.7% (95% CI, 15.0–22.5%) per interquartile range (IQR) increase in BC (4.0 μg/m3) and PM2.5 (149 μg/m3), respectively. In the two-pollutant model, estimated effects of BC were robust, but associations between PM2.5 and eNO decreased with adjustment for BC. We found that eNO was associated with IQR increases in hourly BC concentrations up to 10 hr after exposure, consistent with effects primarily in the first hours after exposure. Conclusions: Recent exposure to BC was associated with acute respiratory inflammation in schoolchildren in Beijing. Lower air pollution levels during the 2008 Olympics also were associated with reduced eNO. PMID:21642045

  5. Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages

    PubMed Central

    Kim, Seung-Jae; Cha, Ji-Young; Kang, Hye Suk; Lee, Jae-Ho; Lee, Ji Yoon; Park, Jae-Hyung; Bae, Jae-Hoon; Song, Dae-Kyu; Im, Seung-Soon

    2016-01-01

    Corosolic acid (CA), a triterpenoid compound isolated from Lagerstroemia speciosa L. (Banaba) leaves, exerts anti-inflammatory effects by regulating phosphorylation of interleukin receptor- associated kinase (IRAK)-2 via the NF-κB cascade. However, the protective effect of CA against endotoxic shock has not been reported. LPS (200 ng/mL, 30 min) induced phosphorylation of IRAK-1 and treatment with CA (10 μM) significantly attenuated this effect. In addition, CA also reduced protein levels of NLRP3 and ASC which are the main components of the inflammasome in BMDMs. LPS-induced inflammasome assembly through activation of IRAK-1 was down-regulated by CA challenge. Treatment with Bay11-7082, an inhibitor of IκB-α, had no effect on CA-mediated inhibition of IRAK-1 activation, indicating that CA-mediated attenuation of IRAK-1 phosphorylation was independent of NF-κB signaling. These results demonstrate that CA ameliorates acute inflammation in mouse BMDMs and CA may be useful as a pharmacological agent to prevent acute inflammation. [BMB Reports 2016; 49(5): 276-281] PMID:26615974

  6. Changing glucocorticoid action: 11β-hydroxysteroid dehydrogenase type 1 in acute and chronic inflammation.

    PubMed

    Chapman, Karen E; Coutinho, Agnes E; Zhang, Zhenguang; Kipari, Tiina; Savill, John S; Seckl, Jonathan R

    2013-09-01

    Since the discovery of cortisone in the 1940s and its early success in treatment of rheumatoid arthritis, glucocorticoids have remained the mainstay of anti-inflammatory therapies. However, cortisone itself is intrinsically inert. To be effective, it requires conversion to cortisol, the active glucocorticoid, by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Despite the identification of 11β-HSD in liver in 1953 (which we now know to be 11β-HSD1), its physiological role has been little explored until recently. Over the past decade, however, it has become apparent that 11β-HSD1 plays an important role in shaping endogenous glucocorticoid action. Acute inflammation is more severe with 11β-HSD1-deficiency or inhibition, yet in some inflammatory settings such as obesity or diabetes, 11β-HSD1-deficiency/inhibition is beneficial, reducing inflammation. Current evidence suggests both beneficial and detrimental effects may result from 11β-HSD1 inhibition in chronic inflammatory disease. Here we review recent evidence pertaining to the role of 11β-HSD1 in inflammation. This article is part of a Special Issue entitled 'CSR 2013'.

  7. Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection

    PubMed Central

    Akthar, Samia; Patel, Dhiren F.; Beale, Rebecca C.; Peiró, Teresa; Xu, Xin; Gaggar, Amit; Jackson, Patricia L.; Blalock, J. Edwin; Lloyd, Clare M.; Snelgrove, Robert J.

    2015-01-01

    Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline–glycine–proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed. PMID:26400771

  8. Violacein Treatment Modulates Acute and Chronic Inflammation through the Suppression of Cytokine Production and Induction of Regulatory T Cells.

    PubMed

    Verinaud, Liana; Lopes, Stefanie Costa Pinto; Prado, Isabel Cristina Naranjo; Zanucoli, Fábio; Alves da Costa, Thiago; Di Gangi, Rosária; Issayama, Luidy Kazuo; Carvalho, Ana Carolina; Bonfanti, Amanda Pires; Niederauer, Guilherme Francio; Duran, Nelson; Costa, Fábio Trindade Maranhão; Oliveira, Alexandre Leite Rodrigues; Höfling, Maria Alice da Cruz; Machado, Dagmar Ruth Stach; Thomé, Rodolfo

    2015-01-01

    Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola), a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 μg of LPS and were treated with viola (3.5mg/kg) via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naïve mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE)-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+). We also found that adoptive transfer of viola-elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation) and stimulation of regulatory T cells (in chronic inflammation). New studies must be conducted in order to

  9. Salmon Thrombin as a Treatment to Attenuate Acute Pain and Promote Tissue Healing by Modulating Local Inflammation

    DTIC Science & Technology

    2012-12-01

    trauma and in association with the absence of pain . Early cleavage of PAR1 by thrombin may provide its anti- nociceptive properties. We were very...1-1002 TITLE: Salmon Thrombin as a Treatment to Attenuate Acute Pain and Promote Tissue Healing by Modulating Local Inflammation... Pain and 5a. CONTRACT NUMBER Promote Tissue Healing by Modulating Local Inflammation 5b. GRANT NUMBER W81XWH-10-1-1002 5c. PROGRAM ELEMENT

  10. Violacein Treatment Modulates Acute and Chronic Inflammation through the Suppression of Cytokine Production and Induction of Regulatory T Cells

    PubMed Central

    Verinaud, Liana; Lopes, Stefanie Costa Pinto; Prado, Isabel Cristina Naranjo; Zanucoli, Fábio; Alves da Costa, Thiago; Di Gangi, Rosária; Issayama, Luidy Kazuo; Carvalho, Ana Carolina; Bonfanti, Amanda Pires; Niederauer, Guilherme Francio; Duran, Nelson; Costa, Fábio Trindade Maranhão; Oliveira, Alexandre Leite Rodrigues; Höfling, Maria Alice da Cruz; Machado, Dagmar Ruth Stach; Thomé, Rodolfo

    2015-01-01

    Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola), a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 μg of LPS and were treated with viola (3.5mg/kg) via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naïve mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE)-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+). We also found that adoptive transfer of viola-elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation) and stimulation of regulatory T cells (in chronic inflammation). New studies must be conducted in order to

  11. Effect of immunologic reactions on rat intestinal epithelium. Correlation of increased permeability to chromium 51-labeled ethylenediaminetetraacetic acid and ovalbumin during acute inflammation and anaphylaxis

    SciTech Connect

    Ramage, J.K.; Stanisz, A.; Scicchitano, R.; Hunt, R.H.; Perdue, M.H.

    1988-06-01

    In these studies we compared jejunal permeability to two probes--chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) (mol wt, 360) and ovalbumin (mol wt, 45,000)--under control conditions, during acute intestinal inflammation, and in response to systemic anaphylaxis. Acute inflammation was produced after infection with Nippostrongylus brasiliensis and rats were studied at day 0 (control), day 4 (early), day 10 (acute), and day 35 (postinfection). At the latter stage, immune rats were also studied during anaphylaxis induced by i.v. N. brasiliensis antigen. In each study, blood and urine were sampled over 5 h after the probes were simultaneously injected into ligated loops in anesthetized rats. In controls, small quantities (less than 0.04% and 0.002% of the administered dose for 51Cr-EDTA and ovalbumin, respectively) appeared in the circulation and plateaued at 1 h. During acute inflammation, the appearance of both probes continued to increase with time. Compared with controls, 5-h values for 51Cr-EDTA and ovalbumin were (a) significantly elevated at day 4 (p less than 0.005), (b) increased approximately 20-fold at day 10 (p less than 0.005 and less than 0.01, respectively), and (c) normal at day 35. Urinary recovery of 51Cr-EDTA followed the same pattern. During anaphylaxis, appearance of the probes in the circulation increased at 1 h to values approximately 10-fold those in controls (p less than 0.001 and less than 0.01, for 51Cr-EDTA and ovalbumin, respectively), and then declined. Urinary recovery of 51Cr-EDTA over 5 h was also significantly increased. We conclude that epithelial barrier function becomes impaired during both acute inflammation and anaphylaxis. In this rat model, gut permeability changes to 51Cr-EDTA reflect gut permeability changes to macromolecular antigens.

  12. Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques

    PubMed Central

    Pandrea, Ivona; Xu, Cuiling; Stock, Jennifer L.; Frank, Daniel N.; Ma, Dongzhu; Policicchio, Benjamin B.; He, Tianyu; Kristoff, Jan; Cornell, Elaine; Haret-Richter, George S.; Trichel, Anita; Ribeiro, Ruy M.; Tracy, Russell; Wilson, Cara; Landay, Alan L.; Apetrei, Cristian

    2016-01-01

    Increased chronic immune activation and inflammation are hallmarks of HIV/SIV infection and are highly correlated with progression to AIDS and development of non-AIDS comorbidities, such as hypercoagulability and cardiovascular disease. Intestinal dysfunction resulting in microbial translocation has been proposed as a lead cause of systemic immune activation and hypercoagulability in HIV/SIV infection. Our goal was to assess the biological and clinical impact of a therapeutic strategy designed to reduce microbial translocation through reduction of the microbial content of the intestine (Rifaximin-RFX) and of gut inflammation (Sulfasalazine-SFZ). RFX is an intraluminal antibiotic that was successfully used in patients with hepatic encephalopathy. SFZ is an antiinflammatory drug successfully used in patients with mild to moderate inflammatory bowel disease. Both these clinical conditions are associated with increased microbial translocation, similar to HIV-infected patients. Treatment was administered for 90 days to five acutely SIV-infected pigtailed macaques (PTMs) starting at the time of infection; seven untreated SIVsab-infected PTMs were used as controls. RFX+SFZ were also administered for 90 days to three chronically SIVsab-infected PTMs. RFX+SFZ administration during acute SIVsab infection of PTMs resulted in: significantly lower microbial translocation, lower systemic immune activation, lower viral replication, better preservation of mucosal CD4+ T cells and significantly lower levels of hypercoagulation biomarkers. This effect was clear during the first 40 days of treatment and was lost during the last stages of treatment. Administration of RFX+SFZ to chronically SIVsab–infected PTMs had no discernible effect on infection. Our data thus indicate that early RFX+SFZ administration transiently improves the natural history of acute and postacute SIV infection, but has no effect during chronic infection. PMID:26764484

  13. Controlling Acute Inflammation with Fast Releasing Dexamethasone-PLGA Microsphere/PVA Hydrogel Composites for Implantable Devices

    PubMed Central

    Bhardwaj, Upkar; Sura, Radhakrishna; Papadimitrakopoulos, Fotios; Burgess, Diane J.

    2007-01-01

    Background Continuous release of dexamethasone from PLGA microsphere/PVA hydrogel composites has been shown to suppress the inflammatory tissue reaction in response to subcutaneously implanted foreign material for a period of one month. The scope of the present work is to investigate whether suppressing the initial acute inflammatory phase with fast releasing dexamethasone-PLGA microsphere/PVA composites (that release the drug over a period of one week) would prevent the development of a foreign body reaction in response to implantation in the subcutaneous tissue using a rat model. Methods Dexamethasone loaded PLGA microspheres were prepared using the solvent evaporation method. In vitro release from microspheres was analyzed using USP apparatus 4 in phosphate buffered saline (PBS) at 37°C. Composites were fabricated in 18G needles by freeze-thaw cycling the PVA/microsphere dispersion. The composites were implanted in the subcutaneous tissue of anesthetized rats. The pharmacodynamic effect was evaluated by histological examination of the tissue surrounding the composites at pre-determined time points. Results In vitro release studies showed that most of the drug entrapped in the microspheres was released within one week. At days 3 and 8, these fast releasing dexamethasone containing composites suppressed the acute phase of inflammation but did not prevent the development of an inflammatory reaction after dexamethasone was completely released from the composites. By day 30, chronic inflammation and fibrosis were observed in the tissue surrounding the drug-containing composites. On days 3 and 8, the number of inflammatory cells in the vicinity of the dexamethasone containing composites was similar to that in normal tissue. However, the number of inflammatory cells was higher in drug-containing composites as compared to drug-free composites by day 30. This was due to the inflammation being in a more advanced stage in drug-free composites where a granulomatous

  14. Topical application of a platelet activating factor receptor agonist suppresses phorbol ester-induced acute and chronic inflammation and has cancer chemopreventive activity in mouse skin.

    PubMed

    Sahu, Ravi P; Rezania, Samin; Ocana, Jesus A; DaSilva-Arnold, Sonia C; Bradish, Joshua R; Richey, Justin D; Warren, Simon J; Rashid, Badri; Travers, Jeffrey B; Konger, Raymond L

    2014-01-01

    Platelet activating factor (PAF) has long been associated with acute edema and inflammatory responses. PAF acts by binding to a specific G-protein coupled receptor (PAF-R, Ptafr). However, the role of chronic PAF-R activation on sustained inflammatory responses has been largely ignored. We recently demonstrated that mice lacking the PAF-R (Ptafr-/- mice) exhibit increased cutaneous tumorigenesis in response to a two-stage chemical carcinogenesis protocol. Ptafr-/- mice also exhibited increased chronic inflammation in response to phorbol ester application. In this present study, we demonstrate that topical application of the non-hydrolysable PAF mimetic (carbamoyl-PAF (CPAF)), exerts a potent, dose-dependent, and short-lived edema response in WT mice, but not Ptafr -/- mice or mice deficient in c-Kit (c-KitW-sh/W-sh mice). Using an ear inflammation model, co-administration of topical CPAF treatment resulted in a paradoxical decrease in both acute ear thickness changes associated with a single PMA application, as well as the sustained inflammation associated with chronic repetitive PMA applications. Moreover, mice treated topically with CPAF also exhibited a significant reduction in chemical carcinogenesis. The ability of CPAF to suppress acute and chronic inflammatory changes in response to PMA application(s) was PAF-R dependent, as CPAF had no effect on basal or PMA-induced inflammation in Ptafr-/- mice. Moreover, c-Kit appears to be necessary for the anti-inflammatory effects of CPAF, as CPAF had no observable effect in c-KitW-sh/W-sh mice. These data provide additional evidence that PAF-R activation exerts complex immunomodulatory effects in a model of chronic inflammation that is relevant to neoplastic development.

  15. Protective Effects of Proanthocyanidin on Cerulein-induced Acute Pancreatic Inflammation in Rats

    PubMed Central

    Akyuz, Cebrail; Sehirli, Ahmet Ozer; Topaloglu, Umit; Ogunc, Ayliz Velioglu; Cetinel, Sule; Sener, Goksel

    2009-01-01

    Background The aim of this study was to assess the possible protective effect of proanthocyanidin against cerulein-induced acute pancreatic inflammation (AP) and oxidative injury. Methods Sprague-Dawley rats were pretreated with proanthocyanidine (100 mg/kg, orally) or saline 15 min before cerulein was given by 20 µg/kg subcutaneously at 1-h intervals within 4 hours. Six hours after cerulein or saline injections, the animals were killed by decapitation. Blood samples were collected to analyze amylase, lipase, and proinflammatory cytokines (TNF-α and IL-1b). Pancreas tissues were taken for the determination of tissue glutathione (GSH) and malondialdehyde (MDA) levels, Na+, K+-ATPase and myeloperoxidase (MPO) activities. Formation of reactive oxygen species in pancreatic tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes, while the extent of tissue injury was analyzed microscopically. Results Acute pancreatitis caused a significant decrease in tissue GSH level and Na+, K+-ATPase activity, which was accompanied with significant increases in the pancreatic MDA, luminol and lucigenin chemiluminescences (CL) levels and MPO activity. Similarly TNF-α and IL-1β levels were elevated in the pancreatic group as compared to control group. On the other hand, proanthocyanidin treatment reversed all these biochemical indices, as well as histopathological alterations that were induced by cerulein. Conclusions Proanthocyanidine can ameliorate pancreatic injury induced by cerulein in rats, this result suggests that proanthocyanidin may have utility in treating acute pancreatititis. PMID:27956946

  16. Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study12

    PubMed Central

    van Vliet, Sara J; Di Giovanni, Valeria; Zhang, Ling; Richardson, Susan; van Rheenen, Patrick F

    2016-01-01

    Background: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear. Objective: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM. Design: Intestinal pathogens (n = 15), cytokines (n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6–59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling. Results: Fatal subjects (n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443–535 mg/kg feces) compared with 698 mg/kg feces (1438–244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112–22 ng/mL) compared with 2036 ng/mL (5800–149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831–131 ng/mL) compared with 3174 ng/mL (5819–357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation. Conclusions: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of

  17. Exacerbated skeletal muscle inflammation and calcification in the acute phase of infection by Mexican Trypanosoma cruzi DTUI strain.

    PubMed

    Vizcaíno-Castillo, Andrea; Jiménez-Marín, Andrea; Espinoza, Bertha

    2014-01-01

    A murine model was used to study the histopathological aspects and cytokine expression levels in skeletal muscle provoked by the infection with Mexican TcI strains. BALB/c mice were inoculated with the virulent Querétaro strain and the nonvirulent Ninoa strain. Parasite numbers were counted in blood and skeletal muscle at different times post-infection, and real time-PCR expression levels of the cytokines IL-12, IL-4, IL-10, IFN- γ , and TNF- α were evaluated. In the acute phase of infection, a high parasitic load, both in blood and skeletal muscle, was detected. The histopathological analyses showed an exacerbated inflammation and granulomatous-like infiltrate with the Querétaro strain. Interestingly, extensive calcification areas were observed in the skeletal muscle surrounded by inflammatory infiltrates. TNF- α and IL-10 expression exhibited a significant increase at the peak of infection. In summary, Querétaro strain, a Mexican TcI strain, is virulent enough to induce high inflammation and calcification in skeletal muscle of the hind limbs, which could be related to high expression levels of TNF- α .

  18. IL-10 distinguishes a unique population of activated, effector-like CD8(+) T cells in murine acute liver inflammation.

    PubMed

    Rood, Julia E; Canna, Scott W; Weaver, Lehn K; Tobias, John W; Behrens, Edward M

    2017-04-01

    Immune-mediated liver injury is a central feature of hyperinflammatory diseases, such as hemophagocytic syndromes, yet the immunologic mechanisms underlying those processes are incompletely understood. In this study, we used the toll-like receptor 9 (TLR9)-mediated model of a hemophagocytic syndrome known as macrophage activation syndrome (MAS) to dissect the predominant immune cell populations infiltrating the liver during inflammation. We identified CD8(+) T cells that unexpectedly produce interleukin-10 (IL-10) in addition to interferon-γ (IFN-γ) as a major hepatic population induced by TLR9 stimulation. Despite their ability to produce this anti-inflammatory cytokine, IL-10(+) hepatic CD8(+) T cells in TLR9-MAS mice did not resemble CD8(+) T suppressor cells. Instead, the induction of these cells occurred independently of antigen stimulation and was partially dependent on IFN-γ. IL-10(+) hepatic CD8(+) T cells demonstrated an activated phenotype and high turnover rate, consistent with an effector-like identity. Transcriptional analysis of this population confirmed a gene signature of effector CD8(+) T cells yet suggested responsiveness to liver injury-associated growth factors. Together, these findings suggest that IL-10(+) CD8(+) T cells induced by systemic inflammation to infiltrate the liver have initiated an inflammatory, rather than regulatory, program and may thus have a pathogenic role in severe, acute hepatitis.

  19. Cerebrolysin reduces mechanical allodynia in a rodent model of peripheral inflammation.

    PubMed

    Morales-Medina, Julio Cesar; Griffiths, Natalie H; Flores, Gonzalo; Mastranzo, Virginia M; Iannitti, Tommaso

    2017-03-06

    Cerebrolysin (Cbl) is a neuropeptide preparation of cerebroproteins that crosses the blood brain barrier displaying neuroprotective properties and promoting neurogenesis. Limited evidence exists on the efficacy of Cbl for the treatment of pain, with many studies focusing on neuropathic pain associated to diabetes. Therefore, we designed a study to test the hypothesis that Cbl would reduce mechanical allodynia in a rat model of peripheral inflammation induced by administration of complete Freund's adjuvant (CFA) in the hind paw. We found that acute administration of Cbl was effective in reducing mechanical allodynia but not peripheral inflammation in the CFA model of inflammatory pain. Our investigation supports further investigation into the therapeutic applications and mechanisms underlying the anti-allodynic effects of Cbl in inflammatory pain.

  20. Taraxerol, a pentacyclic triterpene from Abroma augusta leaf, attenuates acute inflammation via inhibition of NF-κB signaling.

    PubMed

    Khanra, Ritu; Dewanjee, Saikat; Dua, Tarun K; Bhattacharjee, Niloy

    2017-04-01

    Abroma augusta L. (Malvaceae) leaf is traditionally used to treat inflammatory disorders. In our laboratory, we have scientifically validated the anti-inflammatory effect of A. augusta leaf extract. In this study, it has been aimed to evaluate in vivo anti-inflammatory effect of taraxerol isolated from the methanol extract of A. augusta leaf. It was further intended to find out the probable mechanism of anti-inflammatory effect of taraxerol. The anti-inflammatory effect of taraxerol (5 and 10mg/kg, i.p.) was measured employing carrageenan-induced paw edema model of acute inflammation. The carrageenan injection resulted significant edema formation in the right paw when compared with un-injected left paw. However, taraxerol (10mg/kg) treatment could significantly (p<0.05-0.01) attenuate carrageenan induced paw edema 2h onward. The effect of taraxerol at the dose of 5mg/kg was found to be significant (p<0.05) only after 4h of carrageenan treatment. Taraxerol (10mg/kg) treatment could significantly (p<0.01) attenuate carrageenan mediated up-regulation in the levels of IL 1β, IL 6, IL 12 and TNF α in the right paw tissues. In search of molecular mechanism, taraxerol (10mg/kg) could significantly (p<0.05-0.01) reinstate carrageenan provoked NF-κB signaling and thereby caused significant down-regulation in the expressions of COX-2 (p<0.01) and iNOS (p<0.05). In conclusion, taraxerol would attenuate acute inflammation via inhibition of NF-κB signaling.

  1. In vivo effects of phenylbutazone on inflammation and cartilage-derived biomarkers in equine joints with acute synovitis.

    PubMed

    de Grauw, J C; van Loon, J P A M; van de Lest, C H A; Brunott, A; van Weeren, P R

    2014-07-01

    Although phenylbutazone (PBZ) is commonly used in equine orthopaedic practice, little is known about its in vivo effects on joint inflammation and cartilage turnover. This study investigates the effects of PBZ on inflammatory parameters, matrix metalloproteinase (MMP) activity and cartilage biomarkers in equine joints with acute synovitis. In a two-period cross-over study, transient synovitis was induced at T = 0 h in the middle carpal joint of seven ponies by lipopolysaccharide (LPS) injection. Ponies received PBZ (2 mg/kg PO twice daily) or placebo for 1 week, starting at T = 2 h. Arthroscopic assessment of the middle carpal joint was performed at T = -504, 48 and 672 h. Synovial fluid (SF) was sampled at T = -504, 0, 8, 24, 48, 168, 336 and 672 h and analysed for leukocytes and total protein, substance P, general MMP activity, glycosaminoglycans (GAG), collagen II cleavage marker C2C and synthesis marker CPII. Markers in PBZ- vs. placebo-treated joints were compared over time using a linear mixed model. LPS injection caused marked transient synovitis without visible cartilage changes. Substance P and general MMP activity were not significantly reduced by PBZ treatment, nor were SF GAG or C2C concentrations at any time point. Concentration of CPII was significantly lower at T = 24 and 168 h in PBZ treated joints compared to placebo. Although PBZ is clinically effective in treating acute synovitis, it does not limit inflammation-induced cartilage catabolism and may transiently reduce collagen anabolism as evidenced by SF markers.

  2. Anti-inflammatory effects of formoterol and ipratropium bromide against acute cadmium-induced pulmonary inflammation in rats.

    PubMed

    Zhang, Wenhui; Fievez, Laurence; Cheu, Esteban; Bureau, Fabrice; Rong, Weifang; Zhang, Fan; Zhang, Yong; Advenier, Charles; Gustin, Pascal

    2010-02-25

    In this study, the anti-inflammatory properties of formoterol and ipratropium bromide, alone or in combination, were investigated in a rat model of acute pulmonary inflammation induced by cadmium inhalation. Airway resistance and inflammatory responses, including matrix metalloproteinease-2 (MMP-2) and matrix metalloproteinease-9 (MMP-9) activities, were evaluated. Compared to values obtained in rats exposed to cadmium, pretreatment by bronchodilators administered alone significantly prevented the cadmium-induced increase of airway resistance. Formoterol elicited a significant decrease in total cell number, neutrophil and macrophage counts in bronchoalveolar lavage fluid, whereas ipratropium bromide reduced neutrophil numbers. The two compounds administered alone significantly attenuated the lung lesions associated with parenchyma inflammatory cell influx and congestion observed in the cadmium group. The increased MMP-9 activity was significantly attenuated. Although only formoterol induced a decrease protein concentration in bronchoalveolar lavage fluid, both compounds inhibited the pulmonary edema by reducing wet-to-dry weight ratio which returned to values similar to those recorded in the sham group. All the effects of formoterol on the cadmium-induced inflammatory responses were reversed by propranolol. Similar anti-inflammatory effects were obtained in rats pretreated with ilomastat which showed a significant reduction on inflammatory cell infiltration and MMP-9 activity in bronchoalveolar lavage fluid. Neither synergistic nor additive effects were obtained when the two bronchodilators were administered in combination. In conclusion, formoterol and ipratropium bromide partially protect the lungs against the inflammation by reducing neutrophilic infiltration. This protective effect is associated with reduced MMP-9 activity known to play an important pro-inflammatory role in acute inflammatory process.

  3. Mast cells modulate acute ozone-induced inflammation of the murine lung

    SciTech Connect

    Kleeberger, S.R.; Seiden, J.E.; Levitt, R.C.; Zhang, L.Y. )

    1993-11-01

    We hypothesized that mast cells modulate lung inflammation that develops after acute ozone (O3) exposure. Two tests were done: (1) genetically mast-cell-deficient (WBB6F1-W/Wv, WCB6F1-SI/SId) and bone-marrow-transplanted W/Wv mice were exposed to O3 or filtered air, and the inflammatory responses were compared with those of mast-cell-sufficient congenic mice (WBB6F1-(+)/+, WCB6F1-(+)/+); (2) genetically O3-susceptible C57BL/6J mice were treated pharmacologically with putative mast-cell modulators or vehicle, and the O3-induced inflammatory responses were compared. Mice were exposed to 1.75 ppm O3 or air for 3 h, and lung inflammation was assessed by bronchoalveolar lavage (BAL) 6 and 24 h after exposure. Relative to O3-exposed W/Wv and SI/SId mice, the mean numbers of lavageable polymorphonuclear leukocytes (PMNs) and total BAL protein concentration (a marker of permeability) were significantly greater in the respective O3-exposed normal congenic +/+ mice (p < 0.05). Mast cells were reconstituted in W/Wv mice by transplantation of bone marrow cells from congenic +/+ mice, and O3-induced lung inflammation was assessed in the mast-cell-replete W/Wv mice. After O3 exposure, the changes in lavageable PMNs and total protein of mast-cell-replete W/Wv mice were not different from age-matched normal +/+ control mice, and they were significantly greater than those of sham-transplanted W/Wv mice (p < 0.05). Genetically susceptible C57BL/6J mice were pretreated with a mast-cell stabilizer (nedocromil sodium), secretagogue (compound 48/80), or vehicle, and the mice were exposed to O3.

  4. Activation of the contact system and inflammation after thrombolytic therapy in patients with acute myocardial infarction.

    PubMed

    Merlini, Piera Angelica; Cugno, Massimo; Rossi, Marco L; Agricola, Pietro; Repetto, Alessandra; Fetiveau, Raffaella; Diotallevi, Paolo; Canosi, Umberto; Mannucci, Pier Mannuccio; Ardissino, Diego

    2004-04-01

    Thrombolytic therapy activates the contact system, and factor XII activation may activate the coagulation cascade and inflammation. It is not known whether an early inflammatory response is induced by thrombolytic therapy in patients with acute myocardial infarction (AMI). We prospectively measured the plasma levels of activated factor XII, cleaved kininogen, prothrombin fragment 1 + 2 (as indexes of the contact phase and coagulation activation), and interleukin-6 and C-reactive protein (CRP) (as indexes of inflammation) in 39 patients hospitalized for AMI within 12 hours of symptom onset: 26 receiving thrombolytic therapy and 13 heparin alone. Blood samples were collected at baseline and after 90 minutes and 24 hours. Patients undergoing thrombolysis had a significant early increase in activated factor XII (from 2.2 ng/ml at baseline to 4.7 ng/ml after 90 minutes; p = 0.0001), cleaved kininogen (from 26% to 37%; p = 0.001), and fragment 1 + 2 (from 1.4 to 2.1 nmol/L; p = 0.0001), whereas the 24-hour levels were similar to baseline levels. The levels of interleukin-6 significantly increased during the first 90 minutes (from 3.9 to 6.3 microg/ml; p = 0.001), and were even higher after 24 hours (11.9 ng/ml, p = 0.0001). CRP levels increased only after 24 hours (p = 0.0001). There were no changes in these parameters in patients receiving heparin alone, except for a 24-hour increase in interleukin-6 and CRP levels. Thus, in patients with AMI receiving thrombolytic therapy, early activation of inflammation parallels the activation of the contact system and the coagulation cascade, which might contribute to microvascular obstruction and reperfusion injury.

  5. Distinct effects of Lactobacillus plantarum KL30B and Escherichia coli 3A1 on the induction and development of acute and chronic inflammation

    PubMed Central

    Strus, Magdalena; Okoń, Krzysztof; Nowak, Bernadeta; Pilarczyk-Zurek, Magdalena; Heczko, Piotr; Gawda, Anna; Ciszek-Lenda, Marta; Skowron, Beata; Baranowska, Agnieszka

    2016-01-01

    Objective Enteric bacteria are involved in the pathogenesis of ulcerative colitis. In experimental colitis, a breakdown of the intestinal epithelial barrier results in inflow of various gut bacteria, induction of acute inflammation and finally, progression to chronic colitis. Material and methods In the present study we compared pro-inflammatory properties of two bacterial strains isolated from human microbiome, Escherichia coli 3A1 and Lactobacillus plantarum KL30B. The study was performed using two experimental models of acute inflammation: peritonitis in mice and trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. Results Both bacterial strains induced massive neutrophil infiltration upon injection into sterile peritoneal cavity. However, peritoneal exudate cells stimulated in vitro with E. coli 3A1, produced far more nitric oxide, than those stimulated with L. plantarum KL30B. Interestingly, distinct effect on the development of TNBS-induced colitis was observed after oral administration of the tested bacteria. Lactobacillus plantarum KL30B evoked strong acute colitis. On the contrary, the administration of E. coli 3A1 resulted in a progression of colitis to chronicity. Conclusions Our results show that distinct effects of bacterial administration on the development of ongoing inflammation is strain specific and depends on the final effect of cross-talk between bacteria and cells of the innate immune system. PMID:26862305

  6. Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury

    PubMed Central

    Henes, Janek; Schmit, Marthe A.; Morote-Garcia, Julio C.; Mirakaj, Valbona; Köhler, David; Glover, Louise; Eldh, Therese; Walter, Ulrich; Karhausen, Jörn; Colgan, Sean P.; Rosenberger, Peter

    2009-01-01

    Acute lung injury (ALI) is an inflammatory disorder associated with reduced alveolar-capillary barrier function, increased pulmonary vascular permeability, and infiltration of leukocytes into the alveolar space. Pulmonary function might be compromised, its most severe form being the acute respiratory distress syndrome. A protein central to physiological barrier properties is vasodilator-stimulated phosphoprotein (VASP). Given the fact that VASP expression is reduced during periods of cellular hypoxia, we investigated the role of VASP during ALI. Initial studies revealed reduced VASP expressional levels through cytokines in vitro. Studies in the putative human VASP promoter identified NF-κB as a key regulator of VASP transcription. This VASP repression results in increased paracellular permeability and migration of neutrophils in vitro. In a model of LPS-induced ALI, VASP−/− mice demonstrated increased pulmonary damage compared with wild-type animals. These findings were confirmed in a second model of ventilator-induced lung injury. Studies employing bone marrow chimeric animals identified tissue-specific repression of VASP as the underlying cause of decreased barrier properties of the alveolar-capillary barrier during ALI. Taken together these studies identify tissue-specific VASP as a central protein in the control of the alveolar-capillary barrier properties during ALI.—Henes, J., Schmit, M. A., Morote-Garcia, J. C., Mirakaj, V., Köhler, D., Glover, L., Eldh, T., Walter, U., Karhausen, J., Colgan, S. P., Rosenberger, P. Inflammation-associated repression of vasodilator-stimulated phosphoprotein (VASP) reduces alveolar-capillary barrier function during acute lung injury. PMID:19690214

  7. Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness.

    PubMed

    van Zeijl, Clementine J J; Surovtseva, Olga V; Kwakkel, Joan; van Beeren, Hermina C; Bassett, J H Duncan; Duncan Bassett, J H; Williams, Graham R; Wiersinga, Wilmar M; Fliers, Eric; Boelen, Anita

    2014-09-15

    Thyrostimulin, a putative glycoprotein hormone, comprises the subunits GPA2 and GPB5 and activates the TSH receptor (TSHR). The observation that proinflammatory cytokines stimulate GPB5 transcription suggested a role for thyrostimulin in the pathogenesis of nonthyroidal illness syndrome (NTIS). In the present study, we induced acute inflammation by LPS administration to GPB5(-/-) and WT mice to evaluate the role of thyrostimulin in peripheral thyroid hormone metabolism during NTIS. In addition to serum thyroid hormone concentrations, we studied mRNA expression and activity of deiodinase types I, II, and III (D1, D2, and D3) in peripheral T3 target tissues, including liver, muscle, and white and brown adipose tissue (WAT and BAT), of which the latter three express the TSHR. LPS decreased serum free (f)T4 and fT3 indexes to a similar extent in GPB5(-/-) and WT mice. Serum reverse (r)T3 did not change following LPS administration. LPS also induced significant alterations in tissue D1, D2, and D3 mRNA and activity levels, but only the LPS-induced increase in WAT D2 mRNA expression differed between GPB5(-/-) and WT mice. In conclusion, lacking GPB5 during acute illness does not affect the LPS-induced decrease of serum thyroid hormones while resulting in subtle changes in tissue D2 expression that are unlikely to be mediated via the TSHR.

  8. O-Methylated flavonol isorhamnetin prevents acute inflammation through blocking of NF-κB activation.

    PubMed

    Yang, Ji Hye; Kim, Sang Chan; Shin, Bo Yeon; Jin, So Hee; Jo, Mi Jeong; Jegal, Kyung Hwan; Kim, Young Woo; Lee, Jong Rok; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2013-09-01

    Here, we isolated isorhamnetin, a natural 3'-O-methylated flavonoid, from water dropwort (Oenanthe javanica, Umbelliferae) and investigated its ability to protect against acute inflammation in vivo and in vitro. To induce paw swelling, the hind paw of each rat was injected with a carrageenan 1h after vehicle or isorhamnetin treatment. In vitro effect and mechanism studies were performed in lipopolysaccharide (LPS)-activated macrophages. Administration of isorhamnetin markedly inhibited the swelling volume and the thickness of hind paws. Moreover, isorhamnetin significantly reduced inflammatory cell infiltration and pro-inflammatory gene expression in rats. Isorhamnetin pretreatment inhibited inducible nitric oxide synthase (iNOS) expression and NO release in LPS-stimulated cells. Activation of nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1) is the key step in the iNOS gene induction. Isorhamnetin specifically inhibited NF-κB luciferase activity, but not AP-1. Pretreatment with isorhamnetin suppressed NF-κB nuclear translocation in accordance with decreased phosphorylation and degradation of inhibitory-κB. Consistently, TNF-α, IL-1β and IL-6 expression, representative NF-κB target genes, were almost completely prohibited by isorhamnetin. Furthermore, isorhamnetin inhibited LPS-induced JNK and AKT/IKKα/β phosphorylation. Our results suggest that isorhamnetin inhibited JNK, and AKT/IKKα/β activation, leading to NF-κB inactivation, which might contribute to the inhibition of the acute inflammatory response.

  9. Perioperative infliximab application ameliorates acute rejection associated inflammation after intestinal transplantation.

    PubMed

    Pech, T; Finger, T; Fujishiro, J; Praktiknjo, M; Ohsawa, I; Abu-Elmagd, K; Limmer, A; Hirner, A; Kalff, J C; Schaefer, N

    2010-11-01

    As we have shown in the past, acute rejection-related TNF-α upregulation in resident macrophages in the tunica muscularis after small bowel transplantation (SBTx) results in local amplification of inflammation, decisively contributing to graft dysmotility. Therefore, the aim of this study is to investigate the effectiveness of the chimeric-monoclonal-anti-TNF-α antibody infliximab as perioperative single shot treatment addressing inflammatory processes during acute rejection early after transplantation. Orthotopic, isogenic and allogenic SBTx was performed in rats (BN-Lewis/BN-BN) with infliximab treatment. Vehicle and IV-immunoglobulin-treated animals served as controls. Animals were sacrificed after 24 and 168 h. Leukocyte infiltration was investigated in muscularis whole mounts by immunohistochemistry, mediator mRNA expression by Real-Time-RT-PCR, apoptosis by TUNEL and smooth muscle contractility in a standard organ bath. Both, infliximab and Sandoglobulin® revealed antiinflammatory effects. Infliximab resulted in significantly less leukocyte infiltration compared to allogenic controls and IV-immunoglobulin, which was accompanied by lower gene expression of MCP-1 (24 h), IFN-γ (168 h) and infiltration of CD8-positive cells. Smooth muscle contractility improved significantly after 24 h compared to all controls in infliximab treated animals accompanied by lower iNOS expression. Perioperative treatment with infliximab is a possible pharmaceutical approach to overcome graft dysmotility early after SBTx.

  10. Contrasting alterations to synaptic and intrinsic properties in upper-cervical superficial dorsal horn neurons following acute neck muscle inflammation

    PubMed Central

    2014-01-01

    Background Acute and chronic pain in axial structures, like the back and neck, are difficult to treat, and have incidence as high as 15%. Surprisingly, most preclinical work on pain mechanisms focuses on cutaneous structures in the limbs and animal models of axial pain are not widely available. Accordingly, we developed a mouse model of acute cervical muscle inflammation and assessed the functional properties of superficial dorsal horn (SDH) neurons. Results Male C57/Bl6 mice (P24-P40) were deeply anaesthetised (urethane 2.2 g/kg i.p) and the rectus capitis major muscle (RCM) injected with 40 μl of 2% carrageenan. Sham animals received vehicle injection and controls remained anaesthetised for 2 hrs. Mice in each group were sacrificed at 2 hrs for analysis. c-Fos staining was used to determine the location of activated neurons. c-Fos labelling in carrageenan-injected mice was concentrated within ipsilateral (87% and 63% of labelled neurons in C1 and C2 segments, respectively) and contralateral laminae I - II with some expression in lateral lamina V. c-Fos expression remained below detectable levels in control and sham animals. In additional experiments, whole cell recordings were obtained from visualised SDH neurons in transverse slices in the ipsilateral C1 and C2 spinal segments. Resting membrane potential and input resistance were not altered. Mean spontaneous EPSC amplitude was reduced by ~20% in neurons from carrageenan-injected mice versus control and sham animals (20.63 ± 1.05 vs. 24.64 ± 0.91 and 25.87 ± 1.32 pA, respectively). The amplitude (238 ± 33 vs. 494 ± 96 and 593 ± 167 pA) and inactivation time constant (12.9 ± 1.5 vs. 22.1 ± 3.6 and 15.3 ± 1.4 ms) of the rapid A type potassium current (IAr), the dominant subthreshold current in SDH neurons, were reduced in carrageenan-injected mice. Conclusions Excitatory synaptic drive onto, and important intrinsic properties (i.e., IAr) within SDH neurons are

  11. Systemic Atherosclerotic Inflammation Following Acute Myocardial Infarction: Myocardial Infarction Begets Myocardial Infarction

    PubMed Central

    Joshi, Nikhil V; Toor, Iqbal; Shah, Anoop S V; Carruthers, Kathryn; Vesey, Alex T; Alam, Shirjel R; Sills, Andrew; Hoo, Teng Y; Melville, Adam J; Langlands, Sarah P; Jenkins, William S A; Uren, Neal G; Mills, Nicholas L; Fletcher, Alison M; van Beek, Edwin J R; Rudd, James H F; Fox, Keith A A; Dweck, Marc R; Newby, David E

    2015-01-01

    Background Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans. Methods and Results Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non–ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI. Conclusions The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization

  12. Effect of acupuncture on rats with acute gouty arthritis inflammation: a metabonomic method for profiling of both urine and plasma metabolic perturbation.

    PubMed

    Wen, Si-Lan; Liu, Yu-Jie; Yin, Hai-Lin; Zhang, Liu; Xiao, Jin; Zhu, Hong-Yuan; Xue, Jin-Tao; Ye, Li-Ming

    2011-01-01

    Acute gouty arthritis is a common inflammation model with multiple pathogenic mechanisms seen in clinical practice, for which acupuncture may potentially be an alternative therapy. To investigate the effect of acupuncture on acute gouty arthritis and search for its mechanism, a metabonomic method was developed in this investigation. Acute gouty arthritis model rats were induced by monosodium urate (MSU) crystals. The urine and plasma samples were collected at several time points and the endogenous metabolites were analyzed by an ultra-performance liquid chromatography coupled with a mass spectrometry (UPLC-MS). Data were analyzed using principal components analysis (PCA) and partial least squares (PLS) analysis to compare metabolic profiles of MSU crystal-induced acute gouty arthritis rats with MSU crystal-induced acute gouty arthritis, treated with acupuncture rats. The results showed that acupuncture could restore the metabolite network that disturbed by MSU administration. Our study indicates that UPLC-MS-based metabonomics can be used as a potential tool for the investigation of biological effect of acupuncture on acute gouty arthritis.

  13. Effect of Obesity on Acute Ozone-Induced Changes in Airway Function, Reactivity, and Inflammation in Adult Females

    PubMed Central

    Bennett, William D.; Ivins, Sally; Alexis, Neil E.; Wu, Jihong; Bromberg, Philip A.; Brar, Sukhdev S.; Travlos, Gregory; London, Stephanie J.

    2016-01-01

    We previously observed greater ozone-induced lung function decrements in obese than non-obese women. Animal models suggest that obesity enhances ozone-induced airway reactivity and inflammation. In a controlled exposure study, we compared the acute effect of randomized 0.4ppm ozone and air exposures (2 h with intermittent light exercise) in obese (N = 20) (30Inflammation and obesity markers were assessed in the blood (pre, 4h post, and 20h post exposures) and induced-sputum (4h post-exposures and on 24h pre-exposure training day, no exercise): measures of C reactive protein (CRP) (blood only), leptin (blood only), adiponectin, interleukins IL-6, IL-1b, and IL-8, and tumor necrosis factor alpha, and sputum cell differential cell counts. The pre- to post-exposure decrease in forced vital capacity after ozone (adjusted for the change after air exposure) was significantly greater in the obese group (12.5+/-7.5 vs. 8.0+/-5.8%, p<0.05). Post ozone exposure, 6 obese and 6 non-obese subjects responded to methacholine at ≤ 10mg/ml (the maximum dose); the degree of hyperresponsiveness was similar for the two groups. Both BMI groups showed similar and significant ozone-induced increases in sputum neutrophils. Plasma IL-6 was increased by exercise (4 hr post air exposure vs. pre) only in the obese but returned to pre-air exposure levels at 20hr post-exposure. Plasma IL-6 was significantly increased at 4hr post ozone exposure in both groups and returned to pre-exposure levels by 20h post-exposure. These results confirm our previous findings of greater post-ozone spirometric decrements in obese young women. However, acute ozone-induced airway reactivity to methacholine and airway inflammation did not differ by obesity at the exposure and exercise levels used. PMID:27513854

  14. Radionuclide imaging of inflammation and infection in the acute care setting.

    PubMed

    Love, Charito; Palestro, Christopher J

    2013-03-01

    Although infection may be suggested by signs and symptoms such as fever, pain, general malaise, and abnormal laboratory results, imaging tests often are used to confirm its presence. Morphologic imaging tests identify structural alterations of tissues or organs that result from a combination of microbial invasion and the inflammatory response of the host. Functional imaging studies use minute quantities of radioactive material, which are taken up directly by cells, tissues, and organs, or are attached to substances that subsequently migrate to the region of interest. Bone scintigraphy is extremely sensitive and can be positive within 2 days after the onset of symptoms. With an accuracy of more than 90%, 3-phase bone scintigraphy is the radionuclide procedure of choice for diagnosing osteomyelitis in unviolated bone. In patients with acute renal failure, gallium imaging facilitates the differentiation of acute interstitial nephritis from acute tubular necrosis. Gallium imaging also is useful in the evaluation of pulmonary infections and inflammation. Many opportunistic infections affect the lungs, and a normal gallium scan of the chest excludes infection with a high degree of certainty, especially when the chest x-ray is negative. In the human immunodeficiency virus positive patient, lymph node uptake usually is associated with mycobacterial disease or lymphoma. Focal pulmonary parenchymal uptake suggests bacterial pneumonia. Diffuse pulmonary uptake suggests an opportunistic pneumonia. Gallium imaging provides useful information about other acute respiratory conditions, including radiation pneumonitis and hypersensitivity pneumonitis. In vitro labeled leukocyte imaging with indium-111 and technetium-99m labeled leukocytes is useful in various acute care situations. The test facilitates the differentiation of normal postoperative changes from infection and is useful for diagnosing prosthetic vascular graft infection. In inflammatory bowel disease, labeled leukocyte

  15. Signaling through the interleukin-18 receptor α attenuates inflammation in cisplatin-induced acute kidney injury.

    PubMed

    Nozaki, Yuji; Kinoshita, Koji; Yano, Tomohiro; Asato, Kayo; Shiga, Toshihiko; Hino, Shoichi; Niki, Kaoru; Nagare, Yasuaki; Kishimoto, Kazuya; Shimazu, Hideki; Funauchi, Masanori; Matsumura, Itaru

    2012-10-01

    Interleukin (IL)-18 is produced by leukocytes and renal parenchymal cells (tubular epithelial cells, podocytes, and mesangial cells). The IL-18 receptor (IL-18R) is expressed on these cells in cisplatin-induced acute kidney injury, but the role of IL-18R is unknown. To help define this, we compared IL-18Rα knockout with wild-type mice in cisplatin-induced acute kidney injury and found deteriorated kidney function, tubular damage, increased accumulation of leukocytes (CD4(+) and CD8(+) T-cells, macrophages, and neutrophils), upregulation of early kidney injury biomarkers (serum TNF, urinary IL-18, and KIM-1 levels), and increased expression of pro-inflammatory molecules downstream of IL-18. In vitro, leukocytes from the spleen and kidneys of the knockout mice produced greater amounts of pro-inflammatory cytokines upon stimulation with concanavalin A compared to that in wild-type mice. Levels of the suppressor of cytokine signaling 1 and 3 (negative regulators of cytokine signaling) were reduced in the spleen and kidneys of IL-18Rα-deficient compared to wild-type mice. Adoptive transfer of wild-type splenocytes by IL-18Rα-deficient mice led to decreased cisplatin nephrotoxicity compared to control IL-18Rα-deficient mice. In contrast, anti-IL-18Rα and anti-IL-18Rβ antibody treatment tended to increase cisplatin nephrotoxicity in wild-type mice. Thus, signaling through IL-18Rα activates both inflammation-suppressing and pro-injury pathways in cisplatin-induced acute kidney injury.

  16. Resolvin D1 protects against inflammation in experimental acute pancreatitis and associated lung injury.

    PubMed

    Liu, Yong; Zhou, Dan; Long, Fei-Wu; Chen, Ke-Ling; Yang, Hong-Wei; Lv, Zhao-Yin; Zhou, Bin; Peng, Zhi-Hai; Sun, Xiao-Feng; Li, Yuan; Zhou, Zong-Guang

    2016-03-01

    Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure with considerable mortality. Recently, resolvin D1 (RvD1) as an endogenous anti-inflammatory lipid mediator has been confirmed to protect against many inflammatory diseases. This study was designed to investigate the effects of RvD1 in acute pancreatitis and associated lung injury. Acute pancreatitis varying from mild to severe was induced by cerulein or cerulein combined with LPS, respectively. Mice were pretreated with RvD1 at a dose of 300 ng/mouse 30 min before the first injection of cerulein. Severity of AP was assessed by biochemical markers and histology. Serum cytokines and myeloperoxidase (MPO) levels in pancreas and lung were determined for assessing the extent of inflammatory response. NF-κB activation was determined by Western blotting. The injection of cerulein or cerulein combined with LPS resulted in local injury in the pancreas and corresponding systemic inflammatory changes with pronounced severity in the cerulein and LPS group. Pretreated RvD1 significantly reduced the degree of amylase, lipase, TNF-α, and IL-6 serum levels; the MPO activities in the pancreas and the lungs; the pancreatic NF-κB activation; and the severity of pancreatic injury and associated lung injury, especially in the severe acute pancreatitis model. These results suggest that RvD1 is capable of improving injury of pancreas and lung and exerting anti-inflammatory effects through the inhibition of NF-κB activation in experimental acute pancreatitis, with more notable protective effect in severe acute pancreatitis. These findings indicate that RvD1 may constitute a novel therapeutic strategy in the management of severe acute pancreatitis.

  17. Parecoxib Reduces Systemic Inflammation and Acute Lung Injury in Burned Animals with Delayed Fluid Resuscitation

    PubMed Central

    Chong, Si Jack; Wu, Jian; Lu, Jia; Moochhala, Shabbir M.

    2014-01-01

    Burn injuries result in the release of proinflammatory mediators causing both local and systemic inflammation. Multiple organ dysfunctions secondary to systemic inflammation after severe burn contribute to adverse outcome, with the lungs being the first organ to fail. In this study, we evaluate the anti-inflammatory effects of Parecoxib, a parenteral COX-2 inhibitor, in a delayed fluid resuscitation burned rat model. Anaesthetized Sprague Dawley rats were inflicted with 45% total body surface area full-thickness scald burns and subsequently subjected to delayed resuscitation with Hartmann's solution. Parecoxib (0.1, 1.0, and 10 mg/kg) was delivered intramuscularly 20 min after injury followed by 12 h interval and the rats were sacrificed at 6 h, 24 h, and 48 h. Burn rats developed elevated blood cytokines, transaminase, creatinine, and increased lung MPO levels. Animals treated with 1 mg/kg Parecoxib showed significantly reduced plasma level of CINC-1, IL-6, PGEM, and lung MPO. Treatment of 1 mg/kg Parecoxib is shown to mitigate systemic and lung inflammation without significantly affecting other organs. At present, no specific therapeutic agent is available to attenuate the systemic inflammatory response secondary to burn injury. The results suggest that Parecoxib may have the potential to be used both as an analgesic and ameliorate the effects of lung injury following burn. PMID:24579056

  18. Reproducibility Issues: Avoiding Pitfalls in Animal Inflammation Models.

    PubMed

    Laman, Jon D; Kooistra, Susanne M; Clausen, Björn E

    2017-01-01

    In light of an enhanced awareness of ethical questions and ever increasing costs when working with animals in biomedical research, there is a dedicated and sometimes fierce debate concerning the (lack of) reproducibility of animal models and their relevance for human inflammatory diseases. Despite evident advancements in searching for alternatives, that is, replacing, reducing, and refining animal experiments-the three R's of Russel and Burch (1959)-understanding the complex interactions of the cells of the immune system, the nervous system and the affected tissue/organ during inflammation critically relies on in vivo models. Consequently, scientific advancement and ultimately novel therapeutic interventions depend on improving the reproducibility of animal inflammation models. As a prelude to the remaining hands-on protocols described in this volume, here, we summarize potential pitfalls of preclinical animal research and provide resources and background reading on how to avoid them.

  19. Chemical sympathectomy attenuates inflammation, glycocalyx shedding and coagulation disorders in rats with acute traumatic coagulopathy.

    PubMed

    Xu, Lin; Yu, Wen-Kui; Lin, Zhi-Liang; Tan, Shan-Jun; Bai, Xiao-Wu; Ding, Kai; Li, Ning

    2015-03-01

    Acute traumatic coagulopathy (ATC) may trigger sympathoadrenal activation associated with endothelial damage and coagulation disturbances. Overexcitation of sympathetic nerve in this state would disrupt sympathetic-vagal balance, leading to autonomic nervous system dysfunction. The aim of this study was to evaluate the autonomic function in ATC and its influence on inflammation, endothelial and coagulation activation. Male Sprague-Dawley rats were randomly assigned to sham, ATC control (ATCC) and ATC with sympathectomy by 6-hydroxydopamine (ATCS) group. Sham animals underwent the same procedure without trauma and bleeding. Following trauma and hemorrhage, rats underwent heart rate variability (HRV) test, which predicts autonomic dysfunction through the analysis of variation in individual R-R intervals. Then, rats were euthanized at baseline, and at 0, 1 and 2 h after shock and blood gas, conventional coagulation test and markers of inflammation, coagulation, fibrinolysis, endothelial damage and catecholamine were measured. HRV showed an attenuation of total power and high frequency, along with a rise of low frequency and low frequency : high frequency ratio in the ATC rats, which both were reversed by sympathectomy in the ATCS group. Additionally, sympathetic denervation significantly suppressed the increase of proinflammatory cytokines, tumor necrosis factor-α and the fibrinolysis markers including tissue-type plasminogen activator and plasmin-antiplasmin complex. Serum catecholamine, soluble thrombomodulin and syndecan-1 were also effectively inhibited by sympathectomy. These data indicated that autonomic dysfunction in ATC involves both sympathetic activation and parasympathetic inhibition. Moreover, sympathectomy yielded anti-inflammatory, antifibrinolysis and endothelial protective effects in rats with ATC. The role of autonomic neuropathy in ATC should be explored further.

  20. The role of iron in Libby amphibole-induced acute lung injury and inflammation.

    PubMed

    Shannahan, Jonathan H; Ghio, Andrew J; Schladweiler, Mette C; McGee, John K; Richards, Judy H; Gavett, Stephen H; Kodavanti, Urmila P

    2011-05-01

    Complexation of host iron (Fe) on the surface of inhaled asbestos fibers has been postulated to cause oxidative stress contributing to in vivo pulmonary injury and inflammation. We examined the role of Fe in Libby amphibole (LA; mean length 4.99 µm ± 4.53 and width 0.28 µm ± 0.19) asbestos-induced inflammogenic effects in vitro and in vivo. LA contained acid-leachable Fe and silicon. In a cell-free media containing FeCl(3), LA bound #17 µg of Fe/mg of fiber and increased reactive oxygen species generation #3.5 fold, which was reduced by deferoxamine (DEF) treatment. In BEAS-2B cells exposure to LA, LA loaded with Fe (FeLA), or LA with DEF did not increase HO-1 or ferritin mRNA expression. LA increased IL-8 expression, which was reduced by Fe loading but increased by DEF. To determine the role of Fe in LA-induced lung injury in vivo, spontaneously hypertensive rats were exposed intratracheally to either saline (300 µL), DEF (1 mg), FeCl(3) (21 µg), LA (0.5 mg), FeLA (0.5 mg), or LA + DEF (0.5 mg). LA caused BALF neutrophils to increase 24 h post-exposure. Loading of Fe on LA but not chelation slightly decreased neutrophilic influx (LA + DEF > LA > FeLA). At 4 h post-exposure, LA-induced lung expression of MIP-2 was reduced in rats exposed to FeLA but increased by LA + DEF (LA + DEF > LA > FeLA). Ferritin mRNA was elevated in rats exposed to FeLA compared to LA. In conclusion, the acute inflammatory response to respirable fibers and particles may be inhibited in the presence of surface-complexed or cellular bioavailable Fe. Cell and tissue Fe-overload conditions may influence the pulmonary injury and inflammation caused by fibers.

  1. Mouse models of acute exacerbations of allergic asthma.

    PubMed

    Kumar, Rakesh K; Herbert, Cristan; Foster, Paul S

    2016-07-01

    Most of the healthcare costs associated with asthma relate to emergency department visits and hospitalizations because of acute exacerbations of underlying chronic disease. Development of appropriate animal models of acute exacerbations of asthma is a necessary prerequisite for understanding pathophysiological mechanisms and assessing potential novel therapeutic approaches. Most such models have been developed using mice. Relatively few mouse models attempt to simulate the acute-on-chronic disease that characterizes human asthma exacerbations. Instead, many reported models involve relatively short-term challenge with an antigen to which animals are sensitized, followed closely by an unrelated triggering agent, so are better described as models of potentiation of acute allergic inflammation. Triggers for experimental models of asthma exacerbations include (i) challenge with high levels of the sensitizing allergen (ii) infection by viruses or fungi, or challenge with components of these microorganisms (iii) exposure to environmental pollutants. In this review, we examine the strengths and weaknesses of published mouse models, their application for investigation of novel treatments and potential future developments.

  2. Effects of Acute Exposure to Moderate Altitude on Vascular Function, Metabolism and Systemic Inflammation

    PubMed Central

    Stöwhas, Anne-Christin; Latshang, Tsogyal D.; Lo Cascio, Christian M.; Lautwein, Sina; Stadelmann, Katrin; Tesler, Noemi; Ayers, Lisa; Berneis, Kaspar; Gerber, Philipp A.; Huber, Reto; Achermann, Peter; Bloch, Konrad E.; Kohler, Malcolm

    2013-01-01

    Background Travel to mountain areas is popular. However, the effects of acute exposure to moderate altitude on the cardiovascular system and metabolism are largely unknown. Objectives To investigate the effects of acute exposure to moderate altitude on vascular function, metabolism and systemic inflammation. Methods In 51 healthy male subjects with a mean (SD) age of 26.9 (9.3) years, oxygen saturation, blood pressure, heart rate, arterial stiffness, lipid profiles, low density lipoprotein (LDL) particle size, insulin resistance (HOMA-index), highly-sensitive C-reactive protein and pro-inflammatory cytokines were measured at 490 m (Zurich) and during two days at 2590 m, (Davos Jakobshorn, Switzerland) in randomized order. The largest differences in outcomes between the two altitudes are reported. Results Mean (SD) oxygen saturation was significantly lower at 2590 m, 91.0 (2.0)%, compared to 490 m, 96.0 (1.0)%, p<0.001. Mean blood pressure (mean difference +4.8 mmHg, p<0.001) and heart rate (mean difference +3.3 bpm, p<0.001) were significantly higher at 2590 m, compared to 490 m, but this was not associated with increased arterial stiffness. At 2590 m, lipid profiles improved (median difference triglycerides −0.14 mmol/l, p = 0.012, HDL +0.08 mmol/l, p<0.001, total cholesterol/HDL-ratio −0.25, p = 0.001), LDL particle size increased (median difference +0.45 nm, p = 0.048) and hsCRP decreased (median difference −0.18 mg/l, p = 0.024) compared to 490 m. No significant change in pro-inflammatory cytokines or insulin resistance was observed upon ascent to 2590 m. Conclusions Short-term stay at moderate altitude is associated with increased blood pressure and heart rate likely due to augmented sympathetic activity. Exposure to moderate altitude improves the lipid profile and systemic inflammation, but seems to have no significant effect on glucose metabolism. Trial Registration ClinicalTrials.gov NCT01130948 PMID:23936377

  3. Promoting inflammatory lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) aggravated intestinal inflammation in mice with experimental acute colitis

    PubMed Central

    Wang, X.L.; Zhao, J.; Qin, L.; Qiao, M.

    2016-01-01

    Angiogenesis and lymphangiogenesis are thought to play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, it is not understood if inflammatory lymphangiogenesis is a pathological consequence or a productive attempt to resolve the inflammation. This study investigated the effect of lymphangiogenesis on intestinal inflammation by overexpressing a lymphangiogenesis factor, vascular endothelial growth factor-C (VEGF-C), in a mouse model of acute colitis. Forty eight-week-old female C57BL/6 mice were treated with recombinant adenovirus overexpressing VEGF-C or with recombinant VEGF-C156S protein. Acute colitis was then established by exposing the mice to 5% dextran sodium sulfate (DSS) for 7 days. Mice were evaluated for disease activity index (DAI), colonic inflammatory changes, colon edema, microvessel density, lymphatic vessel density (LVD), and VEGFR-3mRNA expression in colon tissue. When acute colitis was induced in mice overexpressing VEGF-C, there was a significant increase in colonic epithelial damage, inflammatory edema, microvessel density, and neutrophil infiltration compared to control mice. These mice also exhibited increased lymphatic vessel density (73.0±3.9 vs 38.2±1.9, P<0.001) and lymphatic vessel size (1974.6±104.3 vs 1639.0±91.5, P<0.001) compared to control mice. Additionally, the expression of VEGFR-3 mRNA was significantly upregulated in VEGF-C156S mice compared to DSS-treated mice after induction of colitis (42.0±1.4 vs 3.5±0.4, P<0.001). Stimulation of lymphangiogenesis by VEGF-C during acute colitis promoted inflammatory lymphangiogenesis in the colon and aggravated intestinal inflammation. Inflammatory lymphangiogenesis may have pleiotropic effects at different stages of IBD. PMID:27074165

  4. The effect of pentoxifylline and its metabolite-1 on inflammation and fibrosis in the TNBS model of colitis.

    PubMed

    Peterson, Theresa C; Peterson, Marc R; Raoul, Jennifer M

    2011-07-15

    TNBS-induced colitis has characteristics resembling human Crohn's disease including transmural inflammation, ulceration, and fibrosis. Current treatments target acute symptoms but do not necessarily prevent fibrotic complications of the disease. The aim of this study was to determine the effect of pentoxifylline and its primary metabolite (M-1) on fibrosis in the TNBS-induced colitis model. Myeloperoxidase activity and interleukin-18 are indicators of inflammation and were elevated in the TNBS model. The morphology damage score assesses colon damage and was also elevated in the TNBS model. Collagen as the indicator of fibrosis was quantified and visualized by the Sirius Red/Fast Green staining technique and collagen type I was assessed by Western analysis. Collagen was elevated in the TNBS-induced model. Pentoxifylline and M-1 treatment significantly attenuated colon damage and inflammation in TNBS-colitis (P<0.05). M-1 treatment significantly reduced the TNBS-induced increase in colon weight, colon thickness and total collagen content (P<0.05). Results suggest that pentoxifylline and M-1 inhibit intestinal fibrosis in this experimental model and may prove beneficial in the treatment of intestinal fibrosis associated with human Crohn's disease with the added benefit of inhibiting inflammation and ulceration. This is the first study to examine the effects of racemic M-1 in vivo and one of the few studies to examine the effect of drugs on both inflammation and fibrosis in an experimental model of colitis.

  5. Involvement of exosomes in lung inflammation associated with experimental acute pancreatitis.

    PubMed

    Bonjoch, Laia; Casas, Vanessa; Carrascal, Montserrat; Closa, Daniel

    2016-10-01

    A frequent complication of acute pancreatitis is the lung damage associated with the systemic inflammatory response. Although various pro-inflammatory mediators generated at both local and systemic levels have been identified, the pathogenic mechanisms of the disease are still poorly understood. In recent years, exosomes have emerged as a new intercellular communication system able to transfer encapsulated proteins and small RNAs and protect them from degradation. Using an experimental model of taurocholate-induced acute pancreatitis in rats, we aimed to evaluate the role of exosomes in the extent of the systemic inflammatory response. Induction of pancreatitis increased the concentration of circulating exosomes, which showed a different proteomic profile to those obtained from control animals. A series of tracking experiments using PKH26-stained exosomes revealed that circulating exosomes effectively reached the alveolar compartment and were internalized by macrophages. In vitro experiments revealed that exosomes obtained under inflammatory conditions activate and polarize these alveolar macrophages towards a pro-inflammatory phenotype. Interestingly, the proteomic analysis of circulating exosomes during acute pancreatitis suggested a multi-organ origin with a relevant role for the liver as a source of these vesicles. Tracking experiments also revealed that the liver retains the majority of exosomes from the peritoneal cavity. We conclude that exosomes are involved in the lung damage associated with experimental acute pancreatitis and could be relevant mediators in the systemic effects of pancreatitis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  6. Age-dependent neutrophil and blood flow responsiveness in acute pulmonary inflammation in rabbits.

    PubMed

    Hyde, D M; Downey, G P; Tablin, F; Rosengren, S; Giclas, P C; Henson, P M; Worthen, G S

    1997-03-01

    Diminished ability of neonatal neutrophils to orient and move in a chemotactic gradient has been linked to compromised pulmonary host defense. We investigated whether deficiency of neonatal neutrophil function in vitro was evident in acute pulmonary inflammation. Analysis of neutrophils in vitro showed impaired chemotaxis in 4-wk-old compared with adult rabbits. In vivo-directed migration of labeled neutrophils into the alveolar space of adult rabbits in response to C5f instillation was significantly less for neutrophils donated from 4-wk-old rabbits compared with those from adults. In contrast, there were no differences in the alveolar accumulation of 4-wk-old and adult labeled neutrophils in 4-wk-old rabbits in response to C5f instillation, although the response showed a shorter time course than seen in adult rabbits. Adult rabbits diverted 46% of the blood away from the right cranial lung lobe, whereas 4-wk-old rabbits showed no change in blood flow after C5f instillation. Megakaryocytes (a source of blood flow mediators) were 3.2-fold greater in adult compared with 4-wk-old lung. These data suggest that the lack of blood flow diversion from inflamed neonatal lung increases neutrophil migration into alveoli, allowing for preservation of an inflammatory response despite neutrophil deficiencies in chemotaxis.

  7. Study of the immunomodulatory properties of gamithromycin and dexamethasone in a lipopolysaccharide inflammation model in calves.

    PubMed

    Plessers, E; Watteyn, A; Wyns, H; Pardon, B; De Backer, P; Croubels, S

    2015-12-01

    The aim of this study was to define the in vivo immunomodulatory properties of the macrolide antibiotic gamithromycin in calves, with respect to the acute phase response. Additionally, the corticosteroid dexamethasone was included as a positive control immunomodulatory drug. Both drugs, as well as their combination,were studied in a previously developed inflammation model,which was initiated by an intravenous lipopolysaccharide (LPS) challenge (0.5 μg/kg body weight). Twenty-four 4-week-old male Holstein Friesian calves were randomized into four groups: no pharmacological treatment (n = 6) or a pharmacological treatment with gamithromycin (n= 6), dexamethasone (n= 6) or their combination (n= 6) 1 h prior to LPS administration. Blood collection and clinical scoring were performed at regular time points until 72 h post LPS challenge. Plasma concentrations of selected cytokines (tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6)) and acute phase proteins (serum amyloid A and haptoglobin) were subsequently determined. Gamithromycin did not have any beneficial effect on the LPS-induced clinical signs (dyspnea, fever, anorexia and depression), nor on the studied inflammatory mediators. In the dexamethasone and combination groups, the occurrence of dyspnea and fever was not prominently influenced, although the calves recovered significantly faster from the challenge. Moreover, dexamethasone significantly inhibited the levels of TNF-α and IL-6, suggesting a key role for these cytokines in sickness behaviour. In conclusion, unlike dexamethasone, gamithromycin did not directly reduce cytokine release in an LPS inflammation model in calves.

  8. The hallucinogenic diterpene salvinorin A inhibits leukotriene synthesis in experimental models of inflammation.

    PubMed

    Rossi, Antonietta; Pace, Simona; Tedesco, Federica; Pagano, Ester; Guerra, Germano; Troisi, Fabiana; Werner, Markus; Roviezzo, Fiorentina; Zjawiony, Jordan K; Werz, Oliver; Izzo, Angelo A; Capasso, Raffaele

    2016-04-01

    Leukotrienes (LTs) are lipid mediators derived from arachidonic acid (AA) involved in a number of autoimmune/inflammatory disorders including asthma, allergic rhinitis and cardiovascular diseases. Salvinorin A (SA), a diterpene isolated from the hallucinogenic plant Salvia divinorum, is a well-established analgesic compound, but its anti-inflammatory properties are under-researched and its effects on LT production is unknown to date. Here, we studied the possible effect of SA on LT production and verified its actions on experimental models of inflammation in which LTs play a prominent role. Peritoneal macrophages (PM) stimulated by calcium ionophore A23187 were chosen as in vitro system to evaluate the effect of SA on LT production. Zymosan-induced peritonitis in mice and carrageenan-induced pleurisy in rats were selected as LT-related models to evaluate the effect of SA on inflammation as well as on LT biosynthesis. SA inhibited, in a concentration-dependent manner, A23187-induced LTB4 biosynthesis in isolated PM. In zymosan-induced peritonitis, SA inhibited cell infiltration, myeloperoxidase activity, vascular permeability and LTC4 production in the peritoneal cavity without decreasing the production of prostaglandin E2. In carrageenan-induced pleurisy in rats, a more sophisticated model of acute inflammation related to LTs, SA significantly inhibited LTB4 production in the inflammatory exudates, along with reducing the phlogistic process in the lung. In conclusion, SA inhibited LT production and it was effective in experimental models of inflammation in which LTs play a pivotal role. SA might be considered as a lead compound for the development of drugs useful in LTs-related diseases.

  9. Fucoidan inhibits LPS-induced inflammation in vitro and during the acute response in vivo.

    PubMed

    Park, Jisang; Cha, Jeong-Dan; Choi, Kyung-Min; Lee, Kyung-Yeol; Han, Kang Min; Jang, Yong-Suk

    2017-02-01

    Studies have been focused on natural products with antibacterial and anti-inflammatory activities, such as fucoidan. Many in vivo studies have evaluated the effect of fucoidan on tumor growth, diabetes, obesity, ischemia reperfusion, and oxidative stress. However, the effects of fucoidan on bacteria-induced gingival inflammation and periodontitis have not been reported. We previously characterized the anti-inflammatory effect of fucoidan in vitro. Here, we confirmed the anti-inflammatory activity of fucoidan in a macrophage cell line in terms of its inhibition of the expression of inflammatory mediators and pro-inflammatory cytokines. Additionally, we confirmed the ability of fucoidan to inhibit gingival inflammation, expression of pro-inflammatory cytokines, and neutrophil recruitment in the gingival tissue of mice injected with LPS prepared from P. gingivalis. Interestingly, however, fucoidan did not inhibit the expression of pro-inflammatory cytokines in a P. gingivalis-infected mouse model of periodontitis. Additionally, fucoidan treatment did not lead to clearance of P. gingivalis or improvement of P. gingivalis infection-mediated bone loss in the periodontitis model. We conclude that fucoidan exerts anti-inflammatory effects in vitro and in vivo, together with a limited antibacterial effect in vivo.

  10. Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, acinar cell damage, and systemic inflammation in acute pancreatitis.

    PubMed

    Seyhun, Ersin; Malo, Antje; Schäfer, Claus; Moskaluk, Christopher A; Hoffmann, Ralf-Thorsten; Göke, Burkhard; Kubisch, Constanze H

    2011-11-01

    In acute pancreatitis, endoplasmic reticulum (ER) stress prompts an accumulation of malfolded proteins inside the ER, initiating the unfolded protein response (UPR). Because the ER chaperone tauroursodeoxycholic acid (TUDCA) is known to inhibit the UPR in vitro, this study examined the in vivo effects of TUDCA in an acute experimental pancreatitis model. Acute pancreatitis was induced in Wistar rats using caerulein, with or without prior TUDCA treatment. UPR components were analyzed, including chaperone binding protein (BiP), phosphorylated protein kinase-like ER kinase (pPERK), X-box binding protein (XBP)-1, phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CCAAT/enhancer binding protein homologues protein, and caspase 12 and 3 activation. In addition, pancreatitis biomarkers were measured, such as serum amylase, trypsin activation, edema formation, histology, and the inflammatory reaction in pancreatic and lung tissue. TUDCA treatment reduced intracellular trypsin activation, edema formation, and cell damage, while leaving amylase levels unaltered. The activation of myeloperoxidase was clearly reduced in pancreas and lung. Furthermore, TUDCA prevented caerulein-induced BiP upregulation, reduced XBP-1 splicing, and caspase 12 and 3 activation. It accelerated the downregulation of pJNK. In controls without pancreatitis, TUDCA showed cytoprotective effects including pPERK signaling and activation of downstream targets. We concluded that ER stress responses activated in acute pancreatitis are grossly attenuated by TUDCA. The chaperone reduced the UPR and inhibited ER stress-associated proapoptotic pathways. TUDCA has a cytoprotective potential in the exocrine pancreas. These data hint at new perspectives for an employment of chemical chaperones, such as TUDCA, in prevention of acute pancreatitis.

  11. Intra-Peritoneal Administration of Mitochondrial DNA Provokes Acute Lung Injury and Systemic Inflammation via Toll-Like Receptor 9

    PubMed Central

    Zhang, Lemeng; Deng, Songyun; Zhao, Shuangping; Ai, Yuhang; Zhang, Lina; Pan, Pinhua; Su, Xiaoli; Tan, Hongyi; Wu, Dongdong

    2016-01-01

    The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner. PMID:27589725

  12. Acute lung inflammation in Klebsiella pneumoniae B5055-induced pneumonia and sepsis in BALB/c mice: a comparative study.

    PubMed

    Kumar, Vijay; Chhibber, Sanjay

    2011-10-01

    Lungs play an important role in the body's defense against a variety of pathogens, but this network of immune system-mediated defense can be deregulated during acute pulmonary infections. The present study compares acute lung inflammation occurring during Klebsiella pneumoniae B5055-induced pneumonia and sepsis in BALB/c mice. Pneumonia was induced by intranasal instillation of bacteria (10(4) cfu), while sepsis was developed by placing the fibrin-thrombin clot containing known amount of bacteria (10(2) cfu) into the peritoneal cavity of animals. Mice with sepsis showed 100% mortality within five post-infection days, whereas all the animals with pneumonia survived. In animals suffering from K. pneumoniae B5055-induced pneumonia, all the inflammatory parameters (TNF-α, IL-1α, MPO, MDA, and NO) were found to be maximum till third post-infection day, after that, a decline was observed, whereas in septic animals, all the above-mentioned markers of inflammation kept on increasing. Histopathological study showed presence of alternatively activated alveolar macrophages (or foam cells) in lungs of mice with pneumonia after third post-infection day, which might have contributed to the induction of resolution of inflammation, but no such observation was made in lungs of septic mice. Hence, during pneumonia, controlled activation of macrophages may lead to resolution of inflammation.

  13. High fat feeding promotes obesity and renal inflammation and protects against post cardiopulmonary bypass acute kidney injury in swine

    PubMed Central

    2013-01-01

    Introduction Obesity confers a survival advantage in the critically ill and in patients undergoing cardiac surgery. We explored whether an obesogenic high fat diet could confer protection against post cardiopulmonary bypass (CPB) acute kidney injury (AKI) in a swine model. Methods In this study, 28 anaesthetised adult female Landrace White swine (55 to 70 kg) were allocated into a 4 group design to either 2.5 hours of CPB or Sham operation with or without pre-procedural high fat (HF) feeding containing 15% lard, 1.5% cholesterol and 1% cholic acid for 12-weeks (Groups: Sham, CPB, CPB + HF and Sham + HF). Our primary endpoint was creatinine clearance measured at 1.5 and 24 hours post intervention. This is a validated index of the glomerular filtration rate (GFR) in swine and an endpoint used in our clinical studies. Secondary endpoints included measures of systemic and renal inflammation, endothelial homeostasis, tubular injury and dysfunction, and inflammatory cell signalling. Differences between groups were calculated using analysis of variance with adjustment for baseline differences for repeated measures. Results CPB in pigs fed a normal chow diet resulted in AKI. This was characterised by reductions in GFR sustained for up to 24 hours post injury relative to Sham operated pigs fed a normal diet; mean difference 50.2 ml/min (95% CI 5.9 to 94.4). Post CPB AKI was also characterised by renal inflammation, parallel activation of both pro-inflammatory (NF-kB, iNOS) and pro-survival pathways (pAkt, p70s6k, HIF-1α) and apoptosis. Pigs fed a 12-week high fat diet developed obesity and hyperlipidaemia. This was associated with increased redox sensitive pro-inflammatory and anti-apoptotic signalling, and tubular epithelial cell proliferation. High fat feeding also protected swine against post CPB AKI; mean difference in creatinine clearance CPB - CPB + HF −65.3 ml/min (95% CI −106.9 to −23.7), by preserving endothelial homeostasis and function

  14. Acute pancreatitis as a model of SIRS.

    PubMed

    Bhatia, Madhav

    2009-01-01

    Acute pancreatitis is a common clinical condition. Excessive systemic inflammatory response syndrome (SIRS) in acute pancreatitis leads to distant organ damage and multiple organ dysfunction syndrome (MODS), which is the primary cause of morbidity and mortality in this condition. Development of in vivo experimental models of acute pancreatitis and associated systemic organ damage has enabled us to study the role played by inflammatory mediators in the pathogenesis of acute pancreatitis and associated systemic organ damage. Using these models, recent studies by us and other investigators have established the critical role played by inflammatory mediators such as TNF-a, IL-1b, IL-6, PAF, IL-10, CD40L, C5a, ICAM-1, chemokines, substance P and hydrogen sulfide in acute pancreatitis and the resultant MODS. This chapter intends to present an overview of different experimental animal models of acute pancreatitis and associated MODS and the role of inflammatory mediators in the pathogenesis of this condition.

  15. Relationship between Cerebrospinal Fluid Biomarkers for Inflammation, Demyelination and Neurodegeneration in Acute Optic Neuritis

    PubMed Central

    Modvig, Signe; Degn, Matilda; Horwitz, Henrik; Cramer, Stig P.; Larsson, Henrik B. W.; Wanscher, Benedikte; Sellebjerg, Finn; Frederiksen, Jette L.

    2013-01-01

    Background Various inflammatory biomarkers show prognostic potential for multiple sclerosis (MS)-risk after clinically isolated syndromes. However, biomarkers are often examined singly and their interrelation and precise aspects of their associated pathological processes remain unclear. Clarification of these relationships could aid the appropriate implementation of prognostic biomarkers in clinical practice. Objective To investigate the interrelation between biomarkers of inflammation, demyelination and neurodegeneration in acute optic neuritis and to assess their association to measures of MS risk. Material and Methods A prospective study at a tertiary referral centre from June 2011 to December 2012 of 56 patients with optic neuritis as a first demyelinating symptom and 27 healthy volunteers. Lumbar puncture was performed within 28 (median 16) days of onset. CSF levels of CXCL13, matrix metalloproteinase (MMP)-9, CXCL10, CCL-2, osteopontin and chitinase-3-like-1, myelin basic protein (MBP) and neurofilament light-chain (NF-L) were determined. MS-risk outcome measures were dissemination in space (DIS) of white matter lesions on cerebral MRI, CSF oligoclonal bands and elevated IgG-index. Results In the interrelation analysis the biomarkers showed close correlations within two distinct groups: Biomarkers of leukocyte infiltration (CXCL13, MMP-9 and CXCL10) were strongly associated (p<0.0001 for all). Osteopontin and chitinase-3-like-1 were also tightly associated (p<0.0001) and correlated strongly to tissue damage markers (NF-L and MBP). The biomarkers of leukocyte infiltration all associated strongly with MS-risk parameters, whereas CHI3L1 and MBP correlated with MRI DIS, but not with CSF MS-risk parameters and osteopontin and NF-L did not correlate with any MS-risk parameters. Conclusions Our findings suggest two distinct inflammatory processes: one of leukocyte infiltration, represented by CXCL13, CXCL10 and MMP-9, strongly associated with and potentially

  16. Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance

    PubMed Central

    Balza, E; Piccioli, P; Carta, S; Lavieri, R; Gattorno, M; Semino, C; Castellani, P; Rubartelli, A

    2016-01-01

    Incidence of sepsis is increasing, representing a tremendous burden for health-care systems. Death in acute sepsis is attributed to hyperinflammatory responses, but the underlying mechanisms are still unclear. We report here that proton pump inhibitors (PPIs), which block gastric acid secretion, selectively inhibited tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) secretion by Toll-like receptor (TLR)-activated human monocytes in vitro, in the absence of toxic effects. Remarkably, the oversecretion of IL-1β that represents a hallmark of monocytes from patients affected by cryopyrin-associated periodic syndrome is also blocked. Based on these propaedeutic experiments, we tested the effects of high doses of PPIs in vivo in the mouse model of endotoxic shock. Our data show that a single administration of PPI protected mice from death (60% survival versus 5% of untreated mice) and decreased TNF-α and IL-1β systemic production. PPIs were efficacious even when administered after lipopolysaccharide (LPS) injection. PPI-treated mice that survived developed a long-term cross-tolerance, becoming resistant to LPS- and zymosan-induced sepsis. In vitro, their macrophages displayed impaired TNF-α and IL-1β to different TLR ligands. PPIs also prevented sodium thioglycollate-induced peritoneal inflammation, indicating their efficacy also in a non-infectious setting independent of TLR stimulation. Lack of toxicity and therapeutic effectiveness make PPIs promising new drugs against sepsis and other severe inflammatory conditions. PMID:27441656

  17. Glycyrrhizic acid pretreatment prevents sepsis-induced acute kidney injury via suppressing inflammation, apoptosis and oxidative stress.

    PubMed

    Zhao, Hongyu; Liu, Zhenning; Shen, Haitao; Jin, Shuai; Zhang, Shun

    2016-06-15

    Glycyrrhizic acid (GA), an active ingredient in licorice, has multiple pharmacological activities. The aim of our study was to investigate the molecular mechanism involved in the protective effects of GA in lipopolysaccharide (LPS) stimulated rat mesangial cells (HBZY-1) and septic rats. Sepsis model was established by injection of 5mg/kg LPS in rats or incubation with 1μg/ml LPS for 24h in HBZY-1 cells. A variety of molecular biological experiments were carried out to assess the effects of GA on inflammation, apoptosis, and oxidative stress. First we found that GA alleviated sepsis-induced kidney injury in vivo. Furthermore, GA suppressed inflammatory response in vivo and in vitro. Additionally, GA inhibited cell apoptosis and the changes in expressions of apoptosis related proteins induced by LPS. Moreover, GA markedly inhibited oxidative stress induced by LPS via activation of ERK signaling pathway. Finally GA could inhibit the activation of NF-κ B induced by LPS. Our present study indicates that GA has a protective effect against sepsis-induced inflammatory response, apoptosis, and oxidative stress damage, which provides a molecular basis for a new medical treatment of septic acute kidney injury.

  18. Mouse model of intrauterine inflammation: sex-specific differences in long-term neurologic and immune sequelae.

    PubMed

    Dada, Tahani; Rosenzweig, Jason M; Al Shammary, Mofeedah; Firdaus, Wance; Al Rebh, Shorouq; Borbiev, Talaibek; Tekes, Aylin; Zhang, Jiangyang; Alqahtani, Eman; Mori, Susumu; Pletnikov, Mikhail V; Johnston, Michael V; Burd, Irina

    2014-05-01

    Preterm infants, especially those that are exposed to prenatal intrauterine infection or inflammation, are at a major risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. We have previously shown in a mouse model that there is an acute fetal brain insult associated with intrauterine inflammation. The objectives of this study were: (1) to elucidate long-term (into adolescence and adulthood) neurological outcomes by assessing neurobehavioral development, MRI, immunohistochemistry and flow cytometry of cells of immune origin and (2) to determine whether there are any sex-specific differences in brain development associated with intrauterine inflammation. Our results have shown that prenatal exposure appeared to lead to changes in MRI and behavior patterns throughout the neonatal period and during adulthood. Furthermore, we observed chronic brain inflammation in the offspring, with persistence of microglial activation and increased numbers of macrophages in the brain, ultimately resulting in neuronal loss. Moreover, our study highlights the sex-specific differences in long-term sequelae. This study, while extending the growing literature of adverse neurologic outcomes following exposure to inflammation during early development, presents novel findings in the context of intrauterine inflammation.

  19. Endoplasmic reticulum stress-activated glycogen synthase kinase 3β aggravates liver inflammation and hepatotoxicity in mice with acute liver failure.

    PubMed

    Ren, Feng; Zhou, Li; Zhang, Xiangying; Wen, Tao; Shi, Hongbo; Xie, Bangxiang; Li, Zhuo; Chen, Dexi; Wang, Zheling; Duan, Zhongping

    2015-01-01

    Endoplasmic reticulum stress (ER stress) has been increasingly recognized as an important mechanism in various liver diseases. However, its intrinsic physiological role in acute liver failure (ALF) remains largely undetermined. This study aimed to examine how ER stress orchestrates glycogen synthase kinase 3β (GSK3β) and inflammation to affect ALF. In a murine ALF model induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS), 4-phenylbutyric acid (4-PBA) is to be administered to relieve ER stress. The lethality rate, liver damage, cytokine expression, and the activity of GSK3β were evaluated. How to regulate LPS-induced inflammation and TNF-α-induced hepatocyte apoptosis by ER stress was investigated in vitro. In vivo, ER stress was triggered in the liver with the progression of mice ALF model. ER stress was essential for the development of ALF because ER stress inhibition by 4-PBA ameliorated the liver damage through decreasing liver inflammation and hepatocyte apoptosis. 4-PBA also decreased GSK3β activity in the livers of ALF mice. In vitro, ER stress induced by tunicamycin synergistically increased LPS-triggered pro-inflammatory cytokine induction and promoted the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway in bone marrow-derived macrophages; moreover, tunicamycin also cooperated with TNF-α to increase hepatocyte apoptosis. ER stress promoted LPS-triggered inflammation depending on GSK3β activation because inhibition of GSK3β by SB216763, the specific inhibitor of GSK3β, resulted in downregulation of pro-inflammatory genes. ER stress contributes to liver inflammation and hepatotoxicity in ALF, particularly by regulating GSK3β, and is therefore a potential therapeutic target for ALF.

  20. Acute inflammation in peritoneal dialysis: experimental studies in rats. Characterization of regulatory mechanisms.

    PubMed

    Bazargani, Farhan

    2005-01-01

    The predominant problems associated with peritoneal dialysis (PD) are ultrafiltration failure and peritonitis. PD maintains a state of intraperitoneal inflammation that affects the structure and function of the peritoneal membrane, potentially impairing ultrafiltration efficiency. Paradoxically, some PD fluids also have anti-inflammatory properties that may compromise the immune defense against peritonitis. This anti-inflammatory feature is mostly due to the glucose degradation products (GDPs), formed during heat-sterilization and storage of PD fluids. The main purpose of the present thesis was to study regulatory mechanisms behind the acute intraperitoneal inflammatory response in PD in the presence and absence of experimental peritonitis. Rats were exposed to a single dose of heat- or filter sterilized PD fluids either as an i.p. injection or as an infusion through an indwelling catheter, with or without supplementations, or pretreatment of the animals. The dwell fluid was analyzed zero, two and four hours later concerning activation of the complement and coagulation cascades, neutrophil recruitment and respiratory burst, ultrafiltration volumes, cytokine-induced neutrophil chemoattractant (CINC-1), rat mast cell protease 2 (RMCP-2), glucose, urea and histamine concentrations and ex vivo/in vitro intraperitoneal chemotactic activity. Exposure to filter sterilized PD fluid alone induced intraperitoneal complement activation and coagulation, neutrophil recruitment and increased the levels of CINC-1 during the dwell. Intraperitoneal concentrations of the mast cell markers histamine and RMCP-2 changed little during the dwells and did not indicate mast cell activation. Low molecular weight heparin (LMWH) and C5 blockade improved ultrafiltration. Pretreatment with cobra venom factor, known decomplementing agent, blocked the CINC-1 release and the neutrophil recruitment and improved ultrafiltration. In combination with experimental peritonitis, heat sterilized PD fluid

  1. The effect of Prometheus device on laboratory markers of inflammation and tissue regeneration in acute liver failure management.

    PubMed

    Rocen, M; Kieslichova, E; Merta, D; Uchytilova, E; Pavlova, Y; Cap, J; Trunecka, P

    2010-11-01

    Prometheus, based on modified fractionated plasma separation and adsorption (FPSA) method, is used in the therapy of acute liver failure as a bridge to liver transplantation. As the therapeutic effect of Prometheus is caused not only by the elimination of terminal metabolites, the aim of the study was to identify the effect of FPSA on the levels of cytokines and markers of inflammation and liver regeneration. Previous studies assessing cytokine levels involved mostly acute-on-chronic liver failure patients. Data concerning markers of inflammation and liver regeneration are not published yet. Eleven patients (three males, eight females) with acute liver failure were investigated. These patients underwent 37 therapeutic sessions on Prometheus device. Before and after each treatment, the plasma levels of selected cytokines, tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), procalcitonin (PCT), hepatocyte growth factor (HGF), and α(1) fetoprotein, were measured, and the kinetics of their plasma concentrations was evaluated. Before the therapy, elevated levels of interleukin (IL)-6, IL-8, IL-10, TNFα, CRP, and PCT were detected. The level of TNFα, CRP, PCT, and α(1) fetoprotein decreased significantly during the therapy. In contrast, an increase of HGF was detected. The decline of IL-6, IL-8, and IL-10 concentrations was not significant. Our results show that Prometheus is highly effective in clearing inflammatory mediators responsible for systemic inflammatory response syndrome and affects the serum levels of inflammatory and regeneration markers important for management of acute liver failure.

  2. Comparative assessment of effectiveness of ketoprofen and ketoprofen/beta-cyclodextrin complex in two experimental models of inflammation in rats.

    PubMed

    Grecu, Mariana; Năstasă, Valentin; Ilie, Cornelia; Miron, Liviu; Mareş, Mihai

    2014-01-01

    Oral administration of non-steroidal anti-inflammatory drugs (NSAIDs) can lead to adverse effects such as gastrointestinal distress. The complexation of different groups of active substances with β-cyclodextrin (β-CD) has drawn considerable interest over recent years. The purpose of this study was to analyze the ketoprofen/β-cyclodextrin (K/β-CD) conjugate complex as well as to assess its anti-inflammatory effect after oral administration (doses of 30 mg/m(2) and 15 mg/m(2) of body surface), compared with ketoprofen. The studies were done on two models of experimentally-induced acute inflammation in rats (n = 48, 6/group), by means of intraplantar administration of a 10% aqueous kaolin suspension and intraperitoneal administration of a 1% sodium thioglycolate solution. The dynamics of the acute inflammatory process and the anti-inflammatory effects were monitored using plethysmometric determinations after 3, 6, 9, 12, 24 and 48 h (plantar inflammation), and the absorbance of the exudates (spectrophotometrically read) and nucleated cell counts after 24 h (peritoneal inflammation). The coupling of ketoprofen with β-CD resulted in increased solubility (100% in 60 min) of the newly-formed product, which further resulted in a higher bioavailability compared with ketoprofen (<40% in 120 min). In both models of experimentally-induced inflammation, the K/β-CD complex had a higher anti-inflammatory activity than ketoprofen.

  3. Neutrophil Extracellular Traps Form a Barrier between Necrotic and Viable Areas in Acute Abdominal Inflammation

    PubMed Central

    Bilyy, Rostyslav; Fedorov, Volodymyr; Vovk, Volodymyr; Leppkes, Moritz; Dumych, Tetiana; Chopyak, Valentyna; Schett, Georg; Herrmann, Martin

    2016-01-01

    Neutrophils form neutrophil extracellular traps (NETs) of decondensed DNA and histones that trap and immobilize particulate matter and microbial pathogens like bacteria. NET aggregates reportedly surround and isolate large objects like monosodium urate crystals, which cannot be sufficiently cleared from tissues. In the setting of acute necrotizing pancreatitis, massive tissue necrosis occurs, which is organized as pancreatic pseudocysts (1). In contrast to regular cysts, these pseudocysts are not surrounded by epithelial layers. We hypothesize that, instead, the necrotic areas observed in necrotizing pancreatitis are isolated from the surrounding healthy tissues by aggregated NETs. These may form an alternative, putatively transient barrier, separating necrotic areas from viable tissue. To test this hypothesis, we investigated histological samples from the necropsy material of internal organs of two patients with necrotizing pancreatitis and peritonitis accompanied by multiple organ failure. Tissues including the inflammatory zone were stained with hematoxylin and eosin and evaluated for signs of inflammation. Infiltrating neutrophils and NETs were detected by immunohistochemistry for DNA, neutrophil elastase (NE), and citrullinated histone H3. Interestingly, in severely affected areas of pancreatic necrosis or peritonitis, chromatin stained positive for NE and citrullinated histone H3, and may, therefore, be considered NET-derived. These NET structures formed a layer, which separated the necrotic core from the areas of viable tissue remains. A condensed layer of aggregated NETs, thus, spatially shields and isolates the site of necrosis, thereby limiting the spread of necrosis-associated proinflammatory mediators. We propose that necrotic debris may initiate and/or facilitate the formation of the NET-based surrogate barrier. PMID:27777576

  4. Impact of Prostate Inflammation on Lesion Development in the POET3+Pten+/− Mouse Model of Prostate Carcinogenesis

    PubMed Central

    Burcham, Grant N.; Cresswell, Gregory M.; Snyder, Paul W.; Chen, Long; Liu, Xiaoqi; Crist, Scott A.; Henry, Michael D.; Ratliff, Timothy L.

    2015-01-01

    Evidence linking prostatitis and prostate cancer development is contradictory. To study this link, the POET3 mouse, an inducible model of prostatitis, was crossed with a Pten-loss model of prostate cancer (Pten+/−) containing the ROSA26 luciferase allele to monitor prostate size. Prostatitis was induced, and prostate bioluminescence was tracked over 12 months, with lesion development, inflammation, and cytokine expression analyzed at 4, 8, and 12 months and compared with mice without induction of prostatitis. Acute prostatitis led to more proliferative epithelium and enhanced bioluminescence. However, 4 months after initiation of prostatitis, mice with induced inflammation had lower grade pre-neoplastic lesions. A trend existed toward greater development of carcinoma 12 months after induction of inflammation, including one of two mice with carcinoma developing perineural invasion. Two of 18 mice at the later time points developed lesions with similarities to proliferative inflammatory atrophy, including one mouse with associated carcinoma. Pten+/− mice developed spontaneous inflammation, and prostatitis was similar among groups of mice at 8 and 12 months. Analyzed as one cohort, lesion number and grade were positively correlated with prostatitis. Specifically, amounts of CD11b+Gr1+ cells were correlated with lesion development. These results support the hypothesis that myeloid-based inflammation is associated with lesion development in the murine prostate, and previous bouts of CD8-driven prostatitis may promote invasion in the Pten+/− model of cancer. PMID:25455686

  5. New Echocardiographic Findings Correlate with Intramyocardial Inflammation in Endomyocardial Biopsies of Patients with Acute Myocarditis and Inflammatory Cardiomyopathy

    PubMed Central

    Escher, Felicitas; Kasner, Mario; Kühl, Uwe; Heymer, Johannes; Wilkenshoff, Ursula; Tschöpe, Carsten; Schultheiss, Heinz-Peter

    2013-01-01

    Background. The diagnosis of acute myocarditis (AMC) and inflammatory cardiomyopathy (DCMi) can be difficult. Speckle tracking echocardiography with accurate assessments of regional contractility could have an outstanding importance for the diagnosis. Methods and Results. N = 25 patients with clinically diagnosed AMC who underwent endomyocardial biopsies (EMBs) were studied prospectively. Speckle tracking imaging was examined at the beginning and during a mean follow-up period of 6.2 months. In the acute phase patients had markedly decreased left ventricular (LV) systolic function (mean LV ejection fraction (LVEF) 40.4 ± 10.3%). At follow-up in n = 8 patients, inflammation persists, correlating with a significantly reduced fractional shortening (FS, 21.5 ± 6.0%) in contrast to those without inflammation in EMB (FS 32.1 ± 7.1%, P < 0.05). All AMC patients showed a reduction in global systolic longitudinal strain (LS, −8.36 ± −3.47%) and strain rate (LSR, 0.53 ± 0.29 1/s). At follow-up, LS and LRS were significantly lower in patients with inflammation, in contrast to patients without inflammation (−9.4 ± 1.4 versus −16.8 ± 2.0%, P < 0.0001; 0.78 ± 0.4 versus 1.3 ± 0.3 1/s). LSR and LS correlate significantly with lymphocytic infiltrates (for CD3 r = 0.7, P < 0.0001, and LFA-1 r = 0.8, P < 0.0001). Conclusion. Speckle tracking echocardiography is a useful adjunctive assisting tool for evaluation over the course of intramyocardial inflammation in patients with AMC and DCMi. PMID:23576857

  6. Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice

    PubMed Central

    Kovacic, Jason C.; Gupta, Rohit; Lee, Angela C.; Ma, Mingchao; Fang, Fang; Tolbert, Claire N.; Walts, Avram D.; Beltran, Leilani E.; San, Hong; Chen, Guibin; St. Hilaire, Cynthia; Boehm, Manfred

    2009-01-01

    Inflammation is a key component of arterial injury, with VSMC proliferation and neointimal formation serving as the final outcomes of this process. However, the acute events transpiring immediately after arterial injury that establish the blueprint for this inflammatory program are largely unknown. We therefore studied these events in mice and found that immediately following arterial injury, medial VSMCs upregulated Rantes in an acute manner dependent on Stat3 and NF-κB (p65 subunit). This led to early T cell and macrophage recruitment, processes also under the regulation of the cyclin-dependent kinase inhibitor p21Cip1. Unique to VSMCs, Rantes production was initiated by Tnf-α, but not by Il-6/gp130. This Rantes production was dependent on the binding of a p65/Stat3 complex to NF-κB–binding sites within the Rantes promoter, with shRNA knockdown of either Stat3 or p65 markedly attenuating Rantes production. In vivo, acute NF-κB and Stat3 activation in medial VSMCs was identified, with acute Rantes production after injury substantially reduced in Tnfa–/– mice compared with controls. Finally, we generated mice with SMC-specific conditional Stat3 deficiency and confirmed the Stat3 dependence of acute Rantes production by VSMCs. Together, these observations unify inflammatory events after vascular injury, demonstrating that VSMCs orchestrate the arterial inflammatory response program via acute Rantes production and subsequent inflammatory cell recruitment. PMID:20038813

  7. Supernatant of stored platelets causes lung inflammation and coagulopathy in a novel in vivo transfusion model.

    PubMed

    Vlaar, Alexander P J; Hofstra, Jorrit J; Kulik, Wim; van Lenthe, Henk; Nieuwland, Rienk; Schultz, Marcus J; Levi, Marcel M; Roelofs, Joris J T H; Tool, Anton T J; de Korte, Dirk; Juffermans, Nicole P

    2010-08-26

    Transfusion-related acute lung injury is suggested to be a "2-hit" event resulting from priming and activation of pulmonary neutrophils. Activation may result from infusion of lysophosphatidylcholines (LysoPCs), which accumulate during storage of blood products. In the present study, we developed a syngeneic in vivo transfusion model to test whether storage of platelet concentrates (PLTs) results in lung injury in healthy rats as well as in a "2-hit" model using lipopolysaccharide-pretreated rats. In addition, the effect of washing of platelets was studied. In healthy rats, transfusion of aged PLTs caused mild lung inflammation. In LPS-pretreated rats, transfusion of aged PLTs, but not fresh PLTs, augmented pulmonary systemic coagulopathy. When PLTs components were transfused separately, supernatant of aged PLTs, but not washed aged platelets, induced pulmonary injury in the "2-hit" model. Supernatants of aged PLTs contained increased concentrations of LysoPCs compared with fresh PLTs, which enhanced neutrophil priming activity in vitro. We conclude that transfusion of aged PLTs induces lung inflammation in healthy rats. In a "2-hit" model, aged PLTs contribute to pulmonary and systemic coagulopathy, which may be mediated by LysoPCs, which accumulate in the supernatant of PLTs during storage.

  8. Genetically engineered mucin mouse models for inflammation and cancer

    PubMed Central

    Joshi, Suhasini; Kumar, Sushil; Bafna, Sangeeta; Rachagani, Satyanarayana; Wagner, Kay-Uwe; Jain, Maneesh

    2015-01-01

    Mucins are heavily O-glycosylated proteins primarily produced by glandular and ductal epithelial cells, either in membrane-tethered or secretory forms, for providing lubrication and protection from various exogenous and endogenous insults. However, recent studies have linked their aberrant overexpression with infection, inflammation, and cancer that underscores their importance in tissue homeostasis. In this review, we present current status of the existing mouse models that have been developed to gain insights into the functional role(s) of mucins under physiological and pathological conditions. Knockout mouse models for membrane-associated (Muc1 and Muc16) and secretory mucins (Muc2) have helped us to elucidate the role of mucins in providing effective and protective barrier functions against pathological threats, participation in disease progression, and improved our understanding of mucin interaction with biotic and abiotic environmental components. Emphasis is also given to available transgenic mouse models (MUC1 and MUC7), which has been exploited to understand the context-dependent regulation and therapeutic potential of human mucins during inflammation and cancer. PMID:25634251

  9. Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice

    PubMed Central

    Bhaskaran, Natarajan; Weinberg, Aaron; Pandiyan, Pushpa

    2015-01-01

    Oropharyngeal Candidiasis (OPC) disease is caused not only due to the lack of host immune resistance, but also the absence of appropriate regulation of infection-induced immunopathology. Although Th17 cells are implicated in antifungal defense, their role in immunopathology is unclear. This study presents a method for establishing oral Th17 immunopathology associated with oral candidal infection in immunodeficient mice. The method is based on reconstituting lymphopenic mice with in vitro cultured Th17 cells, followed by oral infection with Candida albicans (C. albicans). Results show that unrestrained Th17 cells result in inflammation and pathology, and is associated with several measurable read-outs including weight loss, pro-inflammatory cytokine production, tongue histopathology and mortality, showing that this model may be valuable in studying OPC immunopathology. Adoptive transfer of regulatory cells (Tregs) controls and reduces the inflammatory response, showing that this model can be used to test new strategies to counteract oral inflammation. This model may also be applicable in studying oral Th17 immunopathology in general in the context of other oral diseases. PMID:25742163

  10. Th17 inflammation model of oropharyngeal candidiasis in immunodeficient mice.

    PubMed

    Bhaskaran, Natarajan; Weinberg, Aaron; Pandiyan, Pushpa

    2015-02-18

    Oropharyngeal Candidiasis (OPC) disease is caused not only due to the lack of host immune resistance, but also the absence of appropriate regulation of infection-induced immunopathology. Although Th17 cells are implicated in antifungal defense, their role in immunopathology is unclear. This study presents a method for establishing oral Th17 immunopathology associated with oral candidal infection in immunodeficient mice. The method is based on reconstituting lymphopenic mice with in vitro cultured Th17 cells, followed by oral infection with Candida albicans (C. albicans). Results show that unrestrained Th17 cells result in inflammation and pathology, and is associated with several measurable read-outs including weight loss, pro-inflammatory cytokine production, tongue histopathology and mortality, showing that this model may be valuable in studying OPC immunopathology. Adoptive transfer of regulatory cells (Tregs) controls and reduces the inflammatory response, showing that this model can be used to test new strategies to counteract oral inflammation. This model may also be applicable in studying oral Th17 immunopathology in general in the context of other oral diseases.

  11. Inhibition of Carrageenan-Induced Acute Inflammation in Mice by Oral Administration of Anthocyanin Mixture from Wild Mulberry and Cyanidin-3-Glucoside

    PubMed Central

    Hassimotto, Neuza Mariko Aymoto; Moreira, Vanessa; do Nascimento, Neide Galvão; Souto, Pollyana Cristina Maggio de Castro; Teixeira, Catarina; Lajolo, Franco Maria

    2013-01-01

    Anthocyanins are flavonoids which demonstrated biological activities in in vivo and in vitro models. Here in the anti-inflammatory properties of an anthocyanin-enriched fraction (AF) extracted from wild mulberry and the cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, were studied in two acute inflammation experimental models, in the peritonitis and in the paw oedema assays, both of which were induced by carrageenan (cg) in mice. In each trial, AF and C3G (4 mg/100 g/animal) were orally administered in two distinct protocols: 30 min before and 1 h after cg stimulus. The administration of both AF and C3G suppresses the paw oedema in both administration times (P < 0.05). In the peritonitis, AF and C3G reduced the polymorphonuclear leukocytes (PMN) influx in the peritoneal exudates when administered 1 h after cg injection. AF was more efficient reducing the PMN when administered 30 min before cg. Both AF and C3G were found to suppress mRNA as well as protein levels of COX-2 upregulated by cg in both protocols, but the inhibitory effect on PGE2 production in the peritoneal exudates was observed when administered 30 min before cg (P < 0.05). Our findings suggest that AF and C3G minimize acute inflammation and they present positive contributions as dietary supplements. PMID:23484081

  12. Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury.

    PubMed

    Bosmann, Markus; Grailer, Jamison J; Ruemmler, Robert; Russkamp, Norman F; Zetoune, Firas S; Sarma, J Vidya; Standiford, Theodore J; Ward, Peter A

    2013-12-01

    We investigated how complement activation promotes tissue injury and organ dysfunction during acute inflammation. Three models of acute lung injury (ALI) induced by LPS, IgG immune complexes, or C5a were used in C57BL/6 mice, all models requiring availability of both C5a receptors (C5aR and C5L2) for full development of ALI. Ligation of C5aR and C5L2 with C5a triggered the appearance of histones (H3 and H4) in bronchoalveolar lavage fluid (BALF). BALF from humans with ALI contained H4 histone. Histones were absent in control BALF from healthy volunteers. In mice with ALI, in vivo neutralization of H4 with IgG antibody reduced the intensity of ALI. Neutrophil depletion in mice with ALI markedly reduced H4 presence in BALF and was highly protective. The direct lung damaging effects of extracellular histones were demonstrated by airway administration of histones into mice and rats (Sprague-Dawley), which resulted in ALI that was C5a receptor-independent, and associated with intense inflammation, PMN accumulation, damage/destruction of alveolar epithelial cells, together with release into lung of cytokines/chemokines. High-resolution magnetic resonance imaging demonstrated lung damage, edema and consolidation in histone-injured lungs. These studies confirm the destructive C5a-dependent effects in lung linked to appearance of extracellular histones.

  13. A Novel Model of Severe Gallstone Pancreatitis: Murine Pancreatic Duct Ligation Results in Systemic Inflammation and Substantial Mortality

    PubMed Central

    Samuel, Isaac; Yuan, Zuobiao; Meyerholz, David K.; Twait, Erik; Williard, Deborah E.; Kempuraj, Duraisamy

    2010-01-01

    Background Suitable experimental models of gallstone pancreatitis with systemic inflammation and mortality are limited. We developed a novel murine model of duct-ligation-induced acute pancreatitis associated with multiorgan dysfunction and severe mortality. Methods Laparotomy was done on C57/BL6 mice followed by pancreatic duct (PD) ligation, bile duct (BD) ligation without PD ligation, or sham operation. Results Only mice with PD ligation developed acute pancreatitis and had 100% mortality. Pulmonary compliance was significantly reduced after PD ligation but not BD ligation. Bronchoalveolar lavage fluid neutrophil count and interleukin-1β concentration, and the plasma creatinine level, were significantly elevated with PD ligation but not BD ligation. Pancreatic nuclear factor κB (p65) and activator protein 1 (c-Jun) were activated within 1 h of PD ligation. Conclusion PD-ligation-induced acute pancreatitis in mice is associated with systemic inflammation, acute lung injury, multiorgan dysfunction and death. The development of this novel model is an exciting and notable advance in the field. PMID:20975317

  14. Impacts of allergic airway inflammation on lung pathology in a mouse model of influenza A virus infection

    PubMed Central

    Kawaguchi, Akira; Ohara, Yuki; Takahashi, Kenta; Sato, Yuko; Ainai, Akira; Nagata, Noriyo; Tashiro, Masato; Hasegawa, Hideki

    2017-01-01

    Influenza A virus is the respiratory pathogen responsible for influenza. Infection by the 2009 pandemic influenza A (H1N1) virus caused severe lower airway inflammation and pneumonia. Asthma is a chronic inflammatory disorder of the airways that affects the entire brachial tree, and was one of the commonest underlying medical conditions among patients hospitalized with the 2009 pandemic influenza virus infection. Although respiratory virus infections are the major causes of asthma exacerbation, the mechanism by which influenza exacerbates asthma is poorly understood. Animal models of disease comorbidity are crucial to understanding host-pathogen interactions and elucidating complex pathologies. Existing murine models of influenza virus infection in asthmatics show that asthmatic mice are highly resistant to influenza virus infection, which contradicts clinical observations in humans. Here, we developed a murine model of influenza virus/asthma comorbidity using NC/Nga mice, which are highly sensitive to allergic reactions such as atopic dermatitis and allergic airway inflammation. This model was then used to examine the impact of allergic airway inflammation on lung pathology in the 2009 pandemic influenza virus infected mice. The results showed that induction of acute allergic airway inflammation in pre-existing influenza virus infection had additive effects on exacerbation of lung pathology, which mirrors findings in human epidemiological studies. In contrast, pre-existing allergic airway inflammation protected from subsequent influenza virus infection, which was compatible with those of previous murine models of influenza virus infection in asthmatic mice. These variable outcomes of this murine model indicate that the temporal relation between allergic airway inflammation and influenza virus infection might play a critical role in asthma and influenza comorbidity. Thus, this murine model will further our understanding of how influenza virus infection affects an

  15. Characterization of tissue and plasma glycosaminoglycans during experimental AA amyloidosis and acute inflammation. Qualitative and quantitative analysis.

    PubMed

    Snow, A D; Kisilevsky, R; Stephens, C; Anastassiades, T

    1987-06-01

    Qualitative and quantitative methods were used to determine changes in glycosaminoglycans (GAGs) in the spleen and plasma during initial stages of experimental amyloidosis and acute inflammation. GAG deposition in the spleen during the early stages of amyloidosis consists of a 16-fold heparin and heparan sulfate increase. Though splenic weights do increase during protracted inflammation only minor changes arise in splenic GAGs in the absence of amyloid deposition. An overall increase in plasma GAGs, consisting of a 4.5-fold chondroitin-4-sulphate increase, occurred at the time of GAG deposition in the tissues (spleen, liver) and probably accounts for the minor GAG changes seen in the spleen during inflammation. The time course of splenic heparin/heparan sulfate increase during amyloid deposition coincides with the histochemical changes previously described. Plasma GAG changes follow a pattern similar to that of acute phase protein reactants. The results suggest that GAG metabolism, in particular heparin/heparan sulfate, are intimately involved in the process of AA amyloidogenesis.

  16. Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models.

    PubMed

    Lieber, Gissela B; Fernandez, Xiomara; Mingo, Garfield G; Jia, Yanlin; Caniga, Michael; Gil, Malgorzata A; Keshwani, Shanil; Woodhouse, Janice D; Cicmil, Milenko; Moy, Lily Y; Kelly, Nancy; Jimenez, Johanna; Crawley, Yvette; Anthes, John C; Klappenbach, Joel; Ma, Yu-Lu; McLeod, Robbie L

    2013-10-15

    Accumulating evidence indicates protective actions of mineralocorticoid antagonists (MR antagonists) on cardiovascular pathology, which includes blunting vascular inflammation and myocardial fibrosis. We examined the anti-inflammatory and anti-fibrotic potential of MR antagonists in rodent respiratory models. In an ovalbumin allergic and challenged Brown Norway rat model, the total cell count in nasal lavage was 29,348 ± 5451, which was blocked by spironolactone (0.3-60 mg/kg, p.o.) and eplerenone (0.3-30 mg/kg, p.o.). We also found that MR antagonists attenuated pulmonary inflammation in the Brown Norway rat. A series of experiments were conducted to determine the actions of MR blockade in acute/chronic lung injury models. (1) Ex vivo lung slice rat experiments found that eplerenone (0.01 and 10 µM) and spironolactone (10 µM) diminished lung hydroxyproline concentrations by 55 ± 5, 122 ± 9, and 83 ± 8%. (2) In in vivo studies, MR antagonists attenuated the increases in bronchioalveolar lavage (BAL) neutrophils and macrophages caused by lung bleomycin exposure. In separate studies, bleomycin (4.0 U/kg, i.t.) increased lung levels of hydroxyproline by approximately 155%, which was blocked by spironolactone (10-60 mg/kg, p.o.). In a rat Lipopolysaccharide (LPS) model, spironolactone inhibited acute increases in BAL cytokines with moderate effects on neutrophils. Finally, we found that chronic LPS exposure significantly increased end expiratory lung and decreased lung elastance in the mouse. These functional effects of chronic LPS were improved by MR antagonists. Our results demonstrate that MR antagonists have significant pharmacological actions in the respiratory system.

  17. Experimental Models in Syrian Golden Hamster Replicate Human Acute Pancreatitis

    PubMed Central

    Wang, Yunan; Kayoumu, Abudurexiti; Lu, Guotao; Xu, Pengfei; Qiu, Xu; Chen, Liye; Qi, Rong; Huang, Shouxiong; Li, Weiqin; Wang, Yuhui; Liu, George

    2016-01-01

    The hamster has been shown to share a variety of metabolic similarities with humans. To replicate human acute pancreatitis with hamsters, we comparatively studied the efficacy of common methods, such as the peritoneal injections of caerulein, L-arginine, the retrograde infusion of sodium taurocholate, and another novel model with concomitant administration of ethanol and fatty acid. The severity of pancreatitis was evaluated by serum amylase activity, pathological scores, myeloperoxidase activity, and the expression of inflammation factors in pancreas. The results support that the severity of pathological injury is consistent with the pancreatitis induced in mice and rat using the same methods. Specifically, caerulein induced mild edematous pancreatitis accompanied by minimal lung injury, while L-arginine induced extremely severe pancreatic injury including necrosis and neutrophil infiltration. Infusion of Na-taurocholate into the pancreatic duct induced necrotizing pancreatitis in the head of pancreas and lighter inflammation in the distal region. The severity of acute pancreatitis induced by combination of ethanol and fatty acids was between the extent of caerulein and L-arginine induction, with obvious inflammatory cells infiltration. In view of the advantages in lipid metabolism features, hamster models are ideally suited for the studies of pancreatitis associated with altered metabolism in humans. PMID:27302647

  18. HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis

    PubMed Central

    Tenhunen, Jyrki; Tonnessen, Tor Inge

    2017-01-01

    Severe acute pancreatitis (SAP) starts as a local inflammation of pancreatic tissue that induces the development of multiple extrapancreatic organs dysfunction; however, the underlying mechanisms are still not clear. Ischemia-reperfusion, circulating inflammatory cytokines, and possible bile cytokines significantly contribute to gut mucosal injury and intestinal bacterial translocation (BT) during SAP. Circulating HMGB1 level is significantly increased in SAP patients and HMGB1 is an important factor that mediates (at least partly) gut BT during SAP. Gut BT plays a critical role in triggering/inducing systemic inflammation/sepsis in critical illness, and profound systemic inflammatory response syndrome (SIRS) can lead to multiple organ dysfunction syndrome (MODS) during SAP, and systemic inflammation with multiorgan dysfunction is the cause of death in experimental SAP. Therefore, HMGB1 is an important factor that links gut BT and systemic inflammation. Furthermore, HMGB1 significantly contributes to multiple organ injuries. The SAP patients also have significantly increased circulating histones and cell-free DNAs levels, which can reflect the disease severity and contribute to multiple organ injuries in SAP. Hepatic Kupffer cells (KCs) are the predominant source of circulating inflammatory cytokines in SAP, and new evidence indicates that hepatocyte is another important source of circulating HMGB1 in SAP; therefore, treating the liver injury is important in SAP. PMID:28316860

  19. Time course changes of oxidative stress and inflammation in hyperoxia-induced acute lung injury in rats

    PubMed Central

    Yu, Shouli; Shi, Min; Liu, Changting; Liu, Qinghui; Guo, Jun; Yu, Senyang; Jiang, Tingshu

    2015-01-01

    Objective(s): Therapies with high levels of oxygen are commonly used in the management of critical care. However, prolonged exposure to hyperoxia can cause acute lung injury. Although oxidative stress and inflammation are purported to play an important role in the pathogenesis of acute lung injury, the exact mechanisms are still less known in the hyperoxic acute lung injury (HALI). Materials and Methods: In this study, we investigated the time course changes of oxidative stress and inflammation in lung tissues of rats exposed to >95% oxygen for 12-60 hr. Results: We found that at 12 hr after hyperoxia challenge, the activities of superoxide dismutase and glutathione peroxidase were significantly reduced with remarkably increased lipid peroxidation. At 12 hr, NF-κB p65 expression was also upregulated, but Iκ-Bα expression showed a remarkable decline. Significant production of inflammatory mediators, e.g, interleukin-1β, occurred 24 hr after hyperoxia exposure. In addition, the expression of intracellular adhesion molecule 1 expression and the activity of myeloperoxidase were significantly increased at 24 hr with a peak at 48 hr. Conclusion: Our data support that hyperoxia-induced oxidative damage and NF-κB pathway activation implicate in the early phase of HALI pathogenesis. PMID:25810882

  20. Octreotide ameliorates inflammation and apoptosis in acute and kindled murine PTZ paradigms.

    PubMed

    Al-Shorbagy, M Y; Nassar, Noha N

    2017-01-01

    In the present study, the role of octreotide (OCT) in pentylenetetrazole (PTZ) kindling as well as in acute convulsion models was evaluated. Mice were allocated in groups as (1) control saline; (2) acute PTZ (PTZ-a; 60 mg/kg, i.p.), as a single convulsive dose; and (3) kindled (PTZ-k) receiving nine subconvulsive doses of PTZ (40 mg/kg, i.p.) for 17 days. Groups 4-7 received either valproic acid (VPA) 50 mg/kg or OCT (50 μg/kg, Sandostatin®) 30 min by oral gavage before PTZ-a or PTZ-k. The median seizure stage, latency onset of first stage 4/5 seizures, and incidence of convulsing animals were recorded. Cortical dopamine (DA), tumor necrosis factor (TNF)-α, interleukin (IL)-10, caspase (Casp)-3, myeloperoxidase (MPO), and nitric oxide (NO) were assessed in addition to inducible nitric oxide synthase (iNOS) that was evaluated immunohistochemically in a different set of groups. OCT halted PTZ-induced epilepsy delaying convulsion latency via modulating MPO and TNF-α and normalizing IL-10 with both treatment regimens. In PTZ-k, it decreased Casp-3 activity, NO level, and iNOS immunoreactivity. OCT in both paradigms decreased DA concentration. The current investigation implicates a crucial role for OCT in modulating PTZ-induced kindling by regulating inflammatory and apoptotic effects.

  1. Astragalin Attenuates Allergic Inflammation in a Murine Asthma Model.

    PubMed

    Liu, Jiping; Cheng, Yue; Zhang, Xiaoshuang; Zhang, Xue; Chen, Shuxian; Hu, Zongmiao; Zhou, Chunmei; Zhang, Enhu; Ma, Shiping

    2015-10-01

    The present study aimed to determine the protective effects and the underlying mechanisms of astragalin (AG) on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. Our study demonstrated that AG inhibited OVA-induced increases in eosinophil count; IL-4, IL-5, IL-13, and IgE were recovered in bronchoalveolar lavage fluid, and increased IFN-γ level in bronchoalveolar lavage fluid. Histological studies demonstrated that AG substantially inhibited OVA-induced eosinophilia in lung tissue. Western blot analysis demonstrated that AG treatments markedly inhibited OVA-induced SOCS-3 expression and enhancement of SOCS-5 expression in an asthma model. Our findings support the possible use of AG as a therapeutic drug for patients with allergic asthma.

  2. Circuit Resistance Training Attenuates Acute Exertion-Induced Reductions in Arterial Function but Not Inflammation in Obese Women

    PubMed Central

    Franklin, Nina C.; Robinson, Austin T.; Bian, Jing-Tan; Ali, Mohamed M.; Norkeviciute, Edita; McGinty, Patrick

    2015-01-01

    Abstract Background: Cardiovascular disease (CVD) is a leading cause of preventable death among young women in the United States. Habitual resistance exercise training is known to have beneficial effects on endothelial function and CVD risk factors, including obesity; however, previous studies show that acute resistance exercise impairs endothelial function in obese adults who are sedentary, a response that may be linked to inflammation. We sought to determine if circuit-based resistance training (CRT) attenuates acute resistance exercise-induced reductions in endothelial function in a population of young, obese, sedentary women and whether or not inflammation plays a role in this response. Methods: Eighteen obese [body mass index (BMI) 30.0–40.0 kg·m−2] young premenopausal women were randomly assigned to either a CRT group or a no-exercise control group (CON). Conduit artery endothelial function was assessed using brachial artery flow-mediated dilation (FMD) determined by ultrasound before and after a single bout of strenuous weightlifting (SWL). In addition, circulating inflammatory mediators (tumor necrosis factor-α and C-reactive protein), blood pressure, fasting blood lipids, glucose, waist circumference, body composition, and aerobic capacity were assessed. Results: Among participants randomized to the CRT group, 8 weeks of training led to considerable increases in FMD after SWL (P=0.001) compared to the CON group. However, no significant differences between the groups were observed in circulating inflammatory mediators, blood pressure, fasting blood lipids, or other physical and physiological characteristics. Conclusions: This study shows that CRT alleviates acute exertion-induced reductions in endothelial function among obese sedentary women in the absence of changes in inflammation. PMID:25844686

  3. Influence of Pneumococcal Conjugate Vaccine on Acute Otitis Media with Severe Middle Ear Inflammation: A Retrospective Multicenter Study.

    PubMed

    Sugino, Hirotoshi; Tsumura, Shigeru; Kunimoto, Masaru; Noda, Masuhiro; Chikuie, Daisuke; Noda, Chieko; Yamashita, Mariko; Watanabe, Hiroshi; Ishii, Hidemasa; Tashiro, Toru; Iwata, Kazuhiro; Kono, Takashi; Tsumura, Kaoru; Sumiya, Takahiro; Takeno, Sachio; Hirakawa, Katsuhiro

    2015-01-01

    The Japanese guidelines for acute otitis media in children recommend classifying acute otitis media by age, manifestations and local findings, and also recommend myringotomy for moderate-grade cases with severe local findings, severe-grade cases, and treatment-resistant cases. The heptavalent pneumococcal conjugate vaccine was released in Japan in February 2010. In Hiroshima City, public funding allowing free inoculation with this vaccine was initiated from January 2011, and the number of vaccinated individuals has since increased dramatically. This study investigated changes in the number of myringotomies performed to treat acute otitis media during the 5-year period from January 2008 to December 2012 at two hospitals and five clinics in the Asa Area of Hiroshima City, Japan. A total of 3,165 myringotomies for acute otitis media were performed. The rate of procedures per child-year performed in <5-year-old children decreased by 29.1% in 2011 and by 25.2% in 2012 compared to the mean rate performed in the 3 years prior to the introduction of public funding. A total of 895 myringotomies were performed for 1-year-old infants. The rate of myringotomies per child-year performed for acute otitis media in 1-year-old infants decreased significantly in the 2 years after the introduction of public funding for heptavalent pneumococcal conjugate vaccine compared to all years before introduction (p<0.000001). Our results suggest a benefit of heptavalent pneumococcal conjugate vaccine for acute otitis media in reducing the financial burden of myringotomy. In addition, this vaccine may help prevent acute otitis media with severe middle ear inflammation in 1-year-old infants.

  4. Inflammation is independent of steatosis in a murine model of steatohepatitis.

    PubMed

    Wang, Wei; Xu, Ming-Jiang; Cai, Yan; Zhou, Zhou; Cao, Haixia; Mukhopadhyay, Partha; Pacher, Pal; Zheng, Shusen; Gonzalez, Frank J; Gao, Bin

    2017-02-21

    Obesity and alcohol consumption synergistically promote steatohepatitis, and neutrophil infiltration is believed to be associated with steatosis. However, the underlying mechanisms remain obscure. Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a complex role in lipid metabolism and inflammation, therefore, the purpose of this study was to dissect its role in regulating steatosis and neutrophil infiltration in a clinically relevant mouse steatohepatitis model of 3-month high-fat diet (HFD) feeding plus a binge of ethanol (HFD -plus-binge ethanol). Hepatocyte-specific Pparg disruption reduced liver steatosis, but surprisingly increased hepatic neutrophil infiltration after HFD-plus-binge ethanol. Knockout or knockdown of the PPARγ target gene, fat-specific protein 27 (Fsp27), reduced steatosis without affecting neutrophil infiltration in this model. Moreover, hepatocyte-specific deletion of the Pparg gene but not the Fsp27 gene markedly upregulated hepatic levels of Cxcl1 (a chemokine for neutrophil infiltration) in HFD-plus-binge ethanol-fed mice. In vitro, deletion of the Pparg gene also highly augmented palmitic acid or TNF-α induction of Cxcl1 in mouse hepatocytes. In contrast, activation of PPARγ with a PPARγ agonist attenuated Cxcl1 expression in hepatocytes. Palmitic acid also upregulated IL-8 (a key chemokine for human neutrophil recruitment) expression in human hepatocytes, which was attenuated and enhanced by co-treatment with a PPARγ agonist and antagonist, respectively. Finally, acute ethanol binge markedly attenuated HFD-induced hepatic PPARγ activation, which contributed to the upregulation of hepatic Cxcl1 expression post HFD-plus-bigne ethanol. In conclusion, hepatic PPARγ plays an opposing role in controlling steatosis and neutrophil infiltration, leading to dissociation between steatosis and inflammation. Acute ethanol gavage attenuates hepatic PPARγ activation and subsequently upregulates hepatic CXCL1/IL-8 expression

  5. Sodium MRI in Multiple Sclerosis is Compatible with Intracellular Sodium Accumulation and Inflammation-Induced Hyper-Cellularity of Acute Brain Lesions

    PubMed Central

    Biller, Armin; Pflugmann, Isabella; Badde, Stephanie; Diem, Ricarda; Wildemann, Brigitte; Nagel, Armin M.; Jordan, J.; Benkhedah, Nadia; Kleesiek, Jens

    2016-01-01

    The cascade of inflammatory pathogenetic mechanisms in multiple sclerosis (MS) has no specific conventional MRI correlates. Clinicians therefore stipulate improved imaging specificity to define the pathological substrates of MS in vivo including mapping of intracellular sodium accumulation. Based upon preclinical findings and results of previous sodium MRI studies in MS patients we hypothesized that the fluid-attenuated sodium signal differs between acute and chronic lesions. We acquired brain sodium and proton MRI data of N = 29 MS patients; lesion type was defined by the presence or absence of contrast enhancement. N = 302 MS brain lesions were detected, and generalized linear mixed models were applied to predict lesion type based on sodium signals; thereby controlling for varying numbers of lesions among patients and confounding variables such as age and medication. Hierarchical model comparisons revealed that both sodium signals average tissue (χ2(1) = 27.89, p < 0.001) and fluid-attenuated (χ2(1) = 5.76, p = 0.016) improved lesion type classification. Sodium MRI signals were significantly elevated in acute compared to chronic lesions compatible with intracellular sodium accumulation in acute MS lesions. If confirmed in further studies, sodium MRI could serve as biomarker for diagnostic assessment of MS, and as readout parameter in clinical trials promoting attenuation of chronic inflammation. PMID:27507776

  6. Cerium Oxide Nanoparticles in Lung Acutely Induce Oxidative Stress, Inflammation, and DNA Damage in Various Organs of Mice

    PubMed Central

    Yuvaraju, Priya; Beegam, Sumaya; Fahim, Mohamed A.; Ali, Badreldin H.

    2017-01-01

    CeO2 nanoparticles (CeO2 NPs) which are used as a diesel fuel additive are emitted in the particulate phase in the exhaust, posing a health concern. However, limited information exists regarding the in vivo acute toxicity of CeO2 NPs on multiple organs. Presently, we investigated the acute (24 h) effects of intratracheally instilled CeO2 NPs in mice (0.5 mg/kg) on oxidative stress, inflammation, and DNA damage in major organs including lung, heart, liver, kidneys, spleen, and brain. Lipid peroxidation measured by malondialdehyde production was increased in the lungs only, and reactive oxygen species were increased in the lung, heart, kidney, and brain. Superoxide dismutase activity was decreased in the lung, liver, and kidney, whereas glutathione increased in lung but it decreased in the kidney. Total nitric oxide was increased in the lung and spleen but it decreased in the heart. Tumour necrosis factor-α increased in all organs studied. Interleukin- (IL-) 6 increased in the lung, heart, liver, kidney, and spleen. IL-1β augmented in the lung, heart, kidney, and spleen. Moreover, CeO2 NPs induced DNA damage, assessed by COMET assay, in all organs studied. Collectively, these findings indicate that pulmonary exposure to CeO2 NPs causes oxidative stress, inflammation, and DNA damage in multiple organs. PMID:28392888

  7. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction

    SciTech Connect

    Massa, Christopher B.; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L.; Gow, Andrew J.

    2014-07-01

    Acute Cl{sub 2} exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl{sub 2} inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl{sub 2} dose, and were euthanized 3, 24 and 48 h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 h. Cl{sub 2} exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO{sub 3}{sup −} or NO{sub 2}{sup −}. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl{sub 2} exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl{sub 2} inhalation. - Highlights: • Effect of 60 ppm*hr Cl{sub 2} gas on lung inflammation and mechanical function examined. • Pulmonary inflammation is transient and minor.

  8. The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications.

    PubMed

    Dumnicka, Paulina; Maduzia, Dawid; Ceranowicz, Piotr; Olszanecki, Rafał; Drożdż, Ryszard; Kuśnierz-Cabala, Beata

    2017-02-08

    Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients.

  9. The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

    PubMed Central

    Dumnicka, Paulina; Maduzia, Dawid; Ceranowicz, Piotr; Olszanecki, Rafał; Drożdż, Ryszard; Kuśnierz-Cabala, Beata

    2017-01-01

    Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients. PMID:28208708

  10. Protective effect of curcumin on acute airway inflammation of allergic asthma in mice through Notch1-GATA3 signaling pathway.

    PubMed

    Chong, Lei; Zhang, Weixi; Nie, Ying; Yu, Gang; Liu, Liu; Lin, Li; Wen, Shunhang; Zhu, Lili; Li, Changchong

    2014-10-01

    Curcumin, a natural product derived from the plant Curcuma longa, has been found to have anti-inflammatory, antineoplastic and antifibrosis effects. It has been reported that curcumin attenuates allergic airway inflammation in mice through inhibiting NF-κB and its downstream transcription factor GATA3. It also has been proved the antineoplastic effect of curcumin through down-regulating Notch1 receptor and its downstream nuclear transcription factor NF-κB levels. In this study, we aimed to investigate the anti-inflammatory effect of curcumin on acute allergic asthma and its underlying mechanisms. 36 male BALB/c mice were randomly divided into four groups (normal, asthma, asthma+budesonide and asthma+curcumin groups). BALF (bronchoalveolar lavage fluid) and lung tissues were analyzed for airway inflammation and the expression of Notch1, Notch2, Notch3, Notch4 and the downstream transcription factor GATA3. Our findings showed that the levels of Notch1 and Notch2 receptors were up-regulated in asthma group, accompanied by the increased expression of GATA3. But the expression of Notch2 receptor was lower than Notch1 receptor. Curcumin pretreatment improved the airway inflammatory cells infiltration and reversed the increasing levels of Notch1/2 receptors and GATA3. Notch3 receptor was not expressed in all of the four groups. Notch4 receptor protein and mRNA expression level in the four groups had no significant differences. The results of the present study suggested that Notch1 and Notch2 receptor, major Notch1 receptor, played an important role in the development of allergic airway inflammation and the inhibition of Notch1-GATA3 signaling pathway by curcumin can prevent the development and deterioration of the allergic airway inflammation. This may be a possible therapeutic option of allergic asthma.

  11. A better model of acute pancreatitis for evaluating therapy.

    PubMed

    Schmidt, J; Rattner, D W; Lewandrowski, K; Compton, C C; Mandavilli, U; Knoefel, W T; Warshaw, A L

    1992-01-01

    Existing models of acute pancreatitis have limitations to studying novel therapy. Whereas some produce mild self-limited pancreatitis, others result in sudden necrotizing injury. The authors developed an improved model providing homogeneous moderately severe injury by superimposing secretory hyperstimulation on minimal intraductal bile acid exposure. Sprague-Dawley rats (n = 231) received low-pressure intraductal glycodeoxycholic acid (GDOC) at very low (5 or 10 mmol/L) concentrations followed by intravenous cerulein. Cerulein or GDOC alone caused only very mild inflammation. However, GDOC combined with cerulein was uniformly associated with more edema (p less than 0.0005), acinar necrosis (p less than 0.01), inflammation (p less than 0.006), and hemorrhage (p less than 0.01). Pancreatic injury was further increased and death was potentiated by increasing volume and duration of intraductal low-dose GDOC infusion. There was significant morphologic progression between 6 and 24 hours. The authors conclude that (1) combining minimal intraductal bile acid exposure with intravenous hyperstimulation produces homogeneous pancreatitis of intermediate severity that can be modulated at will; (2) the injury is progressive over at least 24 hours with finite mortality rate; (3) the model provides superior opportunity to study innovative therapy.

  12. A better model of acute pancreatitis for evaluating therapy.

    PubMed Central

    Schmidt, J; Rattner, D W; Lewandrowski, K; Compton, C C; Mandavilli, U; Knoefel, W T; Warshaw, A L

    1992-01-01

    Existing models of acute pancreatitis have limitations to studying novel therapy. Whereas some produce mild self-limited pancreatitis, others result in sudden necrotizing injury. The authors developed an improved model providing homogeneous moderately severe injury by superimposing secretory hyperstimulation on minimal intraductal bile acid exposure. Sprague-Dawley rats (n = 231) received low-pressure intraductal glycodeoxycholic acid (GDOC) at very low (5 or 10 mmol/L) concentrations followed by intravenous cerulein. Cerulein or GDOC alone caused only very mild inflammation. However, GDOC combined with cerulein was uniformly associated with more edema (p less than 0.0005), acinar necrosis (p less than 0.01), inflammation (p less than 0.006), and hemorrhage (p less than 0.01). Pancreatic injury was further increased and death was potentiated by increasing volume and duration of intraductal low-dose GDOC infusion. There was significant morphologic progression between 6 and 24 hours. The authors conclude that (1) combining minimal intraductal bile acid exposure with intravenous hyperstimulation produces homogeneous pancreatitis of intermediate severity that can be modulated at will; (2) the injury is progressive over at least 24 hours with finite mortality rate; (3) the model provides superior opportunity to study innovative therapy. Images FIG. 3. FIG. 4. FIG. 5. FIG. 6. FIG. 7. PMID:1731649

  13. Acute Chlorine Gas Exposure Produces Transient Inflammation and a Progressive Alteration in Surfactant Composition with Accompanying Mechanical Dysfunction

    PubMed Central

    Massa, Christopher B; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L; Gow, Andrew J

    2014-01-01

    Acute Cl2 exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl2 inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl2 dose, and were sacrificed 3, 24 and 48 hours later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 hours, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 hours. Cl2 exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO3− or NO2−. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl2 exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 hours, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl2 inhalation. PMID:24582687

  14. Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation.

    PubMed

    Gao, Li; Wu, Wei-Feng; Dong, Lei; Ren, Gui-Ling; Li, Hai-Di; Yang, Qin; Li, Xiao-Feng; Xu, Tao; Li, Zeng; Wu, Bao-Ming; Ma, Tao-Tao; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun; Meng, Xiao-Ming

    2016-01-01

    Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress, and programmed cell death of renal tubular epithelial cells, all of which lead to high mortality rates in patients. In this study, we examined the protective effect of protocatechuic aldehyde (PA) in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza (Lamiaceae). Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA blocks cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients receiving cisplatin treatment.

  15. Protocatechuic Aldehyde Attenuates Cisplatin-Induced Acute Kidney Injury by Suppressing Nox-Mediated Oxidative Stress and Renal Inflammation

    PubMed Central

    Gao, Li; Wu, Wei-Feng; Dong, Lei; Ren, Gui-Ling; Li, Hai-Di; Yang, Qin; Li, Xiao-Feng; Xu, Tao; Li, Zeng; Wu, Bao-Ming; Ma, Tao-Tao; Huang, Cheng; Huang, Yan; Zhang, Lei; Lv, Xiongwen; Li, Jun; Meng, Xiao-Ming

    2016-01-01

    Cisplatin is a classic chemotherapeutic agent widely used to treat different types of cancers including ovarian, head and neck, testicular and uterine cervical carcinomas. However, cisplatin induces acute kidney injury by directly triggering an excessive inflammatory response, oxidative stress, and programmed cell death of renal tubular epithelial cells, all of which lead to high mortality rates in patients. In this study, we examined the protective effect of protocatechuic aldehyde (PA) in vitro in cisplatin-treated tubular epithelial cells and in vivo in cisplatin nephropathy. PA is a monomer of Traditional Chinese Medicine isolated from the root of S. miltiorrhiza (Lamiaceae). Results show that PA prevented cisplatin-induced decline of renal function and histological damage, which was confirmed by attenuation of KIM1 in both mRNA and protein levels. Moreover, PA reduced renal inflammation by suppressing oxidative stress and programmed cell death in response to cisplatin, which was further evidenced by in vitro data. Of note, PA suppressed NAPDH oxidases, including Nox2 and Nox4, in a dosage-dependent manner. Moreover, silencing Nox4, but not Nox2, removed the inhibitory effect of PA on cisplatin-induced renal injury, indicating that Nox4 may play a pivotal role in mediating the protective effect of PA in cisplatin-induced acute kidney injury. Collectively, our data indicate that PA blocks cisplatin-induced acute kidney injury by suppressing Nox-mediated oxidative stress and renal inflammation without compromising anti-tumor activity of cisplatin. These findings suggest that PA and its derivatives may serve as potential protective agents for cancer patients receiving cisplatin treatment. PMID:27999546

  16. MRI-based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE.

    PubMed

    Rausch, M; Hiestand, P; Baumann, D; Cannet, C; Rudin, M

    2003-08-01

    Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model that in several respects mimics human multiple sclerosis (MS), and can be used to design or validate new strategies for treatment of this disease. In the present study, different MRI techniques (macrophage tracking based on labeling cells in vivo by ultrasmall particles of iron oxide (USPIO), blood-brain barrier (BBB) breakdown, and magnetization transfer imaging (MTI)), as well as immunohistological staining were used to study the burden of disease in Lewis rats immunized by guinea pig myelin. The resulting imaging data was compared with behavioral readouts. Animals were studied during the acute phase and the first relapse. Activated monocytes were detected during both episodes in the brain stem or cortex. These areas coincided in part with areas of BBB breakdown. Significant changes of the magnetization transfer ratios (MTRs) of up to 35% were observed in areas of USPIO accumulation. This suggests that infiltrating monocytes are the major source of demyelination in EAE, but monocyte infiltration and breakdown of the BBB are temporally or spatially independent inflammatory processes.

  17. Characterization of rat model of acute anterior uveitis using optical coherence tomography angiography

    NASA Astrophysics Data System (ADS)

    Choi, Woo June; Pepple, Kathryn L.; Zhi, Zhongwei; Wang, Ruikang K.

    2015-03-01

    Uveitis, or ocular inflammation, is a cause of severe visual impairment. Rodent models of uveitis are powerful tools used to investigate the pathological mechanisms of ocular inflammation and to study the efficacy of new therapies prior to human testing. In this paper, we report the utility of spectral-domain optical coherence tomography (SD-OCT) angiography in characterizing the inflammatory changes induced in the anterior segment of a rat model of uveitis. Acute anterior uveitis (AAU) was induced in two rats by intravitreal injection of a killed mycobacterial extract. One of them received a concurrent periocular injection of steroids to model a treatment effect. OCT imaging was performed prior to inflammation induction on day 0 (baseline), and 2 days post-injection (peak inflammation). Baseline and inflamed images were compared. OCT angiography identified swelling of the cornea, inflammatory cells in the anterior and posterior chambers, a fibrinous papillary membrane, and dilation of iris vessels in the inflamed eyes when compared to baseline images. Steroid treatment was shown to prevent the changes associated with inflammation. This is a novel application of anterior OCT imaging in animal models of uveitis, and provides a high resolution, in vivo assay for detecting and quantifying ocular inflammation and the response to new therapies.

  18. Consensus Modeling of Oral Rat Acute Toxicity

    EPA Science Inventory

    An acute toxicity dataset (oral rat LD50) with about 7400 compounds was compiled from the ChemIDplus database. This dataset was divided into a modeling set and a prediction set. The compounds in the prediction set were selected so that they were present in the modeling set used...

  19. Deletion of Galgt2 (B4Galnt2) Reduces Muscle Growth in Response to Acute Injury and Increases Muscle Inflammation and Pathology in Dystrophin-Deficient Mice

    PubMed Central

    Xu, Rui; Singhal, Neha; Serinagaoglu, Yelda; Chandrasekharan, Kumaran; Joshi, Mandar; Bauer, John A.; Janssen, Paulus M.L.; Martin, Paul T.

    2016-01-01

    Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2−/−mdx). Galgt2−/− mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of αDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of αDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdx mice. PMID:26435413

  20. Detection of acute inflammation with /sup 111/In-labeled nonspecific polyclonal IgG

    SciTech Connect

    Fischman, A.J.; Rubin, R.H.; Khaw, B.A.; Callahan, R.J.; Wilkinson, R.; Keech, F.; Nedelman, M.; Dragotakes, S.; Kramer, P.B.; LaMuraglia, G.M.

    1988-10-01

    The detection of focal sites of inflammation is an integral part of the clinical evaluation of the febrile patient. When anatomically distinct abscesses are present, lesion detection can be accomplished by standard radiographic techniques, particularly in patients with normal anatomy. At the phlegmon stage, however, and in patients who have undergone surgery, these techniques are considerably less effective. While radionuclide methods, such as Gallium-67 (67Ga)-citrate and Indium-111 (111In)-labeled WBCs have been relatively successful for the detection of early inflammation, neither approach is ideal. In the course of studies addressing the use of specific organism-directed antibodies for imaging experimental infections in animals, we observed that nonspecific polyclonal immunoglobulin G (IgG) localized as well as specific antibodies. Preliminary experiments suggested that the Fc portion of IgG is necessary for effective inflammation localization. Since polyclonal IgG in gram quantities has been safely used for therapy in patients with immune deficiency states, we decided to test whether milligram quantities of radiolabeled IgG could image focal sites of inflammation in humans. Thus far, we have studied a series of 84 patients with suspected lesions in the abdomen, pelvis, vascular grafts, lungs, or bones/joints. In 48 of 52 patients with focal lesions detected by surgery, computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound (US), the IgG scan correctly localized the site, while 31 patients without focal inflammation had no abnormal focal localization of the radiopharmaceutical. Four patients had false negative scans and one patient had a false positive scan. For this small series, the overall sensitivity and specificity were 92% and 95%, respectively. In this report, we review our experience with this exciting new agent.

  1. Comparison of the prognostic values of inflammation markers in patients with acute pancreatitis: a retrospective cohort study

    PubMed Central

    Li, Yuanyuan; Zhao, Ying; Feng, Limin; Guo, Renyong

    2017-01-01

    Objectives Inflammation-based prognostic markers (neutrophil–lymphocyte ratio (NLR), prognostic nutritional index (PNI), red cell distribution width (RDW) and lymphocyte–monocyte ratio (LMR)) are associated with overall survival in some diseases. This study assessed their prognostic value in mortality and severity in acute pancreatitis (AP). Design A retrospective cohort study. Setting Patients with AP were recruited from the emergency department at our hospital. Participants A total of 359 patients with AP (31 non-survivors) were enrolled. Primary and secondary outcome measures Mortality and severity of AP were the primary and secondary outcome measures, respectively. Biochemistry and haematology results of the first test after admission were collected. Independent relationships between severe AP (SAP) and markers were assessed using multivariate logistic regression models. Mortality prediction ability was evaluated using receiver operating characteristic (ROC) curves. Overall survival was evaluated using the Kaplan-Meier method, with differences compared using the log-rank test. Independent relationships between mortality and each predictor were estimated using the Cox proportional hazard models. Results Compared with survivors of AP, non-survivors had higher RDW (p<0.001), higher NLR (p<0.001), lower LMR (p<0.001) and lower PNI (p<0.001) at baseline. C reactive protein (CRP; OR=8.251, p<0.001), RDW (OR=2.533, p=0.003) and PNI (OR=7.753, p<0.001) were independently associated with the occurrence of SAP. For predicting mortality, NLR had the largest area under the ROC curve (0.804, p<0.001), with a 16.64 cut-off value, 82.4% sensitivity and 75.6% specificity. RDW was a reliable marker for excluding death owing to its lowest negative likelihood ratio (0.11). NLR (HR=4.726, p=0.004), CRP (HR=3.503, p=0.003), RDW (HR=3.139, p=0.013) and PNI (HR=2.641, p=0.011) were independently associated with mortality of AP. Conclusions NLR was the most powerful marker of

  2. Zebrafish Models for Human Acute Organophosphorus Poisoning.

    PubMed

    Faria, Melissa; Garcia-Reyero, Natàlia; Padrós, Francesc; Babin, Patrick J; Sebastián, David; Cachot, Jérôme; Prats, Eva; Arick Ii, Mark; Rial, Eduardo; Knoll-Gellida, Anja; Mathieu, Guilaine; Le Bihanic, Florane; Escalon, B Lynn; Zorzano, Antonio; Soares, Amadeu M V M; Raldúa, Demetrio

    2015-10-22

    Terrorist use of organophosphorus-based nerve agents and toxic industrial chemicals against civilian populations constitutes a real threat, as demonstrated by the terrorist attacks in Japan in the 1990 s or, even more recently, in the Syrian civil war. Thus, development of more effective countermeasures against acute organophosphorus poisoning is urgently needed. Here, we have generated and validated zebrafish models for mild, moderate and severe acute organophosphorus poisoning by exposing zebrafish larvae to different concentrations of the prototypic organophosphorus compound chlorpyrifos-oxon. Our results show that zebrafish models mimic most of the pathophysiological mechanisms behind this toxidrome in humans, including acetylcholinesterase inhibition, N-methyl-D-aspartate receptor activation, and calcium dysregulation as well as inflammatory and immune responses. The suitability of the zebrafish larvae to in vivo high-throughput screenings of small molecule libraries makes these models a valuable tool for identifying new drugs for multifunctional drug therapy against acute organophosphorus poisoning.

  3. Zebrafish Models for Human Acute Organophosphorus Poisoning

    PubMed Central

    Faria, Melissa; Garcia-Reyero, Natàlia; Padrós, Francesc; Babin, Patrick J.; Sebastián, David; Cachot, Jérôme; Prats, Eva; Arick II, Mark; Rial, Eduardo; Knoll-Gellida, Anja; Mathieu, Guilaine; Le Bihanic, Florane; Escalon, B. Lynn; Zorzano, Antonio; Soares, Amadeu M.V.M; Raldúa, Demetrio

    2015-01-01

    Terrorist use of organophosphorus-based nerve agents and toxic industrial chemicals against civilian populations constitutes a real threat, as demonstrated by the terrorist attacks in Japan in the 1990 s or, even more recently, in the Syrian civil war. Thus, development of more effective countermeasures against acute organophosphorus poisoning is urgently needed. Here, we have generated and validated zebrafish models for mild, moderate and severe acute organophosphorus poisoning by exposing zebrafish larvae to different concentrations of the prototypic organophosphorus compound chlorpyrifos-oxon. Our results show that zebrafish models mimic most of the pathophysiological mechanisms behind this toxidrome in humans, including acetylcholinesterase inhibition, N-methyl-D-aspartate receptor activation, and calcium dysregulation as well as inflammatory and immune responses. The suitability of the zebrafish larvae to in vivo high-throughput screenings of small molecule libraries makes these models a valuable tool for identifying new drugs for multifunctional drug therapy against acute organophosphorus poisoning. PMID:26489395

  4. Rheumatoid arthritis: model of systemic inflammation driving atherosclerosis.

    PubMed

    Ku, Ivy A; Imboden, John B; Hsue, Priscilla Y; Ganz, Peter

    2009-06-01

    Similarities between the inflammatory pathways in atherosclerosis and rheumatoid arthritis (RA) are striking. Chronic systemic inflammation in RA patients leads to cardiovascular (CV) events beyond traditional cardiac risk factors. Clinicians typically focus on treating the joint manifestations of RA while neglecting to eliminate systemic inflammation, which leaves RA patients vulnerable to adverse CV events. In this review we provide an understanding of how systemic inflammation in RA accelerates atherosclerosis. This knowledge should guide therapeutic targets to minimize CV risk in RA, and may lead to insights into the inflammatory mechanisms of atherosclerosis in general.

  5. Multimodal analysis of ocular inflammation using the endotoxin-induced uveitis mouse model

    PubMed Central

    Chu, Colin J.; Gardner, Peter J.; Copland, David A.; Liyanage, Sidath E.; Gonzalez-Cordero, Anai; kleine Holthaus, Sophia-Martha; Luhmann, Ulrich F. O.; Smith, Alexander J.; Ali, Robin R.; Dick, Andrew D.

    2016-01-01

    ABSTRACT Endotoxin-induced uveitis (EIU) in rodents is a model of acute Toll-like receptor 4 (TLR4)-mediated organ inflammation, and has been used to model human anterior uveitis, examine leukocyte trafficking and test novel anti-inflammatory therapeutics. Wider adoption has been limited by the requirement for manual, non-specific, cell-count scoring of histological sections from each eye as a measure of disease severity. Here, we describe a comprehensive and efficient technique that uses ocular dissection and multimodal tissue analysis. This allows matched disease scoring by multicolour flow cytometric analysis of the inflammatory infiltrate, protein analysis on ocular supernatants and qPCR on remnant tissues of the same eye. Dynamic changes in cell populations could be identified and mapped to chemokine and cytokine changes over the course of the model. To validate the technique, dose-responsive suppression of leukocyte infiltration by recombinant interleukin-10 was demonstrated, as well as selective suppression of the monocyte (CD11b+Ly6C+) infiltrate, in mice deficient for either Ccl2 or Ccr2. Optical coherence tomography (OCT) was used for the first time in this model to allow in vivo imaging of infiltrating vitreous cells, and correlated with CD11b+Ly6G+ counts to provide another unique measure of cell populations in the ocular tissue. Multimodal tissue analysis of EIU is proposed as a new standard to improve and broaden the application of this model. PMID:26794131

  6. Ameliorative Effects of a Polyphenolic Fraction of Cinnamomum zeylanicum L. Bark in Animal Models of Inflammation and Arthritis.

    PubMed

    Rathi, Badal; Bodhankar, Subhash; Mohan, V; Thakurdesai, Prasad

    2013-01-01

    Cinnamon bark (Cinnamomum zeylanicum Syn C. verum, family: Lauraceae) is one of the oldest traditional medicines for inflammatory- and pain-related disorders. The objective of the present study was to evaluate the efficacy of the polyphenol fraction from Cinnamomum zeylanicum bark (CPP) in animal models of inflammation and rheumatoid arthritis. Dose-response studies of CPP (50, 100, and 200 mg/kg) used in a separate set of in vivo experiments were conducted in acute (carrageenan-induced rat paw edema), subacute (cotton pellet-induced granuloma), and sub-chronic (AIA, adjuvant-induced established polyarthrtis) models of inflammation in rats and the acetic acid-induced writhing model of pain in mice. Effects of CPP on cytokine (IL-2, IL-4, and IFNγ) release from Concanavalin (ConA)-stimulated lymphocytes were also evaluated in vitro. CPP showed a strong and dose-dependent reduction in paw volume, weight loss reversal effects against carrageenan-induced paw edema, and cotton pellet-induced granuloma models in rats. CPP (200 mg/kg p.o. for 10 days) showed a significant reduction in elevated serum TNF-α concentration without causing gastric ulcerogenicity in the AIA model in rats. CPP also demonstrated mild analgesic effects during acute treatment as evidenced by the reduction in the writhing and paw withdrawal threshold of the inflamed rat paw during the acetic acid-induced writhing model and Randall-Selitto test. CPP was found to inhibit cytokine (IL-2, IL-4, and IFNγ) release from ConA-stimulated lymphocytes in vitro. In conclusion, CPP demonstrated prominent action in animal models of inflammation and arthritis and therefore can be considered as a potential anti-rheumatic agent with disease-modifying action.

  7. Effect of acute lipopolysaccharide-induced inflammation in intracerebroventricular-streptozotocin injected rats.

    PubMed

    Murtishaw, Andrew S; Heaney, Chelcie F; Bolton, Monica M; Sabbagh, Jonathan J; Langhardt, Michael A; Kinney, Jefferson W

    2016-02-01

    Lipopolysaccharide (LPS) is often used to investigate the exacerbatory effects of an immune-related challenge in transgenic models of various neurodegenerative diseases. However, the effects of this inflammatory challenge in an insulin resistant brain state, as seen in diabetes mellitus, a major risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), is not as well characterized. We investigated the effects of an LPS-induced inflammatory challenge on behavioral and biological parameters following intracerebroventricular (ICV) injection of streptozotocin (STZ) in male Sprague-Dawley rats. Subjects received a one-time bilateral ICV infusion of STZ (25 mg/mL, 8 μL per ventricle) or ACSF. One week following ICV infusions, LPS (1 mg/mL, i.p.) or saline was administered to activate the immune system. Behavioral testing began on the 22nd day following STZ-ICV infusion, utilizing the open field and Morris water maze (MWM) tasks. Proteins related to immune function, learning and memory, synaptic plasticity, and key histopathological markers observed in VaD and AD were evaluated. The addition of an LPS-induced immune challenge partially attenuated spatial learning and memory deficits in the MWM in STZ-ICV injected animals. Additionally, LPS administration to STZ-treated animals partially mitigated alterations observed in several protein levels in STZ-ICV alone, including NR2A, GABA(B1), and β-amyloid oligomers. These results suggest that an acute LPS-inflammatory response has a modest protective effect against some of the spatial learning and memory deficits and protein alterations associated with STZ-ICV induction of an insulin resistant brain state.

  8. Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature

    PubMed Central

    Haddad, Ramsi; Tromp, Gerard; Kuivaniemi, Helena; Chaiworapongsa, Tinnakorn; Kim, Yeon Mee; Mazor, Moshe; Romero, Roberto

    2006-01-01

    OBJECTIVE The purpose of this study was to identify which biological processes may be involved in normal labor. STUDY DESIGN Transcriptional profiles for chorioamniotic membranes (n=24) and blood (n=20) were generated from patients at term with no labor (TNL) and in labor (TIL). RESULTS Expression of 197 transcripts (P≤0.02) differentiated TIL and TNL chorioamniotic membrane samples. Gene Ontology analysis indicated that TIL samples had increased expression of multiple chemokines and transcripts associated with neutrophil and monocyte recruitment. Microarray results were verified using quantitative real-time RT-PCR with independent samples. Transcriptional profiles from blood RNA revealed no Gene Ontology category enrichment of discriminant probe sets. CONCLUSION Labor induces gene expression changes consistent with localized inflammation, despite the absence of histologically detectable inflammation. PMID:16890549

  9. Heme oxygenase-1 attenuates acute pulmonary inflammation by decreasing the release of segmented neutrophils from the bone marrow.

    PubMed

    Konrad, Franziska M; Braun, Stefan; Ngamsri, Kristian-Christos; Vollmer, Irene; Reutershan, Jörg

    2014-11-01

    Recruiting polymorphonuclear neutrophil granulocytes (PMNs) from circulation and bone marrow to the site of inflammation is one of the pivotal mechanisms of the innate immune system. During inflammation, the enzyme heme oxygenase 1 (HO-1) has been shown to reduce PMN migration. Although these effects have been described in various models, underlying mechanisms remain elusive. Recent studies revealed an influence of HO-1 on different cells of the bone marrow. We investigated the particular role of the bone marrow in terms of HO-1-dependent pulmonary inflammation. In a murine model of LPS inhalation, stimulation of HO-1 by cobalt (III) protoporphyrin-IX-chloride (CoPP) resulted in reduced segmented PMN migration into the alveolar space. In the CoPP group, segmented PMNs were also decreased intravascularly, and concordantly, mature and immature PMN populations were higher in the bone marrow. Inhibition of the enzyme by tin protoporphyrin-IX increased segmented and banded PMN migration into the bronchoalveolar lavage fluid with enhanced PMN release from the bone marrow and aggravated parameters of tissue inflammation. Oxidative burst activity was significantly higher in immature compared with mature PMNs. The chemokine stromal-derived factor-1 (SDF-1), which mediates homing of leukocytes into the bone marrow and is decreased in inflammation, was increased by CoPP. When SDF-1 was blocked by the specific antagonist AMD3100, HO-1 activation was no longer effective in curbing PMN trafficking to the inflamed lungs. In conclusion, we show evidence that the anti-inflammatory effects of HO-1 are largely mediated by inhibiting the release of segmented PMNs from the bone marrow rather than direct effects within the lung.

  10. Lugrandoside attenuates LPS-induced acute respiratory distress syndrome by anti-inflammation and anti-apoptosis in mice

    PubMed Central

    Li, Chengbao; Huang, Ying; Yao, Xueya; Hu, Baoji; Wu, Suzhen; Chen, Guannan; Lv, Xin; Tian, Fubo

    2016-01-01

    This study aimed to investigate the protective effects and specific mechanisms of lugrandoside (LG) on lipopolysaccharides (LPS)-induced acute respiratory distress syndrome (ARDS). LG is a novel phenylpropanoid glycoside with many biological properties, isolated from the culinary leaves of Digitalis lutea L. and Digitalis grandiflora Miller. The primary indicators to assess the lung injury were infiltration of inflammatory cells; pulmonary edema; expression of proinflammatory cytokines, cyclo-oxygenase 2, and intracellular adhesion molecule 1; activation of nuclear factor-κB pathways; and cellular apoptosis. The results showed that LG evidently alleviated the inflammatory response, decreased the apoptosis of alveolar macrophages, and improved the lung injury in mice with LPS-induced ARDS. In conclusion, LG improved LPS-induced ARDS by anti-inflammation and anti-apoptosis and might be a promising pharmacological therapy for ARDS. PMID:28078026

  11. Polymorphisms in the IL-1 gene cluster influence systemic inflammation in patients at risk for acute-on-chronic liver failure.

    PubMed

    Alcaraz-Quiles, José; Titos, Esther; Casulleras, Mireia; Pavesi, Marco; López-Vicario, Cristina; Rius, Bibiana; Lopategi, Aritz; de Gottardi, Andrea; Graziadei, Ivo; Gronbaek, Henning; Ginès, Pere; Bernardi, Mauro; Arroyo, Vicente; Clària, Joan

    2017-01-01

    Acute-on-chronic liver failure (ACLF) in cirrhosis is an increasingly recognized syndrome characterized by acute decompensation, organ failure(s) and high short-term mortality. Recent findings suggest that an overexuberant systemic inflammation plays a primary role in ACLF progression. In this study, we examined whether genetic factors shape systemic immune responses in patients with decompensated cirrhosis. Six single-nucleotide polymorphisms (SNPs) in inflammation-related genes (interleukin [IL]-1 beta [IL-1β], rs1143623; IL-1 receptor antagonist [IL-1ra], rs4251961; IL-10, rs1800871; suppressor of cytokine signaling-3, rs4969170; nucleotide-binding oligomerization domain-containing protein 2, rs3135500; and chemerin chemokine-like receptor 1, rs1878022) were genotyped in 279 patients with cirrhosis with (n = 178) and without (n = 101) ACLF from the CANONIC study of the CLIF consortium. Among these SNPs, we identified two polymorphisms belonging to the IL-1 gene cluster (IL-1β and IL-1ra) in strong association with ACLF. Both SNPs were protective against ACLF; IL-1β (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.13-0.89; P < 0.05) and IL-1ra (OR, 0.58; 95% CI, 0.35-0.95; P < 0.05) under the recessive and overdominant inheritance models, respectively. These protective SNPs translated into reduced circulating levels of IL-1β, IL-1α, IL-6, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, and C-reactive protein at enrollment as well as after 7-14 days of admission. These findings were confirmed in vitro in leukocytes incubated with plasma from patients with decompensated cirrhosis carrying the protective SNP genotypes. Notably, a higher frequency of the protective genotypes was observed in patients without (80%) than in those with (20%) ACLF. Consistently, patients carrying the combined protective genotypes showed a lower 28-day mortality rate.

  12. Activity of Plumbago zeylanica Linn. root and Holoptelea integrifolia Roxb. bark pastes in acute and chronic paw inflammation in Wistar rat

    PubMed Central

    Kumar, Dushyant; Ganguly, Kuntal; Hegde, H. V.; Patil, P. A.; Roy, Subarna; Kholkute, S. D.

    2014-01-01

    Background: The pastes prepared from roots of Plumbago zeylanica Linn. and barks of Holoptelea integrifolia Roxb. are widely used by traditional healers for the treatment of arthritis in rural northern Karnataka. Objective: The present study was undertaken to scientifically evaluate the safety and efficacy of traditionally used formulations in experimental animals. Materials and Methods: The study, approved by IAEC was carried out in male Wistar rats and dermal toxicity in rabbits. Carrageenan model was used to assess effect on acute inflammation. Paw volume were measured at 1, 2, 4, and 6th hour postchallenge. Chronic inflammation was developed by using Complete Freund's Adjuvant (CFA). Paw volume, ankle joint circumference, and body weight were assessed on 1st, 4th, 8th, 14th, 17th, and 21st day. Paste was applied once every day to the inflamed area of the paw of respective groups of animals, continuously for 14 days. Statistics: The data were analyzed by one way analysis of variance followed by Dunnett's post hoc test. P ≤ 0.05 was considered as significant. Results: The formulations did not show any dermal toxicity and found to be safe. Both the pastes significantly (P < 0.05) suppressed, carrageenan-induced paw edema at 6th hour and Holoptelea integrifolia appears to be more effective than Plumbago zeylanica. Significant reduction was observed in paw volume, ankle joint circumference and animal body weight gained. Conclusions: The tested formulations (P. zeylanica root and H. integrifolia bark pastes) showed significant antiinflammatory activity. The present findings therefore support its utility in arthritic pain, inflammation and the claim of traditional practitioners. PMID:24812473

  13. Protective Effects of Dioscin against Lipopolysaccharide-Induced Acute Lung Injury through Inhibition of Oxidative Stress and Inflammation

    PubMed Central

    Yao, Hong; Sun, Yiping; Song, Shasha; Qi, Yan; Tao, Xufeng; Xu, Lina; Yin, Lianhong; Han, Xu; Xu, Youwei; Li, Hua; Sun, Huijun; Peng, Jinyong

    2017-01-01

    The protective effects of dioscin, a natural steroidal saponin from some medicinal plants including Dioscorea nipponica Makino, against lipopolysaccharide (LPS)- induced acute liver and renal damages have been reported in our previous works. However, the actions of dioscin against LPS-induced acute lung injury (ALI) is still unknown. In the present study, we investigated the effects and mechanisms of dioscin against LPS-induced ALI in vitro and in vivo. The results showed that dioscin obviously inhibited cell proliferation and markedly decreased reactive oxidative species level in 16HBE cells treated by LPS. In addition, dioscin significantly protected LPS-induced histological changes, inhibited the infiltration of inflammatory cells, as well as decreased the levels of MDA, SOD, NO and iNOS in mice and rats (p < 0.05). Mechanistically, dioscin significantly decreased the protein levels of TLR4, MyD88, TRAF6, TKB1, TRAF3, phosphorylation levels of PI3K, Akt, IκBα, NF-κB, and the mRNA levels of IL-1β, IL-6, and TNF-α against oxidative stress and inflammation (p < 0.05). Dioscin significantly reduced the overexpression of TLR4, and obviously down-regulated the levels of MyD88, TRAF6, TKB1, TRAF3, p-PI3K, p-Akt, p-IκBα, and p-NF-κB. These findings provide new perspectives for the study of ALI. Dioscin has protective effects on LPS-induced ALI via adjusting TLR4/MyD88- mediated oxidative stress and inflammation, which should be a potent drug in the treatment of ALI. PMID:28377715

  14. Variability in ozone-induced pulmonary injury and inflammation in healthy and cardiovascular-compromised rat models.

    PubMed

    Kodavanti, Urmila P; Ledbetter, Allen D; Thomas, Ronald F; Richards, Judy E; Ward, William O; Schladweiler, Mette C; Costa, Daniel L

    2015-01-01

    The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure dependent on the type and severity of disease. Healthy male 12-14-week-old Wistar Kyoto (WKY), Wistar (WS) and Sprague Dawley (SD); and CVD-compromised spontaneously hypertensive (SH), Fawn-Hooded hypertensive (FHH), stroke-prone spontaneously hypertensive (SHSP), obese spontaneously hypertensive heart failure (SHHF) and obese JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0 ppm ozone for 4 h; pulmonary injury and inflammation were analyzed immediately following (0-h) or 20-h later. Baseline bronchoalveolar lavage fluid (BALF) protein was higher in CVD strains except for FHH when compared to healthy. Ozone-induced increases in protein and inflammation were concentration-dependent within each strain but the degree of response varied from strain to strain and with time. Among healthy rats, SD were least affected. Among CVD strains, lean rats were more susceptible to protein leakage from ozone than obese rats. Ozone caused least neutrophilic inflammation in SH and SHHF while SHSP and FHH were most affected. BALF neutrophils and protein were poorly correlated when considering the entire dataset (r = 0.55). The baseline and ozone-induced increases in cytokine mRNA varied markedly between strains and did not correlate with inflammation. These data illustrate that the degree of ozone-induced lung injury/inflammation response is likely influenced by both genetic and physiological factors that govern the nature of cardiovascular compromise in CVD models.

  15. Glucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1

    PubMed Central

    Vettorazzi, Sabine; Bode, Constantin; Dejager, Lien; Frappart, Lucien; Shelest, Ekaterina; Klaßen, Carina; Tasdogan, Alpaslan; Reichardt, Holger M.; Libert, Claude; Schneider, Marion; Weih, Falk; Henriette Uhlenhaut, N.; David, Jean-Pierre; Gräler, Markus; Kleiman, Anna; Tuckermann, Jan P.

    2015-01-01

    Acute lung injury (ALI) is a severe inflammatory disease for which no specific treatment exists. As glucocorticoids have potent immunosuppressive effects, their application in ALI is currently being tested in clinical trials. However, the benefits of this type of regimen remain unclear. Here we identify a mechanism of glucocorticoid action that challenges the long-standing dogma of cytokine repression by the glucocorticoid receptor. Contrarily, synergistic gene induction of sphingosine kinase 1 (SphK1) by glucocorticoids and pro-inflammatory stimuli via the glucocorticoid receptor in macrophages increases circulating sphingosine 1-phosphate levels, which proves essential for the inhibition of inflammation. Chemical or genetic inhibition of SphK1 abrogates the therapeutic effects of glucocorticoids. Inflammatory p38 MAPK- and mitogen- and stress-activated protein kinase 1 (MSK1)-dependent pathways cooperate with glucocorticoids to upregulate SphK1 expression. Our findings support a critical role for SphK1 induction in the suppression of lung inflammation by glucocorticoids, and therefore provide rationales for effective anti-inflammatory therapies. PMID:26183376

  16. Decreased ADAMTS-13 level is related to inflammation factors and risk stratification of acute lymphoblastic leukemia patients

    PubMed Central

    Liu, Chen; Zhao, Lei; Zhao, Jingzhong; Xu, Qinzhu; Song, Ying; Wang, Hui

    2017-01-01

    Abstract As a kind of metalloprotease of the ADAMTS family, ADAMTS-13 is crucial for maintaining the normal size of von Willebrand factor. Reduced ADAMTS-13 had been reported in patients with both localized and disseminated malignancies. However, the expression and potential role of ADAMTS-13 in hematological malignancies remain unclear. In this research, we measured and compared ADAMTS-13 levels in plasma of 35 acute lymphoblastic leukemia (ALL) patients and 30 healthy controls and found that ALL patients possessed lower level of ADAMTS-13 than controls. Correlations between ADAMTS-13 and inflammation factors were calculated and ADAMTS-13 was negatively correlated with C-reactive protein and interleukin-1β. ALL patients with infections had lower level of ADAMTS-13 than patients without infections. In addition, high-risk ALL patients possessed lower ADAMTS-13 than patients at low risk. To conclude, ADAMTS-13 level is decreased in the plasma of ALL patients and the level of ADAMTS-13 is related to plasma inflammation factors and risk stratification of ALL patients, which could contribute to better understanding of the clinical significance of ADAMTS-13. PMID:28207543

  17. Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy

    PubMed Central

    Mendiola, Andrew S.; Garza, Rolando; Cardona, Sandra M.; Mythen, Shannon A.; Lira, Sergio A.; Akassoglou, Katerina; Cardona, Astrid E.

    2017-01-01

    Fractalkine (FKN) is a chemokine expressed constitutively by healthy neurons and signals to microglia upon interaction with the FKN receptor, CX3CR1. Signaling between FKN and CX3CR1 transduces inhibitory signals that ameliorate microglial activation and proinflammatory cytokine release in neuroinflammatory conditions. The aim of this study is to determine the mechanisms associated with microglial activation and vascular leakage during diabetic retinopathy (DR) and under conditions of low-level endotoxemia, common in diabetic patients. Utilizing the Ins2Akita strain (Akita), a mouse model of type 1 diabetes, our results show that leakage of the blood-protein fibrin(ogen) into the retina occurs as a result of chronic (4 months) but not acute (1.5 months) hyperglycemia. Conversely, inducing endotoxin-mediated systemic inflammation during acute diabetes resulted in fibrinogen deposition in the retina, a phenotype that was exacerbated in mice lacking CX3CR1 signaling. Systemic inflammation in Cx3cr1−/− mice led to robust perivascular clustering of proliferating microglia in areas of fibrinogen extravasation, and induced IL-1β expression in microglia and astrocytes. Lastly, we determined a protective effect of modulating FKN/CX3CR1 signaling in the diabetic retina. We show that intravitreal (iv) administration of recombinant FKN into diabetic FKN-KO mice, reduced fibrinogen deposition and perivascular clustering of microglia in the retina during systemic inflammation. These data suggest that dysregulated microglial activation via loss of FKN/CX3CR1 signaling disrupts the vascular integrity in retina during systemic inflammation. PMID:28119571

  18. [Micro-organism translocation and acute anastomosis inflammation after stomach resection].

    PubMed

    Gulov, M K; Kurbonov, K M

    2003-10-01

    The results of examination of 42 patients with an acute anastomositis after performance of gastric resection were analyzed. Clinical classification was elaborated for detailed interpretation of the anastomosits diagnosis and choice of therapy. Close correlative inter-relatioship between severity of anastomositis and degree of gastric mucosa colonization by micro-organisms was established basing on analysis of the laboratory and bacteriological investigations results.

  19. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis.

    PubMed

    Schwartz, Erica S; La, Jun-Ho; Scheff, Nicole N; Davis, Brian M; Albers, Kathryn M; Gebhart, G F

    2013-03-27

    Visceral afferents expressing transient receptor potential (TRP) channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. Using a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice weekly) of caerulein-induced AP (AP), we studied the involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis and sprouting of pancreatic nerve fibers, and increased TRPV1 and TRPA1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated before week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked the development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1, and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked the development of CP and pain behaviors even when mice were challenged with seven more weeks of twice weekly caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest: (1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, (2) that there is a transition from AP to CP, after which TRP channel antagonism is ineffective, and thus (3) that early intervention with TRP channel antagonists may attenuate the transition to and development of CP effectively.

  20. The effects of celecoxib, a COX-2 selective inhibitor, on acute inflammation induced in irradiated rats.

    PubMed

    Khayyal, M T; El-Ghazaly, Mona A; El-Hazek, R M; Nada, A S

    2009-10-01

    The potential value of selective and non-selective COX-2 inhibitors in preventing some of the biochemical changes induced by ionizing radiation was studied in rats exposed to carrageenan-induced paw edema and 6-day-old air pouch models. The animals were exposed to different exposure levels of gamma-radiation, namely either to single doses of 2 and 7.5 Gy or a fractionated dose level of 7.5 Gy delivered as 0.5 Gy twice weekly for 7.5 weeks. The inflammatory response produced by carrageenan in irradiated rats was markedly higher than that induced in non-irradiated animals, and depended on the extent of irradiation. Celecoxib, a selective COX-2 inhibitor, in doses of 3, 5, 10, and 15 mg/kg was effective in reducing paw edema in irradiated and non-irradiated rats in a dose-dependent manner as well as diclofenac (3 mg/kg), a non-selective COX inhibitor. Irradiation of animals before the induction of the air pouch by an acute dose of 2 Gy led to a significant increase in leukocytic count, as well as in the level of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), LTB(4), PGE(2) (as an index of COX-2 activity), TXB(2) (as an index of COX-1 activity), and the plasma level of MDA. This increase in level of these parameters was more marked than that observed in the non-irradiated animals subjected to the inflammagen. The blood GSH level was not affected by the dose of irradiation used, whereas superoxide dismutase (SOD) activity was suppressed. In many respects, celecoxib (5 mg/kg) was as potent as diclofenac in decreasing the elevated levels of IL-6, IL-1beta, TNF-alpha, LTB(4), PGE(2), but lacked any significant effect on TXB(2) level. Since it is mostly selective for COX-2 with a rare effect on COX-1 enzyme, both drugs at the selected dose levels showed no effect on level of MDA, GSH, and SOD activity.

  1. Acute and Chronic Toxicity, Cytochrome P450 Enzyme Inhibition, and hERG Channel Blockade Studies with a Polyherbal, Ayurvedic Formulation for Inflammation

    PubMed Central

    Dey, Debendranath; Chaskar, Sunetra; Athavale, Nitin; Chitre, Deepa

    2015-01-01

    Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation of Withania somnifera, Boswellia serrata, Zingiber officinale, and Curcuma longa, inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005–1 mg/mL) by MTT/formazan method, an acute single dose (2–10 g/kg bodyweight) toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15–20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL) on six major human cytochrome P450 enzymes and 3H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use. PMID:25893199

  2. Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

    PubMed Central

    2010-01-01

    Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure to diesel exhaust particles (DEP) could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed. PMID:20092634

  3. Oral treatment with Bifidobacterium longum 51A reduced inflammation in a murine experimental model of gout.

    PubMed

    Vieira, A T; Galvão, I; Amaral, F A; Teixeira, M M; Nicoli, J R; Martins, F S

    2015-01-01

    Gout is an acute inflammatory disease characterised by the presence of uric acid crystals in the joint. This event promotes neutrophil infiltration and activation that leads to tissue damage. We investigated here whether the oral administration of the probiotic strain Bifidobacterium longum 5(1A) (BL) could ameliorate monosodium urate crystal (MSU)-induced inflammation in a murine model of gout. Mice received oral administration of BL or saline daily for 7 days and then were injected with MSU in the knee cavity. Treatment with BL significantly alleviated the inflammatory parameters, as seen by reduced hypernociception, reduced neutrophil accumulation in the joint and myeloperoxidase activity in periarticular tissue. There was inhibition of the production of CXCL1 and interleukin(IL)-1β in joints. Levels of the anti-inflammatory cytokine IL-10 were significantly higher in the knee tissue of mice treated with than control mice injected with MSU. In conclusion, oral BL treatment reduced the inflammatory response in an experimental murine model of gout, suggesting it may be useful as an adjuvant treatment in patients with gout.

  4. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    SciTech Connect

    Malaviya, Rama; Venosa, Alessandro; Hall, LeRoy; Gow, Andrew J.; Sinko, Patrick J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  5. Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model

    PubMed Central

    van Gorp, Patrick J.; Jeurissen, Mike L. J.; Houben, Tom; Walenbergh, Sofie M. A.; Debets, Jacques; Oligschlaeger, Yvonne; Gijbels, Marion J. J.; Neumann, Dietbert; Shiri-Sverdlov, Ronit

    2016-01-01

    Non-alcoholic steatohepatitis (NASH) is a common liver disease characterized by hepatic lipid accumulation (steatosis) and inflammation. Currently, therapeutic options are poor and the long-term burden to society is constantly increasing. Previously, macrophage stimulating protein (MSP)—a serum protein mainly secreted by liver—was shown to inhibit oxidized low-density lipoprotein (OxLDL)/lipopolysaccharides (LPS)-induced inflammation in mouse macrophages. Additionally, MSP could reduce palmitic acid (PA)-induced lipid accumulation and lipogenesis in the HepG2 cell line. Altogether, these data suggest MSP as a suppressor for metabolic inflammation. However, so far the potential of MSP to be used as a treatment for NASH was not investigated. We hypothesized that MSP reduces lipid accumulation and hepatic inflammation. To investigate the effects of MSP in the early stage of NASH, low-density lipoprotein receptor (Ldlr-/-) mice were fed either a regular chow or a high fat, high cholesterol (HFC) diet for 7 days. Recombinant MSP or saline (control) was administrated to the mice by utilizing subcutaneously-implanted osmotic mini-pumps for the last 4 days. As expected, mice fed an HFC diet showed increased plasma and hepatic lipid accumulation, as well as enhanced hepatic inflammation, compared with chow-fed controls. Upon MSP administration, the rise in cholesterol and triglyceride levels after an HFC diet remained unaltered. Surprisingly, while hepatic macrophage and neutrophil infiltration was similar between the groups, MSP-treated mice showed increased gene expression of pro-inflammatory and pro-apoptotic mediators in the liver, compared with saline-treated controls. Contrary to our expectations, MSP did not ameliorate NASH. Observed changes in inflammatory gene expression suggest that further research is needed to clarify the long-term effects of MSP. PMID:27685150

  6. Hydrogen sulfide and resolution of acute inflammation: A comparative study utilizing a novel fluorescent probe.

    PubMed

    Dufton, Neil; Natividad, Jane; Verdu, Elena F; Wallace, John L

    2012-01-01

    Hydrogen sulfide is an essential gasotransmitter associated with numerous pathologies. We assert that hydrogen sulfide plays an important role in regulating macrophage function in response to subsequent inflammatory stimuli, promoting clearance of leukocyte infiltrate and reducing TNF-α levels in vivo following zymosan-challenge. We describe two distinct methods of measuring leukocyte hydrogen sulfide synthesis; methylene blue formation following zinc acetate capture and a novel fluorescent sulfidefluor probe. Comparison of these methods, using pharmacological tools, revealed they were complimentary in vitro and in vivo. We demonstrate the application of sulfidefluor probe to spectrofluorimetry, flow cytometry and whole animal imaging, to monitor the regulation of hydrogen sulfide synthesis in vivo during dynamic inflammatory processes. Both methodologies revealed that granulocyte infiltration negatively affects hydrogen sulfide synthesis. Our report offers an insight into the profile of hydrogen sulfide synthesis during inflammation and highlight opportunities raised by the development of novel fluorescent hydrogen sulfide probes.

  7. Hydrogen sulfide and resolution of acute inflammation: A comparative study utilizing a novel fluorescent probe

    PubMed Central

    Dufton, Neil; Natividad, Jane; Verdu, Elena F.; Wallace, John L.

    2012-01-01

    Hydrogen sulfide is an essential gasotransmitter associated with numerous pathologies. We assert that hydrogen sulfide plays an important role in regulating macrophage function in response to subsequent inflammatory stimuli, promoting clearance of leukocyte infiltrate and reducing TNF-α levels in vivo following zymosan-challenge. We describe two distinct methods of measuring leukocyte hydrogen sulfide synthesis; methylene blue formation following zinc acetate capture and a novel fluorescent sulfidefluor probe. Comparison of these methods, using pharmacological tools, revealed they were complimentary in vitro and in vivo. We demonstrate the application of sulfidefluor probe to spectrofluorimetry, flow cytometry and whole animal imaging, to monitor the regulation of hydrogen sulfide synthesis in vivo during dynamic inflammatory processes. Both methodologies revealed that granulocyte infiltration negatively affects hydrogen sulfide synthesis. Our report offers an insight into the profile of hydrogen sulfide synthesis during inflammation and highlight opportunities raised by the development of novel fluorescent hydrogen sulfide probes. PMID:22787557

  8. Triamcinolone acetonide protects the rat retina from STZ-induced acute inflammation and early vascular leakage.

    PubMed

    Kim, Y H; Choi, M Y; Kim, Y S; Park, C H; Lee, J H; Chung, I Y; Yoo, J M; Choi, W S; Cho, G J; Kang, S S

    2007-09-15

    Streptozotocin (STZ) has been commonly used to induce in vivo and in vitro hyperglycemic diabetes and its toxicity leads to inflammation and vascular injury. Triamcinolone acetonide (TA), as an anti-angiogenic/anti-inflammatory drug, is clinically used to improve the visual acuity in neovascular and edematous ocular diseases. The aim of this study was to investigate the effect of TA on early inflammation and vascular leakage in the retina of STZ-induced hyperglycemic rats. Hyperglycemia was induced in 8-week-old male Sprague-Dawley (SD) rats by a single intraperitoneal injection of STZ (65 mg/kg); only rats with blood glucose levels >13.9 mmol/l 1 day after STZ injection were included in STZ-hyperglycemic group. Sex- and age-matched SD rats injected with buffer were used as the control group. One day before STZ and buffer injection, 2 microl TA (4 mg/ml in saline) and 2 microl saline were intravitreal-injected into the right and the left eyes of rats, respectively. Retinal vascular leakage was measured using the Evans-blue method. Changes in pro-inflammatory target genes, such as tumor necrotic factor (TNF)-alpha, intracellular adhesion molecule (ICAM)-1, and vascular endothelial growth factor (VEGF) were assessed by immunoblottings, immunostaining, and ELISA analyses. Vascular hyperleakage and up-regulation of most pro-inflammatory genes peaked within a few days after STZ injection and had recovered. However, these changes were blocked by TA pretreatment. Our data suggest that TA controls STZ-induced early vascular leakage and temporary pro-inflammatory signals in the rat retina.

  9. Acute pulmonary inflammation induced by exposure of the airways to staphylococcal enterotoxin type B in rats

    SciTech Connect

    Desouza, Ivani A. . E-mail: ivanidesouza@fcm.unicamp.br; Franco-Penteado, Carla F.; Camargo, Enilton A.; Lima, Carmen S.P.; Teixeira, Simone A.; Muscara, Marcelo N.; De Nucci, Gilberto; Antunes, Edson

    2006-11-15

    Staphylocococcus aureus is a gram-positive bacterium that produces several enterotoxins, which are responsible for most part of pathological conditions associated to staphylococcal infections, including lung inflammation. This study aimed to investigate the underlying inflammatory mechanisms involved in leukocyte recruitment in rats exposed to staphylococcal enterotoxin B (SEB). Rats were anesthetized with pentobarbital sodium and intratracheally injected with either SEB or sterile phosphate-buffered saline (PBS, 0.4 ml). Airways exposition to SEB (7.5-250 ng/trachea) caused a dose- and time-dependent neutrophil accumulation in BAL fluid, the maximal effects of which were observed at 4 h post-SEB exposure (250 ng/trachea). Eosinophils were virtually absent in BAL fluid, whereas mononuclear cell counts increased only at 24 h post-SEB. Significant elevations of granulocytes in bone marrow (mature and immature forms) and peripheral blood have also been detected. In BAL fluid, marked elevations in the levels of lipid mediators (LTB{sub 4} and PGE{sub 2}) and cytokines (TNF-{alpha}, IL-6 and IL-10) were observed after SEB instillation. The SEB-induced neutrophil accumulation in BAL fluid was reduced by pretreatment with dexamethasone (0.5 mg/kg), the COX-2 inhibitor celecoxib (3 mg/kg), the selective iNOS inhibitor compound 1400 W (5 mg/kg) and the lipoxygenase inhibitor AA-861 (200 {mu}g/kg). In separate experiments carried out with rat isolated peripheral neutrophils, SEB failed to induce neutrophil adhesion to serum-coated plates and chemotaxis. In conclusion, rat airways exposition to SEB causes a neutrophil-dependent lung inflammation at 4 h as result of the release of proinflammatory (NO, PGE{sub 2}, LTB{sub 4}, TNF-{alpha}, IL-6) and anti-inflammatory mediators (IL-10)

  10. Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation.

    PubMed

    Lekander, Mats; Karshikoff, Bianka; Johansson, Emilia; Soop, Anne; Fransson, Peter; Lundström, Johan N; Andreasson, Anna; Ingvar, Martin; Petrovic, Predrag; Axelsson, John; Nilsonne, Gustav

    2016-08-01

    Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double-blind randomized controlled experiment, 52 healthy volunteers were injected with 0.6ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2h 45min. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.

  11. Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation.

    PubMed

    Primiano, Michael J; Lefker, Bruce A; Bowman, Michael R; Bree, Andrea G; Hubeau, Cedric; Bonin, Paul D; Mangan, Matthew; Dower, Ken; Monks, Brian G; Cushing, Leah; Wang, Stephen; Guzova, Julia; Jiao, Aiping; Lin, Lih-Ling; Latz, Eicke; Hepworth, David; Hall, J Perry

    2016-09-15

    A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1β and pro-IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.

  12. Pulmonary oxidative stress, inflammation and dysregulated iron homeostatis in rat models of cardiovascular disease

    EPA Science Inventory

    Underlying cardiovascular disease (CVD) is considered a risk factor for the exacerbation of air pollution health effects. Therefore, rodent models of CVD are increasingly used to examine mechanisms ofvariation in susceptibility. Pulmonary oxidative stress, inflammation and altere...

  13. Prostatic Inflammation Induces Fibrosis in a Mouse Model of Chronic Bacterial Infection

    PubMed Central

    Wong, Letitia; Hutson, Paul R.; Bushman, Wade

    2014-01-01

    Inflammation of the prostate is strongly correlated with development of lower urinary tract symptoms and several studies have implicated prostatic fibrosis in the pathogenesis of bladder outlet obstruction. It has been postulated that inflammation induces prostatic fibrosis but this relationship has never been tested. Here, we characterized the fibrotic response to inflammation in a mouse model of chronic bacterial-induced prostatic inflammation. Transurethral instillation of the uropathogenic E. coli into C3H/HeOuJ male mice induced persistent prostatic inflammation followed by a significant increase in collagen deposition and hydroxyproline content. This fibrotic response to inflammation was accompanied with an increase in collagen synthesis determined by the incorporation of 3H-hydroxyproline and mRNA expression of several collagen remodeling-associated genes, including Col1a1, Col1a2, Col3a1, Mmp2, Mmp9, and Lox. Correlation analysis revealed a positive correlation of inflammation severity with collagen deposition and immunohistochemical staining revealed that CD45+VIM+ fibrocytes were abundant in inflamed prostates at the time point coinciding with increased collagen synthesis. Furthermore, flow cytometric analysis demonstrated an increased percentage of these CD45+VIM+ fibrocytes among collagen type I expressing cells. These data show–for the first time–that chronic prostatic inflammation induces collagen deposition and implicates fibrocytes in the fibrotic process. PMID:24950301

  14. Jumihaidokuto effectively inhibits colon inflammation and apoptosis in mice with acute colitis.

    PubMed

    Sreedhar, Remya; Arumugam, Somasundaram; Karuppagounder, Vengadeshprabhu; Thandavarayan, Rajarajan A; Giridharan, Vijayasree V; Pitchaimani, Vigneshwaran; Afrin, Mst Rejina; Harima, Meilei; Nakamura, Takashi; Nakamura, Masahiko; Suzuki, Kenji; Watanabe, Kenichi

    2015-12-01

    Jumihaidokuto, a Japanese kampo medicine, is prescribed in Japan for its anti-inflammatory activity. Here we have examined its beneficial effects against acute colitis induced by dextran sulfate sodium (DSS) in mice. We have used C57BL/6 female mice, divided into two groups and received 3% DSS in drinking water during the experimental period (8days). Treatment group mice received 1g/kg/day dose of Jumihaidokuto orally whereas DSS control group received equal volume of distilled water. Normal control group mice received plain drinking water. Jumihaidokuto treatment attenuated the colitis symptoms along with suppression of various inflammatory marker proteins such as IL-1β, IL-2Rα, IL-4, CTGF and RAGE. It has also down-regulated the oxidative stress and apoptotic signaling in the colons of mice with colitis. The present study has confirmed the beneficial effects of Jumihaidokuto on DSS induced acute colitis in mice and suggests that it can be a potential agent for the treatment of colitis.

  15. Spores of Aspergillus versicolor isolated from indoor air of a moisture-damaged building provoke acute inflammation in mouse lungs.

    PubMed

    Jussila, Juha; Komulainen, Hannu; Kosma, Veli-Matti; Nevalainen, Aino; Pelkonen, Jukka; Hirvonen, Maija-Riitta

    2002-12-01

    Microbial growth in moisture-damaged buildings has been associated with respiratory health effects, and the spores of the mycotoxin producing fungus Aspergillus versicolor are frequently present in the indoor air. To characterize the potential of these spores to cause harmful respiratory effects, mice were exposed via intratracheal instillation to a single dose of the spores of A. versicolor (1 x 10(5), 1 x 10(6), 5 x 10(6), 1 x 10(7), or 1 x 10(8) spores), isolated from the indoor air of a moisture-damaged building. Inflammation and toxicity in lungs were evaluated 24 h later by assessment of biochemical markers and histopathology. The time course of the effects was investigated with the dose of 5 x 10(6) spores for up to 28 days. The exposure to the spores increased transiently proinflammatory cytokine levels (tumor necrosis factor [TNF] alpha and interleukin [IL]-6) in bronchoalveolar lavage fluid (BALF). The cytokine responses were dose and time dependent. The highest cytokine concentrations were measured at 6 h after the dose, and they returned to the control level by 3 days. Moreover, the spores of A. versicolor recruited inflammatory cells into airways: Neutrophils peaked transiently at 24 h, macrophages at 3 days, and lymphocytes at 7 days after the dosing. The inflammatory cell response did not completely disappear during the subsequent 28 days, though no histopathological changes were seen at that time point. The spores did not induce expression of inducible nitric oxide synthase in lavaged cells. Only the highest spore dose (1 x 10(8)) markedly increased serum IL-6, increased vascular leakage, and caused cytotoxicity (i.e., increased levels of albumin, total protein, lactate dehydrogenase [LDH], and hemoglobin in BALF) in the airways. In summary, the spores of A. versicolor caused acute inflammation in mouse lungs. This indicates that they have potential to provoke adverse health effects in the occupants of moisture-damaged buildings.

  16. Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via β2-adrenergic activation.

    PubMed

    Dimitrov, Stoyan; Hulteng, Elaine; Hong, Suzi

    2017-03-01

    Regular exercise is shown to exert anti-inflammatory effects, yet the effects of acute exercise on cellular inflammatory responses and its mechanisms remain unclear. We tested the hypothesis that sympathoadrenergic activation during a single bout of exercise has a suppressive effect on monocytic cytokine production mediated by β2 adrenergic receptors (AR). We investigated the effects of 20-min moderate (65-70% VO2 peak) exercise-induced catecholamine production on LPS-stimulated TNF production by monocytes in 47 healthy volunteers and determined AR subtypes involved. We also examined the effects of β-agonist isoproterenol and endogenous β- and α-agonists epinephrine and norepinephrine, and receptor-subtype-specific β- and α-antagonists on TNF production in a series of in vitro investigations. LPS-stimulated TNF production by peripheral blood monocytes was determined intracellularly by flow cytometry, using an intracellular protein transport inhibitor. Percent TNF-producing monocytes and per-cell TNF production with and without LPS was suppressed by exercise with moderate to large effects, which was reversed by a β2-AR antagonist in spite that plasma TNF levels did not change. This inhibitory response in TNF production by exercise was mirrored by β-AR agonists in an agonist-specific and dose-dependent manner in vitro: similar isoproterenol (EC50=2.1-4.7×10(-10)M) and epinephrine (EC50=4.4-10×10(-10)M) potency and higher norepinephrine concentrations (EC50=2.6-4.3×10(-8)M) needed for the effects. Importantly, epinephrine levels observed during acute exercise in vivo significantly inhibited TNF production in vitro. The inhibitory effect of the AR agonists was abolished by β2-, but not by β1- or α-AR blockers. We conclude that the downregulation of monocytic TNF production during acute exercise is mediated by elevated epinephrine levels through β2-ARs. Decreased inflammatory responses during acute exercise may protect against chronic conditions with low

  17. An animal model of chronic inflammatory pain: pharmacological and temporal differentiation from acute models.

    PubMed

    Wilson, Alex W; Medhurst, Stephen J; Dixon, Claire I; Bontoft, Nick C; Winyard, Lisa A; Brackenborough, Kim T; De Alba, Jorge; Clarke, Christopher J; Gunthorpe, Martin J; Hicks, Gareth A; Bountra, Chas; McQueen, Daniel S; Chessell, Iain P

    2006-08-01

    Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.

  18. Aerobic Exercise Decreases Lung Inflammation by IgE Decrement in an OVA Mice Model.

    PubMed

    Camargo Hizume-Kunzler, Deborah; Greiffo, Flavia R; Fortkamp, Bárbara; Ribeiro Freitas, Gabriel; Keller Nascimento, Juliana; Regina Bruggemann, Thayse; Melo Avila, Leonardo; Perini, Adenir; Bobinski, Franciane; Duarte Silva, Morgana; Rocha Lapa, Fernanda; Paula Vieira, Rodolfo; Vargas Horewicz, Verônica; Soares Dos Santos, Adair Roberto; Cattelan Bonorino, Kelly

    2017-04-07

    Aerobic exercise (AE) reduces lung function decline and risk of exacerbations in asthmatic patients. However, the inflammatory lung response involved in exercise during the sensitization remains unclear. Therefore, we evaluated the effects of exercise for 2 weeks in an experimental model of sensitization and single ovalbumin-challenge. Mice were divided into 4 groups: mice non-sensitized and not submitted to exercise (Sedentary, n=10); mice non-sensitized and submitted to exercise (Exercise, n=10); mice sensitized and exposed to ovalbumin (OVA, n=10); and mice sensitized, submitted to exercise and exposed to OVA (OVA+Exercise, n=10). 24 h after the OVA/saline exposure, we counted inflammatory cells from bronchoalveolar fluid (BALF), lung levels of total IgE, IL-4, IL-5, IL-10 and IL-1ra, measurements of OVA-specific IgG1 and IgE, and VEGF and NOS-2 expression via western blotting. AE reduced cell counts from BALF in the OVA group (p<0.05), total IgE, IL-4 and IL-5 lung levels and OVA-specific IgE and IgG1 titers (p<0.05). There was an increase of NOS-2 expression, IL-10 and IL-1ra lung levels in the OVA groups (p<0.05). Our results showed that AE attenuated the acute lung inflammation, suggesting immunomodulatory properties on the sensitization process in the early phases of antigen presentation in asthma.

  19. Regulation of Lipolysis and Adipose Tissue Signaling during Acute Endotoxin-Induced Inflammation: A Human Randomized Crossover Trial

    PubMed Central

    Rittig, Nikolaj; Bach, Ermina; Thomsen, Henrik Holm; Pedersen, Steen Bønlykke; Nielsen, Thomas Sava; Jørgensen, Jens O.; Jessen, Niels; Møller, Niels

    2016-01-01

    Background Lipolysis is accelerated during the acute phase of inflammation, a process being regulated by pro-inflammatory cytokines (e.g. TNF-α), stress-hormones, and insulin. The intracellular mechanisms remain elusive and we therefore measured pro- and anti-lipolytic signaling pathways in adipocytes after in vivo endotoxin exposure. Methods Eight healthy, lean, male subjects were investigated using a randomized cross over trial with two interventions: i) bolus injection of saline (Placebo) and ii) bolus injection of lipopolysaccharide endotoxin (LPS). A 3H-palmitate tracer was used to measure palmitate rate of appearance (Rapalmitate) and indirect calorimetry was performed to measure energy expenditures and lipid oxidation rates. A subcutaneous abdominal fat biopsy was obtained during both interventions and subjected to western blotting and qPCR quantifications. Results LPS caused a mean increase in serum free fatty acids (FFA) concentrations of 90% (CI-95%: 37–142, p = 0.005), a median increase in Rapalmitate of 117% (CI-95%: 77–166, p<0.001), a mean increase in lipid oxidation of 49% (CI-95%: 1–96, p = 0.047), and a median increase in energy expenditure of 28% (CI-95%: 16–42, p = 0.001) compared with Placebo. These effects were associated with increased phosphorylation of hormone sensitive lipase (pHSL) at ser650 in adipose tissue (p = 0.03), a trend towards elevated pHSL at ser552 (p = 0.09) and cAMP-dependent protein kinase A (PKA) phosphorylation of perilipin 1 (PLIN1) (p = 0.09). Phosphatase and tensin homolog (PTEN) also tended to increase (p = 0.08) while phosphorylation of Akt at Thr308 tended to decrease (p = 0.09) during LPS compared with Placebo. There was no difference between protein or mRNA expression of ATGL, G0S2, and CGI-58. Conclusion LPS stimulated lipolysis in adipose tissue and is associated with increased pHSL and signs of increased PLIN1 phosphorylation combined with a trend toward decreased insulin signaling. The combination of

  20. [Blood cholesterol spectre in patients with acute and chronic inflammation of infectious origin].

    PubMed

    Panchyshyn, Iu M; Srokopud, O O; Zhakun, I B; Komarytsia, O I; Huk-Leshnevs'ka, S O; Panchyshyn, M V

    2006-12-01

    Low level of blood cholesterol is often found in patients with diseases which pathogenesis is mainly associated with inflamation. To detect blood cholesterol spectre, 383 patients with acute and chronic infections have been observed, level of blood cholesterol of 1259 patients with different pathology was retrospectively analyzed. It was found that an increase in frequency of low cholesterol and decrease in frequency of high cholesterol in patients with diseases not associated with infections do not depend on the age of patients. Extremely low level of cholesterol (Cholesterol < or = 100 mg/dl) is found in 12,8% of patients with inflamation of infectious origion, oftener in patients with community-acquired pneumonia and chronic virus hepatitis. Patients with intestinal infections have extremely low level of cholesterol; two-fold oftener than healthy persons have.

  1. The acute effects of green tea and carbohydrate coingestion on systemic inflammation and oxidative stress during sprint cycling.

    PubMed

    Suzuki, Katsuhiko; Takahashi, Masaki; Li, Chia-Yang; Lin, Shiuan-Pey; Tomari, Miki; Shing, Cecilia M; Fang, Shih-Hua

    2015-10-01

    Green tea (Camellia sinensis) has anti-oxidative and anti-inflammatory effects, which may be beneficial to athletes performing high-intensity exercise. This study investigated the effects of carbohydrate and green tea coingestion on sprint cycling performance and associated oxidative stress and immunoendocrine responses to exercise. In a crossover design, 9 well-trained male cyclists completed 3 sets of 8 repetitions of 100-m uphill sprint cycling while ingesting green tea and carbohydrate (TEA) (22 mg/kg body mass catechins, 6 mg/kg body mass caffeine, 230 mg/kg glucose, and 110 mg/kg fructose) or carbohydrate only (CHO) (230 mg/kg body mass glucose and 110 mg/kg body mass fructose) during each 10-min recovery period between sets. Blood samples were collected before exercise, 10 min after exercise, and 14 h after exercise. There was no effect of acute TEA ingestion on cycling sprint performance (p = 0.29), although TEA maintained postexercise testosterone and lymphocyte concentrations, which decreased significantly in the CHO group (p < 0.001). While there was a trend for lower postexercise neutrophil count with TEA (p = 0.05), there were no significant differences between TEA and CHO for circulating cytokines (p > 0.20), markers of oxidative stress and antioxidant capacity (p > 0.17), adiponectin concentration (p = 0.60), or muscle damage markers (p > 0.64). While acute green tea ingestion prevents the postexercise decrease in testosterone and lymphocytes, it does not appear to benefit cycling sprint performance or reduce markers of oxidation and inflammation when compared with carbohydrate alone.

  2. Scutellaria baicalensis Ameliorates Acute Lung Injury by Suppressing Inflammation In Vitro and In Vivo.

    PubMed

    Chen, Jian-Jung; Huang, Chung-Chun; Chang, Heng-Yuan; Li, Pei-Ying; Liang, Yu-Chia; Deng, Jeng-Shyan; Huang, Shyh-Shyun; Huang, Guan-Jhong

    2017-01-01

    Scutellaria baicalensis has been widely used as both a dietary ingredient and traditional herbal medicine in Taiwan to treat inflammation, cancer, and bacterial and viral infections of the respiratory tract and gastrointestinal tract. This paper aims to investigate the in vitro and in vivo anti-inflammatory effects of S. baicalensis. In HPLC analysis, the fingerprint chromatogram of the water extract of S. baicalensis (WSB) was established. The anti-inflammatory effects of WSB were inverstigated using lipopolysaccharide (LPS)-stimulated mouse macrophage (RAW264.7) in vitro and LPS-induced lung injury in vivo. WSB attenuated the production of LPS-induced nitric oxide (NO), tumor necrosis factor-alpha (TNF-[Formula: see text], interleukin-[Formula: see text] (IL-1[Formula: see text], and IL-6 in vitro and in vivo. Pretreatment with WSB markedly reduced the LPS-induced histological alterations in lung tissues. Furthermore, WSB significantly reduced the number of total cells and the protein concentration levels in the BALF. WSB blocked protein expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), phosphorylation of I[Formula: see text]B-[Formula: see text] protein and MAPKs in LPS-stimulated RAW 264.7 cells and LPS-induce lung injury was also blocked. This study suggests that WSB possesses anti-inflammatory effects in vitro and in vivo, and the results suggested that WSB may be a potential therapeutic candidate for the treatment of inflammatory diseases.

  3. Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction

    PubMed Central

    Hilgers, Rob H. P.; Xing, Dongqi; Gong, Kaizheng; Chen, Yiu-Fai; Chatham, John C.

    2012-01-01

    Acute increases in cellular protein O-linked N-acetyl-glucosamine (O-GlcNAc) modification (O-GlcNAcylation) have been shown to have protective effects in the heart and vasculature. We hypothesized that d-glucosamine (d-GlcN) and Thiamet-G, two agents that increase protein O-GlcNAcylation via different mechanisms, inhibit TNF-α-induced oxidative stress and vascular dysfunction by suppressing inducible nitric oxide (NO) synthase (iNOS) expression. Rat aortic rings were incubated for 3h at 37°C with d-GlcN or its osmotic control l-glucose (l-Glc) or with Thiamet-G or its vehicle control (H2O) followed by the addition of TNF-α or vehicle (H2O) for 21 h. After incubation, rings were mounted in a myograph to assess arterial reactivity. Twenty-four hours of incubation of aortic rings with TNF-α resulted in 1) a hypocontractility to 60 mM K+ solution and phenylephrine, 2) blunted endothelium-dependent relaxation responses to ACh and substance P, and 3) unaltered relaxing response to the Ca2+ ionophore A-23187 and the NO donor sodium nitroprusside compared with aortic rings cultured in the absence of TNF-α. d-GlcN and Thiamet-G pretreatment suppressed the TNF-α-induced hypocontractility and endothelial dysfunction. Total protein O-GlcNAc levels were significantly higher in aortic segments treated with d-GlcN or Thiamet-G compared with controls. Expression of iNOS protein was increased in TNF-α-treated rings, and this was attenuated by pretreatment with either d-GlcN or Thiamet-G. Dense immunostaining for nitrotyrosylated proteins was detected in the endothelium and media of the aortic wall, suggesting enhanced peroxynitrite production by iNOS. These findings demonstrate that acute increases in protein O-GlcNAcylation prevent TNF-α-induced vascular dysfunction, at least in part, via suppression of iNOS expression. PMID:22777418

  4. Blockade of Extracellular High-Mobility Group Box 1 Attenuates Systemic Inflammation and Coagulation Abnormalities in Rats with Acute Traumatic Coagulopathy.

    PubMed

    Xu, Lin; Zhao, Kun; Shen, Xiao; Fan, Xin-Xin; Ding, Kai; Liu, Ren-Min; Wang, Feng

    2016-07-20

    BACKGROUND As an extracellularly released mediator, high-mobility group box 1 (HMGB1) initiates sterile inflammation following severe trauma. Serum HMGB1 levels correlate well with acute traumatic coagulopathy (ATC) in trauma patients, which is independently associated with higher mortality. We investigated the involvement of HMGB1 in ATC through blocking extracellular HMGB1. MATERIAL AND METHODS The ATC model was induced by polytrauma and hemorrhage in male Sprague-Dawley rats, which were randomly assigned to sham, ATC, and ATCH (ATC with HMGB1 blockade) groups. Thrombelastography (TEG) was performed to monitor changes in coagulation function. Serum levels of HMGB1, TNF-α, and IL-6 were measured, as well as lung levels of HMGB1 and nuclear factor (NF)-κB and expression of receptor for advanced glycation end-products (RAGE). RESULTS Compared with the sham group, HMGB1 increased the serum levels of TNF-α and IL-6, whereas HMGB1 blockade inhibited the induction of TNF-α and IL-6. HMGB1 also induced elevated serum soluble P-selectin and fibrinolysis markers plasmin-antiplasmin complex, which both were reduced by HMGB1 blockade. Thrombelastography revealed the hypocoagulability status in the ATC group, which was attenuated by anti-HMGB1 antibody. Furthermore, the lung level of NF-κB and expression of RAGE were decreased by anti-HMGB1 antibody, suggesting the role of RAGE/NF-κB pathway in ATC. CONCLUSIONS HMGB1 blockade can attenuate inflammation and coagulopathy in ATC rats. Anti-HMGB1 antibody might exert protective effects partly through the RAGE/NF-κB pathway. Thus, HMGB1 has potential as a therapeutic target in ATC.

  5. Haemophilus influenzae adherent to contact lenses associated with production of acute ocular inflammation.

    PubMed Central

    Sankaridurg, P R; Willcox, M D; Sharma, S; Gopinathan, U; Janakiraman, D; Hickson, S; Vuppala, N; Sweeney, D F; Rao, G N; Holden, B A

    1996-01-01

    Ten episodes of adverse responses to contact lens wear, including contact lens-induced acute red eye (CLARE), in which Haemophilus influenzae was isolated from contact lenses and/or from one of the external ocular sites at the time of the event, are described. All episodes occurred in patients wearing disposable hydrogel lenses on a 6-night extended-wear schedule. Two of the patients had recurrent episodes. H. influenzae was usually isolated in large numbers, and other bacteria or fungi colonizing the contact lens or the external ocular surface were usually present in low numbers. Those patients who were colonized with H. influenzae were more than 100 times as likely to have had a CLARE or infiltrative response than those subjects who were not colonized with this bacterium. H. influenzae colonization of the contact lens and eye may be subsequent to colonization of the nasopharynx because four of the seven patients presented with fever at the time of the event, with concurrent upper respiratory tract infection. Contact lens wearers should be made aware of the potential risk of CLARE associated with the wearing of contact lenses for extended periods during and subsequent to upper respiratory tract infection. PMID:8880493

  6. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease.

    PubMed

    Smith, Andrew M; Rahman, Farooq Z; Hayee, Bu'Hussain; Graham, Simon J; Marks, Daniel J B; Sewell, Gavin W; Palmer, Christine D; Wilde, Jonathan; Foxwell, Brian M J; Gloger, Israel S; Sweeting, Trevor; Marsh, Mark; Walker, Ann P; Bloom, Stuart L; Segal, Anthony W

    2009-08-31

    The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of (111)In-labeled neutrophils at these sites and clearance of (32)P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.

  7. Modified skin window technique for the extended characterisation of acute inflammation in humans

    PubMed Central

    Marks, D. J. B.; Radulovic, M.; McCartney, S.; Bloom, S.; Segal, A. W.

    2009-01-01

    Objective To modify the skin window technique for extended analysis of acute inflammatory responses in humans, and demonstrate its applicability for investigating disease. Subjects 15 healthy subjects and 5 Crohn’s patients. Treatment Skin windows, created by dermal abrasion, were overlaid for various durations with filter papers saturated in saline, 100 ng/ml muramyl dipeptide (MDP) or 10 μg/ml interleukin-8 (IL-8). Methods Exuded leukocytes were analyzed by microscopy, immunoblot, DNA-bound transcription factor arrays and RT-PCR. Inflammatory mediators were quantified by ELISA. Results Infiltrating leukocytes were predominantly neutrophils. Numerous secreted mediators were detectable. MDP and IL-8 enhanced responses. Many signalling proteins were phosphorylated with differential patterns in Crohn’s patients, notably PKC α/β hyperphosphorylation (11.3 ± 3.1 vs 1.2 ± 0.9 units, P < 0.02). Activities of 44 transcription factors were detectable, and sufficient RNA isolated for expression analysis of over 400 genes. Conclusions The modifications enable broad characterisation of inflammatory responses and administration of exogenous immunomodulators. PMID:17522815

  8. Meningeal inflammation and demyelination in a patient clinically diagnosed with acute disseminated encephalomyelitis.

    PubMed

    Koshihara, Hiroshi; Oguchi, Kenya; Takei, Yo-ichi; Kitazawa, Kazuo; Higuchi, Kayoko; Ohara, Shinji

    2014-11-15

    Acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) are both CNS inflammatory demyelinating diseases with overlapping clinical features. A case is reported of a 51-year-old female who presented with headache, progressive aphasia and hemiparesis without preceding infection or vaccination. Brain MRI revealed multiple, often confluent, subcortical white matter lesions without enhancement, affecting predominantly the left cerebral hemisphere. CSF examination failed to reveal oligoclonal bands. Brain biopsy revealed both pathological features of ADEM and findings are consistent with the early stage of MS, including meningeal B and T lymphocytic infiltration, perivenular demyelination, subpial demyelination and discrete confluent plaque-like foci of demyelination. Steroid treatment resulted in remarkable clinical and radiological improvement and there has been no recurrence in six years of follow-up. This case highlights the difficulties in differentiating between ADEM and the first attack of MS and further suggests that ADEM and the early stage of MS, and its tumefactive variant, may have a common underlying pathologic mechanism, which may have a therapeutic implication in treating these diseases.

  9. A spectrum of inflammation and demyelination in acute disseminated encephalomyelitis (ADEM) of children.

    PubMed

    Esposito, Susanna; Di Pietro, Giada Maria; Madini, Barbara; Mastrolia, Maria Vincenza; Rigante, Donato

    2015-10-01

    Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system that involves multifocal areas of the white matter, rarely the gray matter and spinal cord, mainly affecting children and mostly occurring 1-2weeks after infections or more rarely after vaccinations. Though a specific etiologic agent is not constantly identified, to evaluate carefully patient's clinical history and obtain adequate samples for the search of a potential ADEM causal agent is crucial. In the case of a prompt diagnosis and adequate treatment, most children with ADEM have a favorable outcome with full recovery, but in the case of diagnostic delays or inappropriate treatment some patients might display neurological sequelae and persistent deficits or even show an evolution to multiple sclerosis. The suspicion of ADEM rises on a clinical basis and derives from systemic and neurologic signs combined with magnetic resonance imaging of the central nervous system. Other advanced imaging techniques may help an appropriate differential diagnosis and definition of exact disease extension. Although there is no standardized protocol or management for ADEM, corticosteroids, intravenous immunoglobulin, and plasmapheresis have been successfully used. There is no marker that permits to identify the subset of children with worse prognosis and future studies should try to detect any biological clue for prevision of neurologic damage as well as should optimize treatment strategies using an approach based on the effective risk of negative evolution.

  10. Stanford-A acute aortic dissection, inflammation, and metalloproteinases: a review.

    PubMed

    Cifani, Noemi; Proietta, Maria; Tritapepe, Luigi; Di Gioia, Cira; Ferri, Livia; Taurino, Maurizio; Del Porto, Flavia

    2015-01-01

    Acute aortic dissection (AAD) is a life-threatening disease with an incidence of about 2.6-3.6 cases per 100,000/year. Depending on the site of rupture, AAD is classified as Stanford-A when the ascending aortic thoracic tract and/or the arch are involved, and Stanford-B when the descending thoracic aorta and/or aortic abdominal tract are targeted. It was recently shown that inflammatory pathways underlie aortic rupture in both type A and type B Stanford AAD. An immune infiltrate has been found within the middle and outer tunics of dissected aortic specimens. It has also been observed that the recall and activation of macrophages inside the middle tunic are key events in the early phases of AAD. Macrophages are able to release metalloproteinases (MMPs) and pro-inflammatory cytokines which, in turn, give rise to matrix degradation and neoangiogenesis. An imbalance between the production of MMPs and MMP tissue inhibitors is pivotal in the extracellular matrix degradation underlying aortic wall remodelling in dissections occurring both in inherited conditions and in atherosclerosis. Among MMPs, MMP-12 is considered a specific marker of aortic wall disease, whatever the genetic predisposition may be. The aim of this review is, therefore, to take a close look at the immune-inflammatory mechanisms underlying Stanford-A AAD.

  11. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease

    PubMed Central

    Smith, Andrew M.; Rahman, Farooq Z.; Hayee, Bu'Hussain; Graham, Simon J.; Marks, Daniel J.B.; Sewell, Gavin W.; Palmer, Christine D.; Wilde, Jonathan; Foxwell, Brian M.J.; Gloger, Israel S.; Sweeting, Trevor; Marsh, Mark; Walker, Ann P.; Bloom, Stuart L.

    2009-01-01

    The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of 111In-labeled neutrophils at these sites and clearance of 32P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway. PMID:19652016

  12. Differentiation between Acute Skin Rejection in Allotransplantation and T-Cell Mediated Skin Inflammation Based on Gene Expression Analysis

    PubMed Central

    Wolfram, Dolores; Morandi, Evi M.; Eberhart, Nadine; Hautz, Theresa; Hackl, Hubert; Zelger, Bettina; Riede, Gregor; Wachter, Tanja; Dubrac, Sandrine; Ploner, Christian; Pierer, Gerhard; Schneeberger, Stefan

    2015-01-01

    Advances in microsurgical techniques and immunosuppressive medication have rendered transplantation of vascularized composite allografts possible, when autologous tissue is neither available nor sufficient for reconstruction. However, skin rejection and side effects of long-term immunosuppression still remain a major hurdle for wide adoption of this excellent reconstructive technique. Histopathologic changes during acute skin rejection in vascular composite allotransplantation often mimic inflammatory skin disorders and are hard to distinguish. Hence, the identification of diagnostic and therapeutic markers specific for skin rejection is of particular clinical need. Here we present novel markers allowing for early differentiation between rejection in hind limb allotransplantation and contact hypersensitivity. Assessment of Ccl7, Il18, and Il1b expression is most indicative of distinguishing skin rejection from skin inflammatory disorders. Gene expression levels varied significantly across skin types and regions, indicating localization specific mechanism of leukocyte migration and infiltration. Expression of Il12b, Il17a, and Il1b gene expression levels differed significantly between rejection and inflammation, independent of the skin type. In synopsis of the RNA expression profile and previously assessed protein expression, the Il1 family appears as a promising option for accurate skin rejection diagnosis and, as a following step, for development of novel rejection treatments. PMID:25756043

  13. Inflammation Models of Depression in Rodents: Relevance to Psychotropic Drug Discovery

    PubMed Central

    Dantzer, Robert

    2016-01-01

    Inflammation and depression are closely inter-related; inflammation induces symptoms of depression and, conversely, depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites. By acting on glutamatergic neurotransmission, these neuroactive metabolites play a key role in the development of depression-like behaviors. An important outcome of the preclinical research on inflammation-induced depression is the identification of potential novel targets for antidepressant treatments, which include targeting the kynurenine system and production of downstream metabolites, altering transport of kynurenine into the brain, and modulating glutamatergic transmission. PMID:27026361

  14. Total Coumarins from Hydrangea paniculata Protect against Cisplatin-Induced Acute Kidney Damage in Mice by Suppressing Renal Inflammation and Apoptosis

    PubMed Central

    Jie, Ma; Jingzhi, Yang; Dongjie, Wang; Dongming, Zhang

    2017-01-01

    Aim. Hydrangea paniculata (HP) Sieb. is a medical herb which is widely distributed in southern China, and current study is to evaluate renal protective effect of aqueous extract of HP by cisplatin-induced acute kidney injury (AKI) in animal model and its underlying mechanisms. Materials and Methods. HP extract was prepared and the major ingredients were coumarin glycosides. AKI mouse models were established by single i.p. injection of 20 mg/kg cisplatin, and HP was orally administrated for total five times. The renal biochemical functions, pathological staining, kidney oxidative stress, and inflammatory status were measured. Apoptosis of tubular cells and infiltration of macrophages and neutrophils were also tested. Results. HP administration could improve the renal function by decreasing concentration of blood urea nitrogen (BUN) and creatinine and attenuates renal oxidative stress and tubular pathological injury and apoptosis; further research demonstrated that HP could inhibit the overproduction of proinflammatory cytokines and regulate caspase and BCL-2 family proteins. HP also reduced renal infiltration of macrophages and neutrophils, and its effect might be by downregulating phosphorylation of ERK1/2 and stat3 signaling pathway. Conclusions. This present study suggests that HP could ameliorate cisplatin induced kidney damage by antioxidation and suppressing renal inflammation and tubular cell apoptosis. PMID:28367225

  15. γ-Secretase Inhibitor Alleviates Acute Airway Inflammation of Allergic Asthma in Mice by Downregulating Th17 Cell Differentiation

    PubMed Central

    Zhang, Weixi; Zhang, Xueya; Sheng, Anqun; Weng, Cuiye; Zhu, Tingting; Zhao, Wei; Li, Changchong

    2015-01-01

    T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma. The aim of this study was to evaluate the effect of GSI on Th17 cell differentiation in a mouse model of allergic asthma. OVA was used to induce mouse asthma model in the presence and absence of GSI. GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs. GSI also significantly suppressed Th17-cell responses in spleen and reduced IL-17 levels in serum. These findings suggest that GSI directly regulates Th17 responses through a Notch signaling-dependent pathway in mouse model of allergic asthma, supporting the notion that GSI is a potential therapeutic agent for the treatment of allergic asthma. PMID:26339131

  16. The Effects of Niacin on Inflammation in Patients with Non-ST Elevated Acute Coronary Syndrome

    PubMed Central

    Karacaglar, Emir; Atar, Ilyas; Altin, Cihan; Yetis, Begum; Cakmak, Abdulkadir; Bayraktar, Nilufer; Coner, Ali; Ozin, Bulent; Muderrisoglu, Haldun

    2015-01-01

    Background In this study, we aimed to evaluate the effects of niacin on high sensitivity C reactive protein (hs-CRP) and cholesterol levels in non-ST elevated acute coronary syndrome (NSTE-ACS) patients. Methods In this prospective, open label study, 48 NSTE-ACS were randomized to niacin or control group. Patients continued their optimal medical therapy in the control group. In the niacin group patients were assigned to receive extended-release niacin 500 mg/day. Patients were contacted 1 month later to assess compliance and side effects. Blood samples for hs-CRP were obtained upon admittance to the coronary care unit, in the third day and in the first month of the treatment. Fasting blood samples for cholesterol levels were obtained before and 30 days after the treatment. The primary end point of the study was to evaluate changes in hs-CRP, cholesterol levels, short-term cardiovascular events, and the safety of niacin in NSTE-ACS. Results Baseline demographic, clinical and laboratory characteristics were similar between the two groups. Logarithmic transformation of baseline and 3rd day hs-CRP levels were similar between the groups; but 1 month later, logarithmic transformation of hs-CRP level was significantly lower in the niacin group (0.43 ± 0.39 to 0.83 ± 0.91, p = 0.04). HDL-C level was significantly increased in the niacin group during follow-up. Drug related side effects were seen in 7 patients in the niacin group but no patients discontinued niacin. Conclusions Our findings demonstrate that lower dose extended release niacin can be used safely and decreases hs-CRP and lipid parameters successfully in NSTE-ACS patients. PMID:27122858

  17. Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

    PubMed Central

    Mulchandani, Nikhil; Yang, Weng-Lang; Khan, Mohammad Moshahid; Zhang, Fangming; Marambaud, Philippe; Nicastro, Jeffrey; Coppa, Gene F; Wang, Ping

    2015-01-01

    Sepsis and septic shock are enormous public health problems with astronomical financial repercussions on health systems worldwide. The central nervous system (CNS) is closely intertwined in the septic process but the underlying mechanism is still obscure. AMP-activated protein kinase (AMPK) is a ubiquitous energy sensor enzyme and plays a key role in regulation of energy homeostasis and cell survival. In this study, we hypothesized that activation of AMPK in the brain would attenuate inflammatory responses in sepsis, particularly in the lungs. Adult C57BL/6 male mice were treated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR, 20 ng), an AMPK activator, or vehicle (normal saline) by intracerebroventricular (ICV) injection, followed by cecal ligation and puncture (CLP) at 30 min post-ICV. The septic mice treated with AICAR exhibited elevated phosphorylation of AMPKα in the brain along with reduced serum levels of aspartate aminotransferase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), compared with the vehicle. Similarly, the expressions of TNF-α, IL-1β, keratinocyte-derived chemokine and macrophage inflammatory protein-2 as well as myeloperoxidase activity in the lungs of AICAR-treated mice were significantly reduced. Moreover, histological findings in the lungs showed improvement of morphologic features and reduction of apoptosis with AICAR treatment. We further found that the beneficial effects of AICAR on septic mice were diminished in AMPKα2 deficient mice, showing that AMPK mediates these effects. In conclusion, our findings reveal a new functional role of activating AMPK in the CNS to attenuate inflammatory responses and acute lung injury in sepsis. PMID:26252187

  18. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

    NASA Astrophysics Data System (ADS)

    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  19. Effects of Montelukast in an Experimental Model of Acute Pancreatitis

    PubMed Central

    Angı, Serkan; Eken, Hüseyin; Kılıç, Erol; Karaköse, Oktay; Balci, Gürhan; Somuncu, Erkan

    2016-01-01

    Background We evaluated the hematological, biochemical, and histopathological effects of Montelukast on pancreatic damage in an experimental acute pancreatitis model created by cerulein in rats before and after the induction of pancreatitis. Materials/Methods Forty rats were divided into 4 groups with 10 rats each. The study groups were: the Cerulein (C) group, the Cerulein + early Montelukast (CMe) group, the Cerulein + late Montelukast (CMl) group, and the Control group. The pH, pO2, pCO2, HCO3, leukocyte, hematocrit, pancreatic amylase, and lipase values were measured in the arterial blood samples taken immediately before rats were killed. Results There were statistically significant differences between the C group and the Control group in the values of pancreatic amylase, lipase, blood leukocyte, hematocrit, pH, pO2, pCO2, HCO3, and pancreatic water content, and also in each of the values of edema, inflammation, vacuolization, necrosis, and total histopathological score (P<0.05). When the CMl group and C group were compared, no statistically significant differences were found in any parameter analyzed. When the CMe group was compared with the C group, pancreatic amylase, lipase, pH, PO2, pCO2, HCO3, pancreatic water content, histopathological edema, inflammation, and total histopathological score values were significantly different between the groups (P<0.05). Finally, when the CMe group and the Control group were compared, significant differences were found in all except 2 (leukocyte and pO2) parameters (P<0.05). Conclusions Leukotriene receptor antagonists used in the late phases of pancreatitis might not result in any benefit; however, when they are given in the early phases or prophylactically, they may decrease pancreatic damage. PMID:27479458

  20. H₂S and substance P in inflammation.

    PubMed

    Bhatia, Madhav

    2015-01-01

    Hydrogen sulfide (H2S) and substance P play a key role in inflammation. Using animal models of inflammation of different etiologies such as acute pancreatitis, sepsis, burns, and joint inflammation, studies have recently shown an important role of the proinflammatory action of H2S and substance P. Also, H2S contributes to inflammation in different conditions via substance P. This chapter reviews methods and key data that have led to our current understanding of the role of H2S and substance P in inflammation.

  1. Texture Analysis of T2-Weighted MR Images to Assess Acute Inflammation in Brain MS Lesions

    PubMed Central

    Michoux, Nicolas; Guillet, Alain; Rommel, Denis; Mazzamuto, Giosué; Sindic, Christian; Duprez, Thierry

    2015-01-01

    Brain blood barrier breakdown as assessed by contrast-enhanced (CE) T1-weighted MR imaging is currently the standard radiological marker of inflammatory activity in multiple sclerosis (MS) patients. Our objective was to evaluate the performance of an alternative model assessing the inflammatory activity of MS lesions by texture analysis of T2-weighted MR images. Twenty-one patients with definite MS were examined on the same 3.0T MR system by T2-weighted, FLAIR, diffusion-weighted and CE-T1 sequences. Lesions and mirrored contralateral areas within the normal appearing white matter (NAWM) were characterized by texture parameters computed from the gray level co-occurrence and run length matrices, and by the apparent diffusion coefficient (ADC). Statistical differences between MS lesions and NAWM were analyzed. ROC analysis and leave-one-out cross-validation were performed to evaluate the performance of individual parameters, and multi-parametric models using linear discriminant analysis (LDA), partial least squares (PLS) and logistic regression (LR) in the identification of CE lesions. ADC and all but one texture parameter were significantly different within white matter lesions compared to within NAWM (p < 0.0167). Using LDA, an 8-texture parameter model identified CE lesions with a sensitivity Se = 70% and a specificity Sp = 76%. Using LR, a 10-texture parameter model performed better with Se = 86% / Sp = 84%. Using PLS, a 6-texture parameter model achieved the highest accuracy with Se = 88% / Sp = 81%. Texture parameter from T2-weighted images can assess brain inflammatory activity with sufficient accuracy to be considered as a potential alternative to enhancement on CE T1-weighted images. PMID:26693908

  2. M2A and M2C Macrophage Subsets Ameliorate Inflammation and Fibroproliferation in Acute Lung Injury Through Interleukin 10 Pathway.

    PubMed

    Tang, Lunxian; Zhang, Hua; Wang, Chunmei; Li, Hongqiang; Zhang, Qian; Bai, Jianwen

    2016-12-09

    The role of M2 macrophages in the resolution and fibroproliferation of acute lung injury (ALI) is poorly understood. In this study, we investigated the effects of two M2 macrophage subtypes, M2a induced by interleukin (IL)-4/IL-13 and M2c induced by IL-10/transforming growth factor (TGF)-β, on the pathogenesis of ALI. M2a and M2c were adoptively transferred into LPS-induced ALI mice model. Data showed that Vybrant-labeled macrophages appeared in the lungs of ALI mice. Subsequently, we observed that both subsets significantly reduced lung inflammation and injury including a reduction of neutrophil influx into the lung and an augmentation of apoptosis. Interestingly, M2c macrophages more effectively suppressed indices of lung injury than M2a macrophages. M2c macrophages were also more effective than M2a in reduction of lung fibrosis. In addition, we found that M2c but not M2a macrophages increased IL-10 level in lung tissues of the recipient ALI mice partially mediated by activating the JAK1/STAT3/SOCS3 signaling pathway. After blocking IL-10, these superior effects of M2c over M2a were abolished. These data imply that M2c are more potent than M2a macrophages in protecting against lung injury and subsequent fibrosis due to their ability to produce IL-10. Therefore, reprogramming macrophages to M2c subset may be a novel treatment modality with transitional potential.

  3. The Mongolian Gerbil: A Robust Model of Helicobacter pylori-Induced Gastric Inflammation and Cancer.

    PubMed

    Noto, Jennifer M; Romero-Gallo, Judith; Piazuelo, M Blanca; Peek, Richard M

    2016-01-01

    The Mongolian gerbil is an efficient, robust, and cost-effective rodent model that recapitulates many features of H. pylori-induced gastric inflammation and carcinogenesis in humans, allowing for targeted investigation of the bacterial determinants and environmental factors and, to a lesser degree, host constituents that govern H. pylori-mediated disease. This chapter discusses means through which the Mongolian gerbil model has been used to define mechanisms of H. pylori-inflammation and cancer as well as the current materials and methods for utilizing this model of microbially induced disease.

  4. Hypothermia induced by adenosine 5'-monophosphate attenuates early stage injury in an acute gouty arthritis rat model.

    PubMed

    Miao, Zhimin; Guo, Weiting; Lu, Shulai; Lv, Wenshan; Li, Changgui; Wang, Yangang; Zhao, Shihua; Yan, Shengli; Tao, Zhenyin; Wang, Yunlong

    2013-08-01

    To investigate whether the hypothermia induced by Adenosine 5'-Monophosphate (5'-AMP) could attenuate early stage injury in a rat acute gouty arthritis model. Ankle joint injection with monosodium urate monohydrate crystals (MSU crystals) in hypothermia rat model which was induced by 5'-AMP and then observe whether hypothermia induced by 5'-AMP could be effectively inhibit the inflammation on acute gouty arthritis in rats. AMP-induced hypothermia has protective effects on our acute gouty arthritis, which was demonstrated by the following criteria: (1) a significant reduction in the ankle swelling (p < 0.001); (2) a significant decrease in the occurrence of leukocyte infiltration and mild hemorrhage; (3) a significant reduction in the presence of serum Interleukin-1β (IL-1β, p < 0.001) and metalloproteinase-9 (MMP-9, p < 0.001); and (4) a significant inhibition in the Nuclear Factor -κappaB (NF-κB) activity (p < 0.001). AMP-induced hypothermia could inhibit acute inflammation reaction and protect the synovial tissue against acute injury in a rat acute gouty arthritis model.

  5. Wogonin prevents lipopolysaccharide-induced acute lung injury and inflammation in mice via peroxisome proliferator-activated receptor gamma-mediated attenuation of the nuclear factor-kappaB pathway

    PubMed Central

    Yao, Jing; Pan, Di; Zhao, Yue; Zhao, Li; Sun, Jie; Wang, Yu; You, Qi-Dong; Xi, Tao; Guo, Qing-Long; Lu, Na

    2014-01-01

    Acute lung injury (ALI) from a variety of clinical disorders, characterized by diffuse inflammation, is a cause of acute respiratory failure that develops in patients of all ages. Previous studies reported that wogonin, a flavonoid-like chemical compound which was found in Scutellaria baicalensis, has anti-inflammatory effects in several inflammation models, but not in ALI. Here, the in vivo protective effect of wogonin in the amelioration of lipopolysaccharide (LPS) -induced lung injury and inflammation was assessed. In addition, the in vitro effects and mechanisms of wogonin were studied in the mouse macrophage cell lines Ana-1 and RAW264.7. In vivo results indicated that wogonin attenuated LPS-induced histological alterations. Peripheral blood leucocytes decreased in the LPS-induced group, which was ameliorated by wogonin. In addition, wogonin inhibited the production of several inflammatory cytokines, including tumour necrosis factor-α, interleukin-1β (IL-1β) and IL-6, in the bronchoalveolar lavage fluid and lung tissues after LPS challenge, while the peroxisome proliferator-activated receptor γ (PPARγ) inhibitor GW9662 reversed these effects. In vitro results indicated that wogonin significantly decreased the secretion of IL-6, IL-1β and tumour necrosis factor-α in Ana-1 and RAW264.7 cells, which was suppressed by transfection of PPARγ small interfering RNA and GW9662 treatment. Moreover, wogonin activated PPARγ, induced PPARγ-mediated attenuation of the nuclear translocation and the DNA-binding activity of nuclear factor-κB in vivo and in vitro. In conclusion, all of these results showed that wogonin may serve as a promising agent for the attenuation of ALI-associated inflammation and pathology by regulating the PPARγ-involved nuclear factor-κB pathway. PMID:24766487

  6. Acute Infectious Gastroenteritis Potentiates a Crohn's Disease Pathobiont to Fuel Ongoing Inflammation in the Post-Infectious Period

    PubMed Central

    Small, Cherrie L.; Xing, Lydia; Law, Hong T.

    2016-01-01

    Crohn’s disease (CD) is a chronic inflammatory condition of diverse etiology. Exposure to foodborne pathogens causing acute gastroenteritis produces a long-term risk of CD well into the post-infectious period but the mechanistic basis for this ongoing relationship to disease onset is unknown. We developed two novel models to study the comorbidity of acute gastroenteritis caused by Salmonella Typhimurium or Citrobacter rodentium in mice colonized with adherent-invasive Escherichia coli (AIEC), a bacterial pathobiont linked to CD. Here, we show that disease activity in the post-infectious period after gastroenteritis is driven by the tissue-associated expansion of the resident AIEC pathobiont, with an attendant increase in immunopathology, barrier defects, and delays in mucosal restitution following pathogen clearance. These features required AIEC resistance to host defense peptides and a fulminant inflammatory response to the enteric pathogen. Our results suggest that individuals colonized by AIEC at the time of acute infectious gastroenteritis may be at greater risk for CD onset. Importantly, our data identify AIEC as a tractable disease modifier, a finding that could be exploited in the development of therapeutic interventions following infectious gastroenteritis in at-risk individuals. PMID:27711220

  7. Acute Infectious Gastroenteritis Potentiates a Crohn's Disease Pathobiont to Fuel Ongoing Inflammation in the Post-Infectious Period.

    PubMed

    Small, Cherrie L; Xing, Lydia; McPhee, Joseph B; Law, Hong T; Coombes, Brian K

    2016-10-01

    Crohn's disease (CD) is a chronic inflammatory condition of diverse etiology. Exposure to foodborne pathogens causing acute gastroenteritis produces a long-term risk of CD well into the post-infectious period but the mechanistic basis for this ongoing relationship to disease onset is unknown. We developed two novel models to study the comorbidity of acute gastroenteritis caused by Salmonella Typhimurium or Citrobacter rodentium in mice colonized with adherent-invasive Escherichia coli (AIEC), a bacterial pathobiont linked to CD. Here, we show that disease activity in the post-infectious period after gastroenteritis is driven by the tissue-associated expansion of the resident AIEC pathobiont, with an attendant increase in immunopathology, barrier defects, and delays in mucosal restitution following pathogen clearance. These features required AIEC resistance to host defense peptides and a fulminant inflammatory response to the enteric pathogen. Our results suggest that individuals colonized by AIEC at the time of acute infectious gastroenteritis may be at greater risk for CD onset. Importantly, our data identify AIEC as a tractable disease modifier, a finding that could be exploited in the development of therapeutic interventions following infectious gastroenteritis in at-risk individuals.

  8. Protective effects of a blueberry extract in acute inflammation and collagen-induced arthritis in the rat.

    PubMed

    Figueira, Maria-Eduardo; Oliveira, Mónica; Direito, Rosa; Rocha, João; Alves, Paula; Serra, Ana-Teresa; Duarte, Catarina; Bronze, Rosário; Fernandes, Adelaide; Brites, Dora; Freitas, Marisa; Fernandes, Eduarda; Sepodes, Bruno

    2016-10-01

    Here we investigated the anti-inflammatory effect of a blueberry extract in the carrageenan-induced paw edema model and collagen-induced arthritis model, both in rats. Along with the chemical characterization of the phenolic content of the fruits and extract, the antioxidant potential of the extract, the cellular antioxidant activity and the effects over neutrophils' oxidative burst, were studied in order to provide a mechanistic insight for the anti-inflammatory effects observed. The extract significantly inhibited paw edema formation in an acute model the rat. Our results also demonstrate that the standardized extract had pharmacological activity when administered orally in the collagen-induced arthritis model in the rat and was able to significantly reduce the development of clinical signs of arthritis and the degree of bone resorption, soft tissue swelling and osteophyte formation, consequently improving articular function in treated animals.

  9. The Protective Effects of Melatonin Against Oxidative Stress and Inflammation Induced by Acute Cadmium Exposure in Mice Testis.

    PubMed

    Li, Renyan; Luo, Xue; Li, Lianbing; Peng, Qiang; Yang, Yuyou; Zhao, Letian; Ma, Mingfu; Hou, Zhiwei

    2016-03-01

    Cadmium (Cd) is widely used in daily life and was recently recognized as a possible source of human toxicity due to its ability to accumulate in organs. Previous studies have shown that Cd exposure may cause testicular toxicity through oxidative stress and an inflammatory effect. Melatonin has been demonstrated to be an effective anti-oxidant and has an anti-inflammatory effect. The aim of the present study was to investigate the toxicological effects of Cd on reproduction in male mice and the potential protective action of melatonin against these adverse effects. Adult male mice were injected intraperitoneally with Cd at a dose of 2 mg/kg body weight per day for seven consecutive days with or without melatonin pretreatment. Sex organ weight, sperm parameters including sperm quality, apoptosis, acrosome integrity, mitochondrial membrane potential, testicular morphology, serum sex hormone, inflammatory status, and oxidative stress were evaluated. The results showed that significant adverse effects were observed in the male reproductive system after Cd exposure, including alterations in sperm parameters, increased DNA damage, and sex hormone disturbance. Acute Cd exposure also significantly increased malondialdehyde (MDA) contents, decreased glutathione (GSH) and superoxide dismutase (SOD) activities, and upregulated levels of the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β), in the testis. In contrast, melatonin pretreatment significantly alleviated these toxic effects, and its mechanism may involve inhibiting MDA level, restoring GSH and SOD activities, and reducing the upregulation of TNF-α and IL-1β. Our data suggest that oxidative stress and inflammation are involved in Cd-induced toxicity in the male reproductive system and that co-administration of melatonin exerts a protective effect against Cd-induced male reproductive toxicity.

  10. Acute Lung Injury Following Smoke Inhalation: Predictive Value of Sputum Biomarkers and Time Course of Lung Inflammation

    DTIC Science & Technology

    2007-05-01

    acute lung injury (ALI) and acute respiratory distress syndrome ( ARDS ). Criteria for diagnosing ALI and predicting...Rationale: Smoke inhalation victims are at high risk of developing acute respiratory distress syndrome ( ARDS ). Given the delay of 12 or more hours...Background: Although smoke inhalation injury victims frequently develop acute respiratory distress syndrome ( ARDS ), no early prognostic

  11. Acute Lung Injury Following Smoke Inhalation: Predictive Value of Sputum Biomarkers and Time Course of Lung Inflammation

    DTIC Science & Technology

    2006-04-01

    acute respiratory distress syndrome ( ARDS ). Given the delay of 12 or...Keywords: Inhalation Burns, Acute Respiratory Distress Syndrome , Interleukin-8, Interleukin- 1 beta. 4/14/2006 Markers of Smoke Inhalation Injury 2...Zimmerman 2005; Park et al., 2001), all hallmarks of acute lung injury (ALI) and acute respiratory distress syndrome ( ARDS ). The general

  12. DIETARY FLAXSEED PREVENTS RADIATION-INDUCED OXIDATIVE LUNG DAMAGE, INFLAMMATION AND FIBROSIS IN A MOUSE MODEL OF THORACIC RADIATION INJURY

    PubMed Central

    Lee, James C.; Krochak, Ryan; Blouin, Aaron; Kanterakis, Stathis; Chatterjee, Shampa; Arguiri, Evguenia; Vachani, Anil; Solomides, Charalambos C.; Cengel, Keith A.; Christofidou-Solomidou, Melpo

    2009-01-01

    Flaxseed (FS) has high contents of omega-3 fatty acids and lignans with antioxidant properties. Its use in preventing thoracic X-ray radiation therapy (XRT)-induced pneumonopathy has never been evaluated. We evaluated FS supplementation given to mice given before and post-XRT. FS-derived lignans, known for their direct antioxidant properties, were evaluated in abrogating ROS generation in cultured endothelial cells following gamma radiation exposure. Mice were fed 10% FS or isocaloric control diet for three weeks and given 13.5 Gy thoracic XRT. Lungs were evaluated at 24 hours for markers of radiation-induced injury, three weeks for acute lung damage (lipid peroxidation, lung edema and inflammation), and at four months for late lung damage (inflammation and fibrosis). FS-Lignans blunted ROS generation in vitro, resulting from radiation in a dose-dependent manner. FS-fed mice had reduced expression of lung injury biomarkers (Bax, p21, and TGF-beta1) at 24 hours following XRT and reduced oxidative lung damage as measured by malondialdehyde (MDA) levels at 3 weeks following XRT. In addition, FS-fed mice had decreased lung fibrosis as determined by hydroxyproline content and decreased inflammatory cell influx into lungs at 4 months post XRT. Importantly, when Lewis Lung carcinoma cells were injected systemically in mice, FS dietary supplementation did not appear to protect lung tumors from responding to thoracic XRT. Dietary FS is protective against pulmonary fibrosis, inflammation and oxidative lung damage in a murine model. Moreover, in this model, tumor radioprotection was not observed. FS lignans exhibited potent radiation-induced ROS scavenging action. Taken together, these data suggest that dietary flaxseed may be clinically useful as an agent to increase the therapeutic index of thoracic XRT by increasing the radiation tolerance of lung tissues. PMID:18981722

  13. Anti-inflammatory activity of four solvent fractions of ethanol extract of Mentha spicata L. investigated on acute and chronic inflammation induced rats.

    PubMed

    Arumugam, P; Priya, N Gayatri; Subathra, M; Ramesh, A

    2008-07-01

    Anti-inflammatory effects of four solvent fractions of ethanol extract of Mentha spicata were evaluated in acute and chronic inflammation induced in Wistar albino rats. Lipid peroxidation (LPO) and some antioxidants produced during chronic inflammation were quantitated. Hexane (320mg/kg of body weight in 25% DMSO), chloroform (320mg/kg body weight in 25% DMSO), ethyl acetate (160mg/kg body weight in 25% DMSO), aqueous (320mg/kg of body weight in ddH(2)O) fractions, two negative control groups (25% DMSO and ddH(2)O) and two anti-inflammatory drugs (Diclofenac: 25mg/kg of body weight; Indomethacin: 10mg/kg of body weight both in ddH(2)O) were administered by oral intubations to the eight groups of rats consisting six animals, each. In acute study, 1% carrageenan was injected subcutaneously in the sub-plantar region of the right hind paw after 1h of administration of test doses. The increased paw edema was measured at 0.5, 1, 2, 4, 8, 16 and 24h intervals. In the chronic study, the oral administration was carried out for seven consecutive days. On eighth day, four sterile cotton pellets (50mg each) were implanted subcutaneously in the dorsal region of the rats. On the sixteenth day, the rats were sacrificed and the cotton pellets with granulomatous tissue were dissected out and weighed (fresh and dry). Both in chronic and acute inflammation, ethyl acetate (EAF) and aqueous fraction (AF) were effective. EAF is comparable with the positive standards in chronic inflammation. The results indicate that EAF's anti-inflammatory activity is largely due to its ability to modulate in vivo antioxidants.

  14. Animal models of acute renal failure.

    PubMed

    Singh, Amrit Pal; Junemann, Anselm; Muthuraman, Arunachalam; Jaggi, Amteshwar Singh; Singh, Nirmal; Grover, Kuldeep; Dhawan, Ravi

    2012-01-01

    The animal models are pivotal for understanding the characteristics of acute renal failure (ARF) and development of effective therapy for its optimal management. Since the etiology for induction of renal failure is multifold, therefore, a large number of animal models have been developed to mimic the clinical conditions of renal failure. Glycerol-induced renal failure closely mimics the rhabdomyolysis; ischemia-reperfusion-induced ARF simulate the hemodynamic changes-induced changes in renal functioning; drug-induced such as gentamicin, cisplatin, NSAID, ifosfamide-induced ARF mimics the renal failure due to clinical administration of respective drugs; uranium, potassium dichromate-induced ARF mimics the occupational hazard; S-(1,2-dichlorovinyl)-L-cysteine-induced ARF simulate contaminated water-induced renal dysfunction; sepsis-induced ARF mimics the infection-induced renal failure and radiocontrast-induced ARF mimics renal failure in patients during use of radiocontrast media at the time of cardiac catheterization. Since each animal model has been created with specific methodology, therefore, it is essential to describe the model in detail and consequently interpret the results in the context of a specific model.

  15. Role of C16, angiopoietin-1 and regeneration gene protein 2 in attenuating inflammation in an experimental rat model of autoimmune encephalomyelitis.

    PubMed

    Tian, Ke-Wei; Zhang, Fan; Jiang, Hong; Wang, Beibei; Han, Shu

    2017-01-01

    Multiple sclerosis (MS) is a chronic neurological disorder that affects the central nervous system (CNS), and results in CNS inflammation and damage to myelin. In this study, we examined the possible synergistic effects of C16, angiopoietin-1 (Ang-1) and regeneration gene protein 2 (Reg-2) in alleviating inflammation in an acute experimental autoimmune encephalomyelitis (EAE) model. We employed multiple histological, morphological and iconographic assays to examine the effect of those drugs on disease onset, clinical scores and behavioral deficits. Our results demonstrated that triple combination therapy was more efficient than the monotherapy in EAE treatment. The triple therapy significantly delayed the onset of motor symptoms, reduced disease severity, attenuated inflammatory cell infiltration and suppressed the secretion of proinflammatory cytokines. Additionally, treatment increased anti-inflammatory cytokines expression, inhibited reactive astrocytes proliferation, reduced demyelination and axonal loss, and finally reduced the neural death. Specifically, Reg-2 administration rescued oligodendrocytes and neuronal axons mainly by direct neurotrophic effects, while C16+Ang-1 (C+A) mainly improved the inflammatory milieu. In conclusion, our study suggests a possible synergistic effect through targeting a variety of pathways in relieving the clinical symptoms of inflammation in acute EAE model. Therefore, using molecules that target different molecular pathways can be beneficial for exploring novel therapeutic approaches for MS treatment.

  16. The Effects of Proresolution of Ellagic Acid in an Experimental Model of Allergic Airway Inflammation

    PubMed Central

    de Freitas Alves, Claudiney; Angeli, Giovanna Natalia; Favarin, Daniely Cornélio; Lemos de Andrade, Edinéia; Lazo Chica, Javier Emilio; Faccioli, Lúcia Helena; Roberto da Silva, Paulo; de Paula Rogerio, Alexandre

    2013-01-01

    Asthma is a disease of airway inflammation characterized by airway hyperresponsiveness, eosinophilic inflammation, and hypersecretion of mucus. Ellagic acid, a compound derived from medicinal plants and fruits, has shown anti-inflammatory activity in several experimental disease models. We used the classical experimental model, in BALB/c mice, of sensibilization with ovalbumin to determine the effect of ellagic acid (10 mg/kg; oral route) in the resolution of allergic airways response. Dexamethasone (1 mg/kg; subcutaneous route) was used as a positive control. The control group consisted of nonimmunized mice that received challenge with ovalbumin. Ellagic acid and dexamethasone or vehicle (water) were administered before or after intranasal allergen challenge. Ellagic acid accelerated the resolution of airways inflammation by decreasing total leukocytes and eosinophils numbers in the bronchoalveolar lavage fluid (BALF), the mucus production and lung inflammation in part by reducing IL-5 concentration, eosinophil peroxidase (EPO) activity, and P-selectin expression, but not activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) pathways. In addition, ellagic acid enhanced alveolar macrophage phagocytosis of IgG-OVA-coated beads ex vivo, a new proresolving mechanism for the clearance of allergen from the airways. Together, these findings identify ellagic acid as a potential therapeutic agent for accelerating the resolution of allergic airways inflammation. PMID:24376308

  17. Poultry enteric inflammation model with dextran sodium sulfate mediated chemical induction and feed restriction in broilers.

    PubMed

    Kuttappan, V A; Berghman, L R; Vicuña, E A; Latorre, J D; Menconi, A; Wolchok, J D; Wolfenden, A D; Faulkner, O B; Tellez, G I; Hargis, B M; Bielke, L R

    2015-06-01

    Gut inflammation is a cardinal event occurring in various gastrointestinal diseases regardless of etiology. A potential mechanism of action for antibiotic growth promoters and probiotics is alleviation or attenuation of such inflammation. In vivo inflammation models and markers to quantify changes in inflammation, such as paracellular leakage and tight junction function, are necessary tools in the search for methods to reduce enteric inflammation. Dextran sodium sulfate (DSS) and feed restriction (FRS), and fluorescein isothiocyanate dextran (FITC-d; 3 to 5 kDa) marker were evaluated for induction and assessment of enteric inflammation in broilers. Three independent experiments were conducted where birds received an inflammation inducer treatment and an oral gavage of FITC-d (2.2 mg/bird) 2.5 h before killing on d 4, followed by measurement of serum FITC-d levels and release of FITC-d from different regions of gastrointestinal tract (GIT) to evaluate tight junction function. Experiment 1 tested control (CON) and DSS; Experiments 2 and 3 evaluated CON, DSS, and FRS. In all experiments DSS, as well as FRS in Experiments 2 and 3, showed higher (P<0.05) leakage of FITC-d into serum than CON, but FRS was not different from DSS. The amount of FITC-d retained in duodenal and cecal tissue was affected (P<0.05) by FRS in Experiments 2 and 3, and DSS affected FITC-d retention in duodenum only, suggesting differences in gut passage or absorption/adsorption. In conclusion, DSS oral gavage and FRS could induce leaky gut, with changes in serum FITC-d and migration of FITC-d from GIT.

  18. Leptin and interleukin-6 alter the function of mesolimbic dopamine neurons in a rodent model of prenatal inflammation.

    PubMed

    Aguilar-Valles, Argel; Jung, Suna; Poole, Stephen; Flores, Cecilia; Luheshi, Giamal N

    2012-07-01

    Maternal inflammation during critical stages of gestation is thought to underlie the link between prenatal infection and several neurodevelopmental psychiatric disorders in the offspring, including schizophrenia. Increased activity of mesolimbic dopamine (DA) neurons, a hallmark of psychosis, is found in offspring of rodents exposed to a prenatal inflammatory challenge but it is unclear how this effect is elicited. Using an experimental model of localized aseptic inflammation with turpentine oil (TURP) we sought to establish whether circulating interleukin-6 (IL-6) and leptin play a role in the effects of prenatal inflammation on DA neurons. Both mediators are involved in the systemic inflammatory response to immunogens, with IL-6 mediating the early phase, followed by leptin in the late phase of the response. Maternal treatment with TURP at gestational day (GD) 15 enhanced the locomotor response to the DA indirect agonist, amphetamine (AMPH), increased the expression of tyrosine hydroxylase (TH), an enzyme involved in DA synthesis, DA levels and the expression of the post-synaptic protein spinophilin in the nucleus accumbens (NAcc) in the adult offspring. All of these alterations were totally abolished by co-treating the pregnant dams with a neutralizing IL-6 antiserum. Neutralization of maternal leptin prevented the enhanced behavioral sensitization and elevation of DA and spinophilin in the NAcc but spared other changes regulated by IL-6, such as increased NAcc TH levels and acute locomotor response to AMPH. Our results provide novel evidence to suggest that prenatal surges in both maternal circulating IL-6 and leptin contribute to the appearance of sensitized DA function in the adult offspring.

  19. Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model

    PubMed Central

    Ludewig, Burkhard; Freigang, Stefan; Jäggi, Martin; Kurrer, Michael O.; Pei, Yao-Chang; Vlk, Lenka; Odermatt, Bernhard; Zinkernagel, Rolf M.; Hengartner, Hans

    2000-01-01

    Arterial inflammatory responses are thought to be a significant component of atherosclerotic disease. We describe here, using a transgenic approach, the mutual perpetuation of immune-mediated arterial inflammation and cholesterol-induced atherosclerosis. Mice expressing the bacterial transgene β-galactosidase exclusively in cardiomyocytes and in smooth muscle cells in lung arteries and the aorta (SM-LacZ), and hypercholesterolemic apolipoprotein E-deficient SM-LacZ mice (SM-LacZ/apoE−/−) developed myocarditis and arteritis after immunization with dendritic cells presenting a β-galactosidase-derived immunogenic peptide. Hypercholesterolemia amplified acute arteritis and perpetuated chronic arterial inflammation in SM-LacZ/apoE−/− mice, but had no major impact on acute myocarditis or the subsequent development of dilated cardiomyopathy. Conversely, arteritis significantly accelerated cholesterol-induced atherosclerosis. Taken together, these data demonstrate that the linkage of immune-mediated arteritis and hypercholesterolemia favors initiation and maintenance of atherosclerotic lesion formation. Therapeutic strategies to prevent or disrupt such self-perpetuating vicious circles may be crucial for the successful treatment of atherosclerosis. PMID:11050173

  20. A guide to histomorphological evaluation of intestinal inflammation in mouse models

    PubMed Central

    Erben, Ulrike; Loddenkemper, Christoph; Doerfel, Katja; Spieckermann, Simone; Haller, Dirk; Heimesaat, Markus M; Zeitz, Martin; Siegmund, Britta; Kühl, Anja A

    2014-01-01

    Histomorphology remains a powerful routine evaluating intestinal inflammation in animal models. Emphasizing the focus of a given animal study, histopathology can overstate differences between established models. We aimed to systematize histopathological evaluation of intestinal inflammation in mouse models facilitating inter-study comparisons. Samples of all parts of the intestinal tract from well-established mouse models of intestinal inflammation were evaluated from hematoxylin/eosin-stained sections and specific observations confirmed by subsequent immunohistochemistry. Three main categories sufficiently reflected the severity of histopathology independent of the localization and the overall extent of an inflammation: (i) quality and dimension of inflammatory cell infiltrates, (ii) epithelial changes and (iii) overall mucosal architecture. Scoring schemata were defined along specified criteria for each of the three categories. The direction of the initial hit proved crucial for the comparability of histological changes. Chemical noxes, infection with intestinal parasites or other models where the barrier was disturbed from outside, the luminal side, showed high levels of similarity and distinct differences to changes in the intestinal balance resulting from inside events like altered cytokine responses or disruption of the immune cell homeostasis. With a high degree of generalisation and maximum scores from 4-8 suitable scoring schemata accounted specific histopathological hallmarks. Truly integrating demands and experiences of gastroenterologists, mouse researchers, microbiologists and pathologists we provide an easy-to-use guideline evaluating histomorphology in mouse models of intestinal inflammation. Standard criteria and definitions facilitate classification and rating of new relevant models, allow comparison in animal studies and transfer of functional findings to comparable histopathologies in human disease. PMID:25197329

  1. A guide to histomorphological evaluation of intestinal inflammation in mouse models.

    PubMed

    Erben, Ulrike; Loddenkemper, Christoph; Doerfel, Katja; Spieckermann, Simone; Haller, Dirk; Heimesaat, Markus M; Zeitz, Martin; Siegmund, Britta; Kühl, Anja A

    2014-01-01

    Histomorphology remains a powerful routine evaluating intestinal inflammation in animal models. Emphasizing the focus of a given animal study, histopathology can overstate differences between established models. We aimed to systematize histopathological evaluation of intestinal inflammation in mouse models facilitating inter-study comparisons. Samples of all parts of the intestinal tract from well-established mouse models of intestinal inflammation were evaluated from hematoxylin/eosin-stained sections and specific observations confirmed by subsequent immunohistochemistry. Three main categories sufficiently reflected the severity of histopathology independent of the localization and the overall extent of an inflammation: (i) quality and dimension of inflammatory cell infiltrates, (ii) epithelial changes and (iii) overall mucosal architecture. Scoring schemata were defined along specified criteria for each of the three categories. The direction of the initial hit proved crucial for the comparability of histological changes. Chemical noxes, infection with intestinal parasites or other models where the barrier was disturbed from outside, the luminal side, showed high levels of similarity and distinct differences to changes in the intestinal balance resulting from inside events like altered cytokine responses or disruption of the immune cell homeostasis. With a high degree of generalisation and maximum scores from 4-8 suitable scoring schemata accounted specific histopathological hallmarks. Truly integrating demands and experiences of gastroenterologists, mouse researchers, microbiologists and pathologists we provide an easy-to-use guideline evaluating histomorphology in mouse models of intestinal inflammation. Standard criteria and definitions facilitate classification and rating of new relevant models, allow comparison in animal studies and transfer of functional findings to comparable histopathologies in human disease.

  2. Chronic prostatic infection and inflammation by Propionibacterium acnes in a rat prostate infection model.

    PubMed

    Olsson, Jan; Drott, Johanna Bergh; Laurantzon, Lovisa; Laurantzon, Oscar; Bergh, Anders; Elgh, Fredrik

    2012-01-01

    Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic

  3. A Conceptual Model for Episodes of Acute, Unscheduled Care.

    PubMed

    Pines, Jesse M; Lotrecchiano, Gaetano R; Zocchi, Mark S; Lazar, Danielle; Leedekerken, Jacob B; Margolis, Gregg S; Carr, Brendan G

    2016-10-01

    We engaged in a 1-year process to develop a conceptual model representing an episode of acute, unscheduled care. Acute, unscheduled care includes acute illnesses (eg, nausea and vomiting), injuries, or exacerbations of chronic conditions (eg, worsening dyspnea in congestive heart failure) and is delivered in emergency departments, urgent care centers, and physicians' offices, as well as through telemedicine. We began with a literature search to define an acute episode of care and to identify existing conceptual models used in health care. In accordance with this information, we then drafted a preliminary conceptual model and collected stakeholder feedback, using online focus groups and concept mapping. Two technical expert panels reviewed the draft model, examined the stakeholder feedback, and discussed ways the model could be improved. After integrating the experts' comments, we solicited public comment on the model and made final revisions. The final conceptual model includes social and individual determinants of health that influence the incidence of acute illness and injury, factors that affect care-seeking decisions, specific delivery settings where acute care is provided, and outcomes and costs associated with the acute care system. We end with recommendations for how researchers, policymakers, payers, patients, and providers can use the model to identify and prioritize ways to improve acute care delivery.

  4. Regulatory T Cells Contribute to the Inhibition of Radiation-Induced Acute Lung Inflammation via Bee Venom Phospholipase A2 in Mice

    PubMed Central

    Shin, Dasom; Lee, Gihyun; Sohn, Sung-Hwa; Park, Soojin; Jung, Kyung-Hwa; Lee, Ji Min; Yang, Jieun; Cho, Jaeho; Bae, Hyunsu

    2016-01-01

    Bee venom has long been used to treat various inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Previously, we reported that bee venom phospholipase A2 (bvPLA2) has an anti-inflammatory effect through the induction of regulatory T cells. Radiotherapy is a common anti-cancer method, but often causes adverse effects, such as inflammation. This study was conducted to evaluate the protective effects of bvPLA2 in radiation-induced acute lung inflammation. Mice were focally irradiated with 75 Gy of X-rays in the lung and administered bvPLA2 six times after radiation. To evaluate the level of inflammation, the number of immune cells, mRNA level of inflammatory cytokine, and histological changes in the lung were measured. BvPLA2 treatment reduced the accumulation of immune cells, such as macrophages, neutrophils, lymphocytes, and eosinophils. In addition, bvPLA2 treatment decreased inflammasome-, chemokine-, cytokine- and fibrosis-related genes’ mRNA expression. The histological results also demonstrated the attenuating effect of bvPLA2 on radiation-induced lung inflammation. Furthermore, regulatory T cell depletion abolished the therapeutic effects of bvPLA2 in radiation-induced pneumonitis, implicating the anti-inflammatory effects of bvPLA2 are dependent upon regulatory T cells. These results support the therapeutic potential of bvPLA2 in radiation pneumonitis and fibrosis treatments. PMID:27144583

  5. Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms.

    PubMed

    Klafke, J Z; da Silva, M A; Rossato, M F; de Prá, S Dal Toé; Rigo, F K; Walker, C I B; Bochi, G V; Moresco, R N; Ferreira, J; Trevisan, G

    2016-02-01

    Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain.

  6. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation

    PubMed Central

    Keleku-Lukwete, Nadine; Suzuki, Mikiko; Otsuki, Akihito; Tsuchida, Kouhei; Katayama, Saori; Hayashi, Makiko; Naganuma, Eriko; Moriguchi, Takashi; Tanabe, Osamu; Engel, James Douglas; Imaizumi, Masue; Yamamoto, Masayuki

    2015-01-01

    Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells’ hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage. PMID:26371321

  7. Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation.

    PubMed

    Keleku-Lukwete, Nadine; Suzuki, Mikiko; Otsuki, Akihito; Tsuchida, Kouhei; Katayama, Saori; Hayashi, Makiko; Naganuma, Eriko; Moriguchi, Takashi; Tanabe, Osamu; Engel, James Douglas; Imaizumi, Masue; Yamamoto, Masayuki

    2015-09-29

    Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.

  8. Multiplex immunoassay characterization and species comparison of inflammation in acute and non-acute ischemic infarcts in human and mouse brain tissue.

    PubMed

    Nguyen, Thuy-Vi V; Frye, Jennifer B; Zbesko, Jacob C; Stepanovic, Kristina; Hayes, Megan; Urzua, Alex; Serrano, Geidy; Beach, Thomas G; Doyle, Kristian P

    2016-09-06

    This study provides a parallel characterization of the cytokine and chemokine response to stroke in the human and mouse brain at different stages of infarct resolution. The study goal was to address the hypothesis that chronic inflammation may contribute to stroke-related dementia. We used C57BL/6 and BALB/c mice to control for strain related differences in the mouse immune response. Our data indicate that in both mouse strains, and humans, there is increased granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), interleukin-12 p70 (IL-12p70), interferon gamma-induced protein-10 (IP-10), keratinocyte chemoattractant/interleukin-8 (KC/IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β), regulated on activation, normal T cell expressed and secreted (RANTES), and Tumor necrosis factor-α (TNF-α) in the infarct core during the acute time period. Nevertheless, correlation and two-way ANOVA analyses reveal that despite this substantial overlap between species, there are still significant differences, particularly in the regulation of granulocyte colony-stimulating factor (G-CSF), which is increased in mice but not in humans. In the weeks after stroke, during the stage of liquefactive necrosis, there is significant resolution of the inflammatory response to stroke within the infarct. However, CD68+ macrophages remain present, and levels of IL-6 and MCP-1 remain chronically elevated in infarcts from both mice and humans. Furthermore, there is a chronic T cell response within the infarct in both species. This response is differentially polarized towards a T helper 1 (Th1) response in C57BL/6 mice, and a T helper 2 (Th2) response in BALB/c mice, suggesting that the chronic inflammatory response to stroke may follow a different trajectory in different patients. To control for the fact that the average age of the patients used in this study was 80 years, they

  9. A mouse model for pathogen-induced chronic inflammation at local and systemic sites.

    PubMed

    Papadopoulos, George; Kramer, Carolyn D; Slocum, Connie S; Weinberg, Ellen O; Hua, Ning; Gudino, Cynthia V; Hamilton, James A; Genco, Caroline A

    2014-08-08

    Chronic inflammation is a major driver of pathological tissue damage and a unifying characteristic of many chronic diseases in humans including neoplastic, autoimmune, and chronic inflammatory diseases. Emerging evidence implicates pathogen-induced chronic inflammation in the development and progression of chronic diseases with a wide variety of clinical manifestations. Due to the complex and multifactorial etiology of chronic disease, designing experiments for proof of causality and the establishment of mechanistic links is nearly impossible in humans. An advantage of using animal models is that both genetic and environmental factors that may influence the course of a particular disease can be controlled. Thus, designing relevant animal models of infection represents a key step in identifying host and pathogen specific mechanisms that contribute to chronic inflammation. Here we describe a mouse model of pathogen-induced chronic inflammation at local and systemic sites following infection with the oral pathogen Porphyromonas gingivalis, a bacterium closely associated with human periodontal disease. Oral infection of specific-pathogen free mice induces a local inflammatory response resulting in destruction of tooth supporting alveolar bone, a hallmark of periodontal disease. In an established mouse model of atherosclerosis, infection with P. gingivalis accelerates inflammatory plaque deposition within the aortic sinus and innominate artery, accompanied by activation of the vascular endothelium, an increased immune cell infiltrate, and elevated expression of inflammatory mediators within lesions. We detail methodologies for the assessment of inflammation at local and systemic sites. The use of transgenic mice and defined bacterial mutants makes this model particularly suitable for identifying both host and microbial factors involved in the initiation, progression, and outcome of disease. Additionally, the model can be used to screen for novel therapeutic strategies

  10. Acute Lung Injury Following Smoke Inhalation: Predictive Value of Sputum Biomarkers and Time Course of Lung Inflammation

    DTIC Science & Technology

    2005-05-01

    acute respiratory distress syndrome ( ARDS ). Laboratory assays on the bronchial lavage samples...at high risk of developing acute respiratory distress syndrome ( ARDS ). Given the delay of 12 or more hours from exposure to development of ARDS , a...AD Award Number: DAMD17-02-1-0673 TITLE : Acute Lung Injury Following Smoke Inhalation: Predictive Value of Sputum Biomarkers and Time Course of

  11. Caloric Restriction and Formalin-Induced Inflammation: An Experimental Study in Rat Model

    PubMed Central

    Nozad, Aisan; Safari, Mir Bahram; Saboory, Ehsan; Derafshpoor, Leila; Mohseni Moghaddam, Parvaneh; Ghaffari, Farzaneh; Naseri, Mohsen

    2015-01-01

    Background: Acute and chronic inflammations are difficult to control. Using chemical anti-inflammatory medications along with their complications considerably limit their use. According to Traditional Iranian Medicine (TIM), there is an important relation between inflammation and Imtila (food and blood accumulation in the body); food reduction or its more modern equivalent Caloric Restriction (CR) may act against both Imtila and inflammation. Objectives: This experimental study aimed to investigate the effect of 30% reduction in daily calorie intake on inflammation in rats. Materials and Methods: A total of 18 male rats (Rattus rattus) weighing 220 to 270 g were obtained. Then, the inflammation was induced by injecting formalin in their paws. Next, the rats were randomized by generating random numbers into two equal groups (9 + 9) putting on either normal diet (controls) or a similar diet with 30% reduction of calorie (cases). Paw volume changes were recorded twice per day by one observer in both groups using a standard plethysmometer for 8 consecutive days. Serum C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), complete blood count (erythrocyte, platelet, and white blood cell) and hemoglobin were compared between the groups. Results: Decline of both body weight and paw volume was significantly more prominent in the case than in the control rats within the study period (P < 0.001 and < 0.001, respectively). Paw volume decrease was more prominent after day 3. On day 8, serum CRP-positive (1 or 2 +) rats were more frequent in ad libitum fed group comparing with those received CR (33.3% vs. 11.1%). This difference, however, was insignificant (P = 0.58). At the same time, mean ESR was significantly higher in the control rats comparing with that in the case group (29.00 ± 2.89 h vs. 14.00 ± 1.55 h; P = 0.001). Other serum parameters were not significantly different between the two groups at endpoint. Conclusions: Rats fed with a 30% calorie

  12. Novel Faces of Fibroblast Growth Factor 23 (FGF23): Iron Deficiency, Inflammation, Insulin Resistance, Left Ventricular Hypertrophy, Proteinuria and Acute Kidney Injury.

    PubMed

    Kanbay, Mehmet; Vervloet, Marc; Cozzolino, Mario; Siriopol, Dimitrie; Covic, Adrian; Goldsmith, David; Solak, Yalcin

    2017-03-01

    FGF23 is a hormone that appears as the core regulator of phosphate metabolism. Great deal of data has accumulated to demonstrate increased FGF23 secretion from the bone to compensate for even subtle increases in serum phosphorus long before intact PTH. However, recent evidence points to the fact that actions and interactions of FGF23 are not limited solely to phosphate metabolism. FGF23 may be implicated in iron metabolism and erythropoiesis, inflammation, insulin resistance, proteinuria, acute kidney injury and left ventricular hypertrophy. In this review, we will summarize latest experimental and clinical data examining impact of FGF23 on aforementioned pathophysiologic pathways/disorders.

  13. Infections and inflammation in prostate cancer.

    PubMed

    Sfanos, Karen S; Isaacs, William B; De Marzo, Angelo M

    2013-12-25

    The frequent observation of both acute and chronic inflammation of unknown stimulus in the adult prostate has motivated a large body of research aimed at identifying potential infectious agents that may elicit prostatic inflammation. The overarching hypothesis is that infection-induced inflammation may be associated with prostate cancer development or progression, as inflammation is known to serve as an "enabling characteristic" of cancer. With recent advances in molecular techniques for microorganism identification, a panoply of microorganisms has been scrutinized in prostate tissues and in relation to prostate carcinogenesis. The aim of this review is to summarize the current literature on the evidence for infectious agents as a contributing factor to prostatic inflammation and prostate cancer, and to highlight recent literature suggesting an infectious etiology to the biogenesis of prostatic corpora amylacea and on the development of mouse models of prostatic infections.

  14. Infections and inflammation in prostate cancer

    PubMed Central

    Sfanos, Karen S; Isaacs, William B; Marzo, Angelo M De

    2013-01-01

    The frequent observation of both acute and chronic inflammation of unknown stimulus in the adult prostate has motivated a large body of research aimed at identifying potential infectious agents that may elicit prostatic inflammation. The overarching hypothesis is that infection-induced inflammation may be associated with prostate cancer development or progression, as inflammation is known to serve as an “enabling characteristic” of cancer. With recent advances in molecular techniques for microorganism identification, a panoply of microorganisms has been scrutinized in prostate tissues and in relation to prostate carcinogenesis. The aim of this review is to summarize the current literature on the evidence for infectious agents as a contributing factor to prostatic inflammation and prostate cancer, and to highlight recent literature suggesting an infectious etiology to the biogenesis of prostatic corpora amylacea and on the development of mouse models of prostatic infections. PMID:25110720

  15. Impact of a Met(11)Thr single nucleotide polymorphism of surfactant protein D on allergic airway inflammation in a murine asthma model.

    PubMed

    Winkler, Carla; Bahlmann, Olaf; Viereck, Janika; Knudsen, Lars; Wedekind, Dirk; Hoymann, Heinz Gerd; Madsen, Jens; Thum, Thomas; Hohlfeld, Jens M; Ochs, Matthias

    2014-04-01

    The surfactant-associated proteins SP-A and D are pattern recognition molecules with collectin structure. A single nucleotide polymorphism (SNP) exchanging a methionine (Met) for a threonine (Thr) in the amino-terminal SP-D domain influences the oligomeric structure and function of the protein. In this study, we investigated the susceptibility of mice transgenic for the human SP-D Met(11)Thr SNP to allergic airway inflammation and consequences for microRNA (miRNA, miR) expression. Mice expressing either human Met or Thr SP-D were sensitized and challenged with ovalbumin (OVA) in an acute model of allergic asthma. The influence of the SP-D polymorphism on the allergic airway inflammation was evaluated by lung function measurement, pulmonary inflammation parameters, morphological analysis and miRNA expression. Airway hyperresponsiveness, allergic inflammation, and mucus metaplasia were not significantly different between mice expressing one or the other allelic variant of SP-D. OVA sensitization and challenge led to significant airway hyperresponsiveness in wildtype mice and significantly lower eosinophil numbers and interleukin 5 levels in Thr SP-D mice. OVA challenge induced an upregulation of miR-21 and 155 in Thr SP-D mice and a downregulation of miR-21 in Met SP-D mice. Our results show that murine expression of human polymorphic SP-D variants does not significantly influence the severity of allergic airway inflammation. MiR-21 and 155 are differentially regulated in transgenic mice in response to allergic inflammation. Further studies are required to elucidate the impact of this SNP on inflammatory conditions of the lung.

  16. Addressing the translational dilemma: dynamic knowledge representation of inflammation using agent-based modeling.

    PubMed

    An, Gary; Christley, Scott

    2012-01-01

    Given the panoply of system-level diseases that result from disordered inflammation, such as sepsis, atherosclerosis, cancer, and autoimmune disorders, understanding and characterizing the inflammatory response is a key target of biomedical research. Untangling the complex behavioral configurations associated with a process as ubiquitous as inflammation represents a prototype of the translational dilemma: the ability to translate mechanistic knowledge into effective therapeutics. A critical failure point in the current research environment is a throughput bottleneck at the level of evaluating hypotheses of mechanistic causality; these hypotheses represent the key step toward the application of knowledge for therapy development and design. Addressing the translational dilemma will require utilizing the ever-increasing power of computers and computational modeling to increase the efficiency of the scientific method in the identification and evaluation of hypotheses of mechanistic causality. More specifically, development needs to focus on facilitating the ability of non-computer trained biomedical researchers to utilize and instantiate their knowledge in dynamic computational models. This is termed "dynamic knowledge representation." Agent-based modeling is an object-oriented, discrete-event, rule-based simulation method that is well suited for biomedical dynamic knowledge representation. Agent-based modeling has been used in the study of inflammation at multiple scales. The ability of agent-based modeling to encompass multiple scales of biological process as well as spatial considerations, coupled with an intuitive modeling paradigm, suggest that this modeling framework is well suited for addressing the translational dilemma. This review describes agent-based modeling, gives examples of its applications in the study of inflammation, and introduces a proposed general expansion of the use of modeling and simulation to augment the generation and evaluation of knowledge

  17. Quantitative Assessment of Anterior Segment Inflammation in a Rat Model of Uveitis Using Spectral-Domain Optical Coherence Tomography

    PubMed Central

    Pepple, Kathryn L.; Choi, Woo June; Wilson, Leslie; Van Gelder, Russell N.; Wang, Ruikang K.

    2016-01-01

    Purpose To develop anterior segment spectral-domain optical coherence tomography (SD-OCT) and quantitative image analysis for use in experimental uveitis in rats. Methods Acute anterior uveitis was generated in Lewis rats. A spectral domain anterior segment OCT system was used to image the anterior chamber (AC) and ciliary body at baseline and during peak inflammation 2 days later. Customized MatLab image analysis algorithms were developed to segment the AC, count AC cells, calculate central corneal thickness (CCT), segment the ciliary body and zonules, and quantify the level of ciliary body inflammation with the ciliary body index (CBI). Images obtained at baseline and during peak inflammation were compared. Finally, longitudinal imaging and image analysis was performed over the 2-week course of inflammation. Results Spectral-domain optical coherence tomography identifies structural features of inflammation. Anterior chamber cell counts at peak inflammation obtained by automated image analysis and human grading were highly correlated (r = 0.961), and correlated well with the histologic score of inflammation (r = 0.895). Inflamed eyes showed a significant increase in average CCT (27 μm, P = 0.02) and an increase in average CBI (P < 0.0001). Longitudinal imaging and quantitative image analysis identified a significant change in AC cell and CBI on day 2 with spontaneous resolution of inflammation by day 14. Conclusions Spectral-domain optical coherence tomography provides high-resolution images of the structural changes associated with anterior uveitis in rats. Anterior chamber cell count and CBI determined by semi-automated image analysis strongly correlates with inflammation, and can be used to quantify inflammation longitudinally in single animals. PMID:27388049

  18. Cholera-toxin suppresses carcinogenesis in a mouse model of inflammation-driven sporadic colon cancer.

    PubMed

    Doulberis, Michael; Angelopoulou, Katerina; Kaldrymidou, Eleni; Tsingotjidou, Anastasia; Abas, Zaphiris; Erdman, Suzan E; Poutahidis, Theofilos

    2015-02-01

    Human studies and clues from animal models have provided important links between gastrointestinal (GI) tract bacteria and colon cancer. Gut microbiota antigenic stimuli play an important role in shaping the intestinal immune responses. Therefore, especially in the case of inflammation-associated colon cancer, gut bacteria antigens may affect tumorigenesis. The present study aimed to investigate the effects of the oral administration of a bacterial product with known immunomodulatory properties on inflammation-driven colorectal neoplasmatogenesis. For that, we used cholera-toxin and a well-established mouse model of colon cancer in which neoplasia is initiated by a single dose of the genotoxic agent azoxymethane (AOM) and subsequently promoted by inflammation caused by the colitogenic substance dextran sodium sulfate (DSS). We found that a single, low, non-pathogenic dose of CT, given orally at the beginning of each DSS treatment cycle downregulated neutrophils and upregulated regulatory T-cells and IL-10 in the colonic mucosa. The CT-induced disruption of the tumor-promoting character of DSS-induced inflammation led to the reduction of the AOM-initiated colonic polypoidogenesis. This result adds value to the emerging notion that certain GI tract bacteria or their products affect the immune system and render the microenvironment of preneoplastic lesions less favorable for promoting their evolution to cancer.

  19. Evaluation of allergic lung inflammation by computed tomography in a rat model in vivo.

    PubMed

    Jobse, B N; Johnson, J R; Farncombe, T H; Labiris, R; Walker, T D; Goncharova, S; Jordana, M

    2009-06-01

    The ability of micro-computed tomography (CT) to noninvasively evaluate allergic pulmonary inflammation in an experimental model was investigated. In addition, two image segmentation methods and the value of respiratory gating were investigated in the context of this model. Brown Norway rats were exposed to one of four doses of house dust mite (HDM) extract (0, 0.15, 15 or 150 microg) delivered intratracheally every 24 h for 10 days. CT scanning was performed at baseline and after several longitudinal HDM exposures. Both thoracic- and lung-segmentation methods yielded similar results when standardisation practices were employed. While tissue histology correlated well with CT images, cell counts from bronchoalveolar lavage depicted greater inflammation than did density measures from CT images. Evidence from representative CT slices and transaxial density distribution indicated that inflammation was primarily associated with major airways and extended into the periphery from these focal points. Respiratory gating demonstrated that images of the inspiratory state provided greater contrast of inflammatory processes. Lastly, decreases in tidal volumes indicated significant mechanical respiratory changes in animals exposed to both 15 and 150 microg. In summary, CT image segmentation can extract pertinent data on in vivo allergic airway/lung inflammation. Furthermore, respiratory gating provides additional contrast and insight into these quantification practices.

  20. [Role of anti-inflammatory drugs in the treatment of acute coronary syndromes. From athero-inflammation to athero-thrombosis].

    PubMed

    Altman, Raúl; Scazziota, Alejandra

    2003-01-01

    Coronary thrombosis is the most important cause of morbidity and mortality and the most severe manifestation of atherosclerosis. Knowledge of the pathophysiology of atheroma formation and the causes of atheroma accidents have allowed the development of new therapeutic measures for reducing thrombotic events after a coronary episode. Treating the thrombosis after plaque rupture is useful, but a late measure once coronary flow is disturbed. Therefore, treatment at an earlier stage, which we call athero-inflammation, a central event in atheroma progression leading to atherothrombosis, seems wise. There is evidence of an inflammatory component in the pathogenesis of atheroma rupture in acute coronary events. Earlier studies of anti-inflammatory medication have not demonstrated a reduction in thrombotic complications after an acute coronary episode. However, there are pathophysiological arguments and clinical findings that suggest that it would be advisable to include anti-inflammatory medications, especially those that inhibit preferentially COX-2, in the therapeutic arsenal for this pathology. We postulated that blocking athero-inflammation could prevent thrombosis. A pilot study was carried out in 120 patients with acute coronary syndrome without ST-segment elevation in which 60 patients were treated with meloxicam, a preferential COX-2 inhibitor. All patients received heparin and aspirin. During the stay in the coronary care unit, as well as after 90 days, meloxicam lowered composite outcomes (myocardial infarction, death and revascularization procedures) compared with the control group. These results and available pathophysiological and clinical evidence support the hypothesis of potential benefits of non-steroidal anti-inflammatory drugs with preferential inhibitory activity on COX-2 in patients with acute coronary syndromes. More trials are needed to confirm their preventive effect.

  1. Postpartum Circulating Markers of Inflammation and the Systemic Acute-Phase Response After Early-Onset Preeclampsia.

    PubMed

    van Rijn, Bas B; Bruinse, Hein W; Veerbeek, Jan H; Post Uiterweer, Emiel D; Koenen, Steven V; van der Bom, Johanna G; Rijkers, Ger T; Roest, Mark; Franx, Arie

    2016-02-01

    Preeclampsia is an inflammatory-mediated hypertensive disorder of pregnancy and seems to be an early indicator of increased cardiovascular risk, but mechanisms underlying this association are unclear. In this study, we identified levels of circulating inflammatory markers and dynamic changes in the systemic acute-phase response in 44 women with a history of severe early-onset preeclampsia, compared with 29 controls with only uneventful pregnancies at 1.5 to 3.5 years postpartum. Models used were in vivo seasonal influenza vaccination and in vitro whole-blood culture with T-cell stimulants and the toll-like receptor-4 ligand lipopolysaccharide. Outcome measures were C-reactive protein, interleukin-6 (IL-6), IL-18, fibrinogen, myeloperoxidase, and a panel of 13 cytokines representative of the innate and adaptive inflammatory response, in addition to established cardiovascular markers. The in vivo acute-phase response was higher for women with previous preeclampsia than that for controls without such a history, although only significant for C-reactive protein (P=0.04). Preeclampsia was associated with higher IL-1β (P<0.05) and IL-8 (P<0.01) responses to T-cell activation. Hierarchical clustering revealed 2 distinct inflammatory clusters associated with previous preeclampsia: an adaptive response cluster associated with increased C-reactive protein and IL-6 before and after vaccination, increased weight, and low high-density lipoprotein cholesterol; and a toll-like receptor-4 mediated the cluster associated with increased IL-18 before and after vaccination but not associated with other cardiovascular markers. Furthermore, we found interactions between previous preeclampsia, common TLR4 gene variants, and the IL-18 response to vaccination. In conclusion, preeclampsia is associated with alterations in the inflammatory response postpartum mostly independent of other established cardiovascular risk markers.

  2. Iron deposition is independent of cellular inflammation in a cerebral model of multiple sclerosis

    PubMed Central

    2011-01-01

    Background Perivenular inflammation is a common early pathological feature in multiple sclerosis (MS). A recent hypothesis stated that CNS inflammation is induced by perivenular iron deposits that occur in response to altered blood flow in MS subjects. In order to evaluate this hypothesis, an animal model was developed, called cerebral experimental autoimmune encephalomyelitis (cEAE), which presents with CNS perivascular iron deposits. This model was used to investigate the relationship of iron deposition to inflammation. Methods In order to generate cEAE, mice were given an encephalitogen injection followed by a stereotactic intracerebral injection of TNF-α and IFN-γ. Control animals received encephalitogen followed by an intracerebral injection of saline, or no encephalitogen plus an intracerebral injection of saline or cytokines. Laser Doppler was used to measure cerebral blood flow. MRI and iron histochemistry were used to localize iron deposits. Additional histological procedures were used to localize inflammatory cell infiltrates, microgliosis and astrogliosis. Results Doppler analysis revealed that cEAE mice had a reduction in cerebral blood flow compared to controls. MRI revealed T2 hypointense areas in cEAE animals that spatially correlated with iron deposition around vessels and at some sites of inflammation as detected by iron histochemistry. Vessels with associated iron deposits were distributed across both hemispheres. Mice with cEAE had more iron-labeled vessels compared to controls, but these vessels were not commonly associated with inflammatory cell infiltrates. Some iron-laden vessels had associated microgliosis that was above the background microglial response, and iron deposits were observed within reactive microglia. Vessels with associated astrogliosis were more commonly observed without colocalization of iron deposits. Conclusion The findings indicate that iron deposition around vessels can occur independently of inflammation providing

  3. Efficacy of Polaprezinc for Acute Radiation Proctitis in a Rat Model

    SciTech Connect

    Doi, Hiroshi; Kamikonya, Norihiko; Takada, Yasuhiro; Fujiwara, Masayuki; Tsuboi, Keita; Inoue, Hiroyuki; Tanooka, Masao; Nakamura, Takeshi; Shikata, Toshiyuki; Tsujimura, Tohru; Hirota, Shozo

    2011-07-01

    Purpose: The purpose of the present study was to standardize the experimental rat model of radiation proctitis and to examine the efficacy of polaprezinc on radiation proctitis. Methods and Materials: A total of 54 female Wistar rats (5 weeks old) were used. The rats were divided into three groups: those treated with polaprezinc (PZ+), those treated with base alone, exclusive of polaprezinc (PZ-), and those treated without any medication (control). All the rats were irradiated to the rectum. Polaprezinc was prepared as an ointment. The ointment was administered rectally each day after irradiation. All rats were killed on the 10th day after irradiation. The mucosal changes were evaluated endoscopically and pathologically. The results were graded from 0 to 4 and compared according to milder or more severe status, as applicable. Results: According to the endoscopic findings, the proportion of mild changes in the PZ+, PZ-, and control group was 71.4%, 25.0%, and 14.3% respectively. On pathologic examination, the proportion of low-grade findings in the PZ+, PZ-, and control group was 80.0%, 58.3%, and 42.9% for mucosal damage, 85.0%, 41.7%, and 42.9% for a mild degree of inflammation, and 50.0%, 33.3%, and 4.8% for a shallow depth of inflammation, respectively. The PZ+ group tended to have milder mucosal damage than the other groups, according to all criteria used. In addition, significant differences were observed between the PZ+ and control groups regarding the endoscopic findings, degree of inflammation, and depth of inflammation. Conclusions: This model was confirmed to be a useful experimental rat model for radiation proctitis. The results of the present study have demonstrated the efficacy of polaprezinc against acute radiation-induced rectal disorders using the rat model.

  4. Muscle wasting and impaired muscle regeneration in a murine model of chronic pulmonary inflammation.

    PubMed

    Langen, Ramon C J; Schols, Annemie M W J; Kelders, Marco C J M; van der Velden, Jos L J; Wouters, Emiel F M; Janssen-Heininger, Yvonne M W

    2006-12-01

    Muscle wasting and increased circulating levels of inflammatory cytokines, including TNF-alpha, are common features of chronic obstructive pulmonary disease. To investigate whether inflammation of the lung is responsible for systemic inflammation and muscle wasting, we adopted a mouse model of pulmonary inflammation resulting from directed overexpression of a TNF-alpha transgene controlled by the surfactant protein C (SP-C) promoter. Compared with wild-type mice, SP-C/TNF-alpha mice exhibited increased levels of TNF-alpha in the circulation and increased endogenous TNF-alpha expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF-alpha. Decreased muscle and body weights observed in SP-C/TNF-alpha mice were indicative of muscle wasting. Further evaluation of the SP-C/TNF-alpha mouse musculature revealed a decreased muscle regenerative capacity, shown by attenuated myoblast proliferation and differentiation in response to reloading of disuse-atrophied muscle, which may contribute to skeletal muscle wasting. Importantly, incubation of cultured myoblasts with TNF-alpha also resulted in elevated TNF-alpha mRNA levels and inhibition of myoblast differentiation. Collectively, our results demonstrate that chronic pulmonary inflammation results in muscle wasting and impaired muscle regeneration in SP-C/TNF-alpha mice, possibly as a consequence of an amplificatory TNF-alpha expression circuit extending from the lung to skeletal muscle.

  5. Experimental models of hepatotoxicity related to acute liver failure

    PubMed Central

    Maes, Michaël; Vinken, Mathieu; Jaeschke, Hartmut

    2015-01-01

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. PMID:26631581

  6. Complement system dysregulation and inflammation in the retinal pigment epithelium of a mouse model for Stargardt macular degeneration.

    PubMed

    Radu, Roxana A; Hu, Jane; Yuan, Quan; Welch, Darcy L; Makshanoff, Jacob; Lloyd, Marcia; McMullen, Stephen; Travis, Gabriel H; Bok, Dean

    2011-05-27

    Accumulation of vitamin A-derived lipofuscin fluorophores in the retinal pigment epithelium (RPE) is a pathologic feature of recessive Stargardt macular dystrophy, a blinding disease caused by dysfunction or loss of the ABCA4 transporter in rods and cones. Age-related macular degeneration, a prevalent blinding disease of the elderly, is strongly associated with mutations in the genes for complement regulatory proteins (CRP), causing chronic inflammation of the RPE. Here we explore the possible relationship between lipofuscin accumulation and complement activation in vivo. Using the abca4(-/-) mouse model for recessive Stargardt, we investigated the role of lipofuscin fluorophores (A2E-lipofuscin) on oxidative stress and complement activation. We observed higher expression of oxidative-stress genes and elevated products of lipid peroxidation in eyes from abca4(-/-) versus wild-type mice. We also observed higher levels of complement-activation products in abca4(-/-) RPE cells. Unexpectedly, expression of multiple CRPs, which protect cells from attack by the complement system, were lower in abca4(-/-) versus wild-type RPE. To test whether acute exposure of healthy RPE cells to A2E-lipofuscin affects oxidative stress and expression of CRPs, we fed cultured fetal-derived human RPE cells with rod outer segments from wild-type or abca4(-/-) retinas. In contrast to RPE cells in abca4(-/-) mice, human RPE cells exposed to abca4(-/-) rod outer segments adaptively increased expression of both oxidative-stress and CRP genes. These results suggest that A2E accumulation causes oxidative stress, complement activation, and down-regulation of protective CRP in the Stargardt mouse model. Thus, Stargardt disease and age-related macular degeneration may both be caused by chronic inflammation of the RPE.

  7. The Effects of a Calorie Reduced Diet on Periodontal Inflammation and Disease in a Non Human Primate Model

    PubMed Central

    Branch-Mays, Grishondra L.; Dawson, Dolphus R.; Gunsolley, John C.; Reynolds, Mark A.; Ebersole, Jeffrey L.; Novak, Karen F.; Mattison, Julie A.; Ingram, Donald K.; Novak, M. John

    2008-01-01

    Background Low calorie diets are commonplace for reducing body weight. However, no information is available on the effects of a reduced calorie diet on periodontal inflammation and disease. The purpose of this study was to evaluate the clinical effects of a long term calorie restricted diet (CR) on periodontitis in an animal model of periodontitis. Methods Periodontitis was induced in 55 young, healthy, adult rhesus monkeys (Macaca mulatta) by tying 2.0 silk ligatures at the gingival margins of maxillary premolar/molar teeth. Animals on a CR diet (30% CR; n=23) were compared to ad libitum diet controls (n=32). Clinical measures including plaque (PLI), probing pocket depth (PD), clinical attachment level (CAL), modified Gingival Index (GI) and bleeding on probing (BOP) were taken at baseline and 1, 2, and 3 months after ligature placement. Results Significant effects of CR were observed on the development of inflammation and the progression of periodontal destruction in this model. When compared to controls, CR resulted in a significant reduction in ligature induced GI (p<0.0001), BOP (p<0.0015), PD (p<0.0016), and CAL (p<0.0038). When viewed over time, periodontal destruction, as measured by CAL, progressed significantly more slowly in the CR animals than in the controls (p<0.001). Conclusions These clinical findings are consistent with available evidence that CR has anti-inflammatory effects. Moreover, these experimental findings are the first observations that CR dampens the inflammatory response and reduces active periodontal breakdown associated with an acute microbial challenge. PMID:18597600

  8. Effect of Increased Neutrophil-to-Lymphocyte Ratio (NLR) and Decreased Mean Platelet Volume (MPV) Values on Inflammation in Acute Mania

    PubMed Central

    MAYDA, Hasan; AHSEN, Ahmet; BAĞCIOĞLU, Erman; ÖZTÜRK, Ahmet; BAHÇECİ, Bülent; SOYUÇOK, Etem; BAŞPINAR, Erol; ULU, Memnune Sena

    2016-01-01

    Introduction The neutrophil-to-lymphocyte ratio (NLR) and mean platelet volume (MPV) are simple, low-cost, and useful inflammatory markers detected in routine complete blood count (CBC), and their use has recently become widespread. In this study, we aimed to investigate the presence of an inflammatory state in manic patients on the basis of NLR and MPV values. Methods This retrospective study was performed on 76 patients with acute mania who were admitted to the Inpatients Psychiatry Clinic of Afyon Kocatepe University Hospital in Turkey. Diagnoses were based on Diagnostic and Statistical Manuel of Mental disorder (DSM-IV). The control group consisted of 74 healthy individuals recruited from the community. They were age- and sex-matched with the study group. Results NLR values of the manic patient group were 2.2±1.4 and those of the control group were 1.6±0.5. NLR values were significantly higher (p=0.004) and MPV values were significantly lower in the manic patient group than in the control group (10.0±1.2 vs. 10.9±2.3, p=0.027). Conclusion Increased NLR and decreased MPV levels may reflect inflammation in manic patients, and inflammation may play a role in the complex pathophysiology of acute mania. PMID:28360805

  9. Metabolic Cost of the Activation of Immune Response in the Fish-Eating Myotis (Myotis vivesi): The Effects of Inflammation and the Acute Phase Response.

    PubMed

    Otálora-Ardila, Aída; Herrera M, L Gerardo; Flores-Martínez, José Juan; Welch, Kenneth C

    2016-01-01

    Inflammation and activation of the acute phase response (APR) are energetically demanding processes that protect against pathogens. Phytohaemagglutinin (PHA) and lipopolysaccharide (LPS) are antigens commonly used to stimulate inflammation and the APR, respectively. We tested the hypothesis that the APR after an LPS challenge was energetically more costly than the inflammatory response after a PHA challenge in the fish-eating Myotis bat (Myotis vivesi). We measured resting metabolic rate (RMR) after bats were administered PHA and LPS. We also measured skin temperature (Tskin) after the LPS challenge and skin swelling after the PHA challenge. Injection of PHA elicited swelling that lasted for several days but changes in RMR and body mass were not significant. LPS injection produced a significant increase in Tskin and in RMR, and significant body mass loss. RMR after LPS injection increased by 140-185% and the total cost of the response was 6.50 kJ. Inflammation was an energetically low-cost process but the APR entailed a significant energetic investment. Examination of APR in other bats suggests that the way in which bats deal with infections might not be uniform.

  10. Metabolic Cost of the Activation of Immune Response in the Fish-Eating Myotis (Myotis vivesi): The Effects of Inflammation and the Acute Phase Response

    PubMed Central

    Otálora-Ardila, Aída; Herrera M., L. Gerardo; Flores-Martínez, José Juan; Welch, Kenneth C.

    2016-01-01

    Inflammation and activation of the acute phase response (APR) are energetically demanding processes that protect against pathogens. Phytohaemagglutinin (PHA) and lipopolysaccharide (LPS) are antigens commonly used to stimulate inflammation and the APR, respectively. We tested the hypothesis that the APR after an LPS challenge was energetically more costly than the inflammatory response after a PHA challenge in the fish-eating Myotis bat (Myotis vivesi). We measured resting metabolic rate (RMR) after bats were administered PHA and LPS. We also measured skin temperature (Tskin) after the LPS challenge and skin swelling after the PHA challenge. Injection of PHA elicited swelling that lasted for several days but changes in RMR and body mass were not significant. LPS injection produced a significant increase in Tskin and in RMR, and significant body mass loss. RMR after LPS injection increased by 140–185% and the total cost of the response was 6.50 kJ. Inflammation was an energetically low-cost process but the APR entailed a significant energetic investment. Examination of APR in other bats suggests that the way in which bats deal with infections might not be uniform. PMID:27792729

  11. Acute pulmonary exacerbation and lung function decline in patients with cystic fibrosis: high-mobility group box 1 (HMGB1) between inflammation and infection.

    PubMed

    Chirico, V; Lacquaniti, A; Leonardi, S; Grasso, L; Rotolo, N; Romano, C; Di Dio, G; Lionetti, E; David, A; Arrigo, T; Salpietro, C; La Rosa, M

    2015-04-01

    Airway inflammation plays a central role in cystic fibrosis (CF) lung disease, and biomarkers of inflammation, such as high-mobility group box 1 (HMGB1) could be used to monitor disease activity. The main aim of this study was to confirm the role of HMGB1 in CF patients, correlating its serum and sputum levels with pulmonary function and inflammation. Serum and sputum HMGB1 were evaluated in a cohort of 31 CF patients and 30 non-smoking healthy subjects (HS group). Acute pulmonary exacerbation events and lung function decline have been also evaluated during a 3-year follow-up period. Serum HMGB1 levels were significantly higher than those measured in HS, such as sputum HMGB1. Kaplan-Meier survival curves revealed that patients with high HMGB1 values experienced a significantly faster evolution to decline of lung function. A multiple Cox regression analysis assessed that an increase of serum HMGB1 was associated with 5% increased risk of pulmonary disease progression, whereas elevated sputum HMGB1 was related to a 10% increased risk of lung function decline. In CF patients, HMGB1 closely reflects the entity of pulmonary impairment and represents a strong and independent risk marker for progression of lung function decline.

  12. Copper toxicology, oxidative stress and inflammation using zebrafish as experimental model.

    PubMed

    Pereira, Talita Carneiro Brandão; Campos, Maria Martha; Bogo, Maurício Reis

    2016-07-01

    Copper is an essential micronutrient and a key catalytic cofactor in a wide range of enzymes. As a trace element, copper levels are tightly regulated and both its deficit and excess are deleterious to the organism. Under inflammatory conditions, serum copper levels are increased and trigger oxidative stress responses that activate inflammatory responses. Interestingly, copper dyshomeostasis, oxidative stress and inflammation are commonly present in several chronic diseases. Copper exposure can be easily modeled in zebrafish; a consolidated model in toxicology with increasing interest in immunity-related research. As a result of developmental, economical and genetic advantages, this freshwater teleost is uniquely suitable for chemical and genetic large-scale screenings, representing a powerful experimental tool for a whole-organism approach, mechanistic studies, disease modeling and beyond. Copper toxicological and more recently pro-inflammatory effects have been investigated in both larval and adult zebrafish with breakthrough findings. Here, we provide an overview of copper metabolism in health and disease and its effects on oxidative stress and inflammation responses in zebrafish models. Copper-induced inflammation is highlighted owing to its potential to easily mimic pro-oxidative and pro-inflammatory features that combined with zebrafish genetic tractability could help further in the understanding of copper metabolism, inflammatory responses and related diseases. Copyright © 2016 John Wiley & Sons, Ltd.

  13. Close teamwork between Nrf2 and peroxiredoxins 1 and 6 for the regulation of prostaglandin D2 and E2 production in macrophages in acute inflammation.

    PubMed

    Ishii, Tetsuro

    2015-11-01

    Inflammation is a complex biological self-defense reaction triggered by tissue damage or infection by pathogens. Acute inflammation is regulated by the time- and cell type-dependent production of cytokines and small signaling molecules including reactive oxygen species and prostaglandins. Recent studies have unveiled the important role of the transcription factor Nrf2 in the regulation of prostaglandin production through transcriptional regulation of peroxiredoxins 1 and 6 (Prx1 and Prx6) and lipocalin-type prostaglandin D synthase (L-PGDS). Prx1 and Prx6 are multifunctional proteins important for cell protection against oxidative stress, but also work together to facilitate production of prostaglandins E2 and D2 (PGE2 and PGD2). Prx1 secreted from cells under mild oxidative stress binds Toll-like receptor 4 and induces NF-κB activation, important for the expression of cyclooxygenase-2 and microsomal PGE synthase-1 (mPGES-1) expression. The activated MAPKs p38 and ERK phosphorylate Prx6, leading to NADPH oxidase-2 activation, which contributes to production of PGD2 by hematopoietic prostaglandin D synthase (H-PGDS). PGD2 and its end product 15-deoxy-∆(12,14)-prostaglandin J2 (15d-PGJ2) activate Nrf2 thereby forming a positive feedback loop for further production of PGD2 by L-PGDS. Maintenance of cellular glutathione levels is an important role of Nrf2 not only for cell protection but also for the synthesis of prostaglandins, as mPGES-1 and H-PGDS require glutathione for their activities. This review is aimed at describing the functions of Prx1 and Prx6 in the regulation of PGD2 and PGE2 production in acute inflammation in macrophages and the importance of 15d-PGJ2 as an intrinsic Nrf2 activator.

  14. Toxoplasma gondii infection induces suppression in a mouse model of allergic airway inflammation.

    PubMed

    Fenoy, Ignacio M; Chiurazzi, Romina; Sánchez, Vanesa R; Argenziano, Mariana A; Soto, Ariadna; Picchio, Mariano S; Martin, Valentina; Goldman, Alejandra

    2012-01-01

    Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact-independent and correlated with high levels of TGF-β and CD4(+)FoxP3(+) cells.

  15. Toxoplasma gondii Infection Induces Suppression in a Mouse Model of Allergic Airway Inflammation

    PubMed Central

    Fenoy, Ignacio M.; Chiurazzi, Romina; Sánchez, Vanesa R.; Argenziano, Mariana A.; Soto, Ariadna; Picchio, Mariano S.; Martin, Valentina; Goldman, Alejandra

    2012-01-01

    Allergic asthma is an inflammatory disorder characterized by infiltration of the airway wall with inflammatory cells driven mostly by activation of Th2-lymphocytes, eosinophils and mast cells. There is a link between increased allergy and a reduction of some infections in Western countries. Epidemiological data also show that respiratory allergy is less frequent in people exposed to orofecal and foodborne microbes such as Toxoplasma gondii. We previously showed that both acute and chronic parasite T. gondii infection substantially blocked development of airway inflammation in adult BALB/c mice. Based on the high levels of IFN-γ along with the reduction of Th2 phenotype, we hypothesized that the protective effect might be related to the strong Th1 immune response elicited against the parasite. However, other mechanisms could also be implicated. The possibility that regulatory T cells inhibit allergic diseases has received growing support from both animal and human studies. Here we investigated the cellular mechanisms involved in T. gondii induced protection against allergy. Our results show for the first time that thoracic lymph node cells from mice sensitized during chronic T. gondii infection have suppressor activity. Suppression was detected both in vitro, on allergen specific T cell proliferation and in vivo, on allergic lung inflammation after adoptive transference from infected/sensitized mice to previously sensitized animals. This ability was found to be contact- independent and correlated with high levels of TGF-β and CD4+FoxP3+ cells. PMID:22952678

  16. Induction of psoriasiform inflammation by a bacterial superantigen in the SCID-hu xenogeneic transplantation model.

    PubMed

    Boehncke, W H; Zollner, T M; Dressel, D; Kaufmann, R

    1997-01-01

    Psoriasis is a chronic skin disease affecting about 2% of the Caucasian population, characterized by co-existing inflammation and epidermal hyperproliferation. A T-lymphocyte-mediated autoimmune reaction induced by bacterial superantigens might be central in its pathogenesis. To model psoriasiform inflammation, we transplanted clinically uninvolved skin from psoriatic patients onto SCID mice. Repetitive intradermal injections with a bacterial superantigen and simultaneous intraperitoneal injections with the patients superantigen-stimulated peripheral mononuclear blood cells resulted in an inflammatory reaction exhibiting some of the hallmarks of psoriasis, e.g. epidermal hyperproliferation, papillomatosis, focal neo-expression of ICAMI, and an exocytotic T-lymphocytic infiltrate characterized by the expression of the cutaneous lymphocyte-associated antigen. These observations document the potential of superantigens to trigger psoriasiform dermatitis and provide a model to study lymphocyte homing.

  17. An aqueous extract of Ilex paraguariensis reduces carrageenan-induced edema and inhibits the expression of cyclooxygenase-2 and inducible nitric oxide synthase in animal models of inflammation.

    PubMed

    Schinella, Guillermo; Neyret, Elisa; Cónsole, Gloria; Tournier, Horacio; Prieto, José M; Ríos, José-Luis; Giner, Rosa María

    2014-08-01

    Mate (Ilex paraguariensis) is a highly popular herbal beverage in South America due to its high content of caffeine. Its hypolipidemic and antioxidant properties are of increasing interest in the treatment of cardiovascular disorders and for weight control. In the present study, we show for the first time both the local and systemic anti-inflammatory effects of an aqueous extract of mate in three classic in vivo models, namely acute and chronic 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema and acute carrageenan-induced mouse paw edema. Caffeine, rutin, chlorogenic acid, 3,5-dicafeoyl quinic acid, and 4,5-dicafeoyl quinic acid, accompanied by a complex mixture of other simple phenolic acids, were identified in the extract by HPLC-UV analyses. In the acute edema model, mate extract applied topically (1 mg/ear) halved the 12-O-tetradecanoylphorbol 13-acetate-induced acute edema (50 %) and almost suppressed neutrophil infiltration (93 %), while in the 12-O-tetradecanoylphorbol 13-acetate-induced subchronic inflammation, the edema was significantly reduced by 62 % (1 mg/ear/day × seven doses). The oral administration of the mate extract (250 mg/kg) significantly reduced the carrageenan-induced edema at all time points, an effect which was accompanied by a 43 % and 53 % reduction of the expression of cyclooxygenase-2 and inducible nitric oxide synthase, respectively. Histological analyses confirmed a reduction of epithelium thickness, dermis with mild inflammation, hair follicles with some secretory cells of sebaceous glands, and hypodermic adipocytes. In conclusion, mate is endowed with in vivo preventative or therapeutic anti-inflammatory effects in both local and systemic inflammatory processes.

  18. Herbal medicine treatment reduces inflammation in a murine model of cockroach allergen–induced asthma

    PubMed Central

    Kim, Jiyoun; Natarajan, Sudha; Bae, Hyunsu; Jung, Sung-Ki; Cruikshank, William; Remick, Daniel G.

    2013-01-01

    Background Asthma is a significant disease among children, and its prevalence has increased notably during the last 2 decades. A traditional Korean medicine, So-Cheong-Ryong-Tang (SCRT), has been used for the treatment of asthma in Asia for centuries, but its mechanism for reducing bronchopulmonary inflammation in asthma has yet to be elucidated. Objective To investigate whether the herbal extract SCRT inhibits inflammation in a mouse model of cockroach allergen–induced asthma. Methods A house dust extract containing endotoxin and cockroach allergens was used for immunization and 2 additional pulmonary challenges in BALB/c mice. Mice were treated with SCRT or vehicle 1 hour before each pulmonary challenge. Respiratory parameters were evaluated by whole-body plethysmography and forced oscillation methods 24 hours after the last challenge. Bronchoalveolar lavage (BAL) fluid was collected, and histologic sections of lung were prepared either 4 or 24 hours after the last house dust extract challenge. Results SCRT treatment significantly reduced the hyperreactivity of the airways as measured by whole-body plethysmography and direct measurement of airway resistance. Inflammation was significantly inhibited by SCRT treatment as demonstrated by reduced plasma IgE levels and improved pulmonary histologic characteristics. SCRT significantly reduced the number of neutrophils in the BAL fluid and also significantly reduced the BAL levels of CXC chemokines, providing a potential mechanism for the reduced inflammation. In a similar fashion, SCRT reduced eosinophil recruitment and BAL levels of eotaxin and RANTES. Conclusion These data indicate that SCRT treatment alleviates asthma-like pulmonary inflammation via suppression of specific chemokines. PMID:21802024

  19. 11C-Methionine PET of Myocardial Inflammation in a Rat Model of Experimental Autoimmune Myocarditis.

    PubMed

    Maya, Yoshifumi; Werner, Rudolf A; Schütz, Claudia; Wakabayashi, Hiroshi; Samnick, Samuel; Lapa, Constantin; Zechmeister, Christina; Jahns, Roland; Jahns, Valérie; Higuchi, Takahiro

    2016-12-01

    Myocarditis represents a major cause of dilated cardiomyopathy and sudden cardiac death in younger adults. Currently, definitive diagnosis of myocarditis requires endomyocardial biopsy, which is highly invasive and has the drawback of variable sensitivity due to inherent sampling error. Therefore, reliable noninvasive methods to detect and monitor cardiac inflammation are clinically relevant. In this study, we explored the potential of radiolabeled methionine to assess myocardial inflammatory activity in a rat model of experimental autoimmune myocarditis (EAM).

  20. Transmembrane TNF-α is sufficient for articular inflammation and hypernociception in a mouse model of gout.

    PubMed

    Amaral, Flávio A; Bastos, Leandro F S; Oliveira, Thiago H C; Dias, Ana C F; Oliveira, Vívian L S; Tavares, Lívia D; Costa, Vivian V; Galvão, Izabela; Soriani, Frederico M; Szymkowski, David E; Ryffel, Bernhard; Souza, Danielle G; Teixeira, Mauro M

    2016-01-01

    Gout manifests as recurrent episodes of acute joint inflammation and pain due to the deposition of monosodium urate (MSU) crystals within the affected tissue in a process dependent on NLRP3 inflammasome activation. The synthesis, activation, and release of IL-1β are crucial for MSU-induced inflammation. The current study evaluated the mechanism by which TNF-α contributed to MSU-induced inflammation. Male C57BL/6J or transgenic mice were used in this study and inflammation was induced by the injection of MSU crystals into the joint. TNF-α was markedly increased in the joint after the injection of MSU. There was inhibition in the infiltration of neutrophils, production of CXCL1 and IL-1β, and decreased hypernociception in mice deficient for TNF-α or its receptors. Pharmacological blockade of TNF-α with Etanercept or pentoxyfylline produced similar results. Mechanistically, TNF-α blockade resulted in lower amounts of IL-1β protein and pro-IL-1β mRNA transcripts in joints. Gene-modified mice that express only transmembrane TNF-α had an inflammatory response similar to that of WT mice and blockade of soluble TNF-α (XPro™1595) did not decrease MSU-induced inflammation. In conclusion, TNF-α drives expression of pro-IL-1β mRNA and IL-1β protein in experimental gout and that its transmembrane form is sufficient to trigger MSU-induced inflammation in mice.

  1. Proteomic dissection of LPS-inducible, PHF8-dependent secretome reveals novel roles of PHF8 in TLR4-induced acute inflammation and T cell proliferation

    PubMed Central

    Erdoğan, Özgün; Xie, Ling; Wang, Li; Wu, Bing; Kong, Qing; Wan, Yisong; Chen, Xian

    2016-01-01

    Endotoxin (LPS)-induced changes in histone lysine methylation contribute to the gene-specific transcription for control of inflammation. Still unidentified are the chromatin regulators that drive the transition from a transcriptional-repressive to a transcriptional-active chromatin state of pro-inflammatory genes. Here, using combined approaches to analyze LPS-induced changes in both gene-specific transcription and protein secretion to the extracellular compartment, we characterize novel functions of the lysine demethylase PHF8 as a pro-inflammatory, gene-specific chromatin regulator. First, in the LPS-induced, acute-inflamed macrophages, PHF8 knockdown led to both a reduction of pro-inflammatory factors and an increase in a transcriptional-repressive code (H3K9me2) written by the methyltransferase G9a. Through unbiased quantitative secretome screening we discovered that LPS induces the secretion of a cluster of PHF8-dependent, ‘tolerizable’ proteins that are related to diverse extracellular pathways/processes including those for the activation of adaptive immunity. Specifically, we determined that PHF8 promotes T-cell activation and proliferation, thus providing the first link between the epigenetic regulation of inflammation and adaptive immunity. Further, we found that, in the acute-inflamed macrophages, the acute-active PHF8 opposes the H3K9me1/2-writing activity of G9a to activate specific protein secretions that are suppressed by G9a in the endotoxin-tolerant cells, revealing the inflammatory-phenotypic chromatin drivers that regulate the gene-specific chromatin plasticity. PMID:27112199

  2. Whole Blood Human Neutrophil Trafficking in a Microfluidic Model of Infection and Inflammation

    PubMed Central

    Hamza, Bashar; Irimia, Daniel

    2015-01-01

    Appropriate inflammatory responses to wounds and infections require adequate numbers of neutrophils arriving at injury sites. Both insufficient and excessive neutrophil recruitment can be detrimental, favouring systemic spread of microbes or triggering severe tissue damage. Despite its importance in health and disease, the trafficking of neutrophils through tissues remains difficult to control and the mechanisms regulating it are insufficiently understood. These mechanisms are also complex and difficult to isolate using traditional in vivo models. Here we designed a microfluidic model of tissue infection/inflammation, in which human neutrophils emerge from a droplet-size samples of whole blood and display bi-directional traffic between this and micro-chambers containing chemoattractant and microbe-like particles. Two geometrical barriers restrict the entrance of red blood cells from the blood to the micro-chambers and simulate the mechanical function of the endothelial barrier separating the cells in blood from cells in tissues. We found that in the presence of chemoattractant, the number of neutrophils departing the chambers by retrotaxis is in dynamic equilibrium with the neutrophils recruited by chemotaxis. We also found that in the presence of microbe-like particles, the number of neutrophils trapped in the chambers is proportional to the number of particles. Together, the dynamic equilibrium between migration, reversed-migration and trapping processes determine the optimal number of neutrophils at a site. These neutrophils are continuously refreshed and responsive to the number of microbes. Further studies using this infection-inflammation-on-a-chip-model could help study the processes of inflammation resolution. The new in vitro experimental tools may also eventually help testing new therapeutic strategies to limit neutrophil accumulation in tissues during chronic inflammation, without increasing the risk for infections. PMID:25987163

  3. PET imaging of brain inflammation during early epileptogenesis in a rat model of temporal lobe epilepsy

    PubMed Central

    2012-01-01

    Background Recently, inflammatory cascades have been suggested as a target for epilepsy therapy. Positron emission tomography (PET) imaging offers the unique possibility to evaluate brain inflammation longitudinally in a non-invasive translational manner. This study investigated brain inflammation during early epileptogenesis in the post-kainic acid-induced status epilepticus (KASE) model with post-mortem histology and in vivo with [18F]-PBR111 PET. Methods Status epilepticus (SE) was induced (N = 13) by low-dose injections of KA, while controls (N = 9) received saline. Translocator protein (TSPO) expression and microglia activation were assessed with [125I]-CLINDE autoradiography and OX-42 immunohistochemistry, respectively, 7 days post-SE. In a subgroup of rats, [18F]-PBR111 PET imaging with metabolite-corrected input function was performed before post-mortem evaluation. [18F]-PBR111 volume of distribution (Vt) in volume of interests (VOIs) was quantified by means of kinetic modelling and a VOI/metabolite-corrected plasma activity ratio. Results Animals with substantial SE showed huge overexpression of TSPO in vitro in relevant brain regions such as the hippocampus and amygdala (P < 0.001), while animals with mild symptoms displayed a smaller increase in TSPO in amygdala only (P < 0.001). TSPO expression was associated with OX-42 signal but without obvious cell loss. Similar in vivo [18F]-PBR111 increases in Vt and the simplified ratio were found in key regions such as the hippocampus (P < 0.05) and amygdala (P < 0.01). Conclusion Both post-mortem and in vivo methods substantiate that the brain regions important in seizure generation display significant brain inflammation during epileptogenesis in the KASE model. This work enables future longitudinal investigation of the role of brain inflammation during epileptogenesis and evaluation of anti-inflammatory treatments. PMID:23136853

  4. Sinomenine attenuates airway inflammation and remodeling in a mouse model of asthma

    PubMed Central

    BAO, HAI-RONG; LIU, XIAO-JU; LI, YUN-LIN; MEN, XIANG; ZENG, XIAO-LI

    2016-01-01

    Asthma is an inflammatory disease that involves airway inflammation and remodeling. Sinomenine (SIN) has been demonstrated to have immunosuppressive and anti-inflammatory properties. The aim of the present study was to investigate the inhibitory effects of SIN on airway inflammation and remodeling in an asthma mouse model and observe the effects of SIN on the transforming growth factor-β1 (TGF-β1)/connective tissue growth factor (CTGF) pathway and oxidative stress. Female BALB/c mice were sensitized by repetitive ovalbumin (OVA) challenge for 6 weeks in order to develop a mouse model of asthma. OVA-sensitized animals received SIN (25, 50 and 75 mg/kg) or dexamethasone (2 mg/kg). A blank control group received saline only. The area of smooth muscle and collagen, levels of mucus secretion and inflammatory cell infiltration were evaluated 24 h subsequent to the final OVA challenge. mRNA and protein levels of TGF-β1 and CTGF were determined by reverse transcription-quantitative polymerase chain reaction and immunohistology, respectively. The indicators of oxidative stress were detected by spectrophotometry. SIN significantly reduced allergen-induced increases in smooth muscle thickness, mucous gland hypertrophy, goblet cell hyperplasia, collagen deposition and eosinophilic inflammation. The levels of TGF-β1 and CTGF mRNA and protein were significantly reduced in the lungs of mice treated with SIN. Additionally, the total antioxidant capacity was increased in lungs following treatment with SIN. The malondialdehyde content and myeloperoxidase activities in the lungs from OVA-sensitized mice were significantly inhibited by SIN. In conclusion, SIN may inhibit airway inflammation and remodeling in asthma mouse models, and may have therapeutic efficacy in the treatment of asthma. PMID:26820806

  5. Redox imaging of skeletal muscle using in vivo DNP-MRI and its application to an animal model of local inflammation.

    PubMed

    Eto, Hinako; Hyodo, Fuminori; Kosem, Nutavutt; Kobayashi, Ryoma; Yasukawa, Keiji; Nakao, Motonao; Kiniwa, Mamoru; Utsumi, Hideo

    2015-12-01

    Disorders of skeletal muscle are often associated with inflammation and alterations in redox status. A non-invasive technique that could localize and evaluate the severity of skeletal muscle inflammation based on its redox environment would be useful for disease identification and monitoring, and for the development of treatments; however, no such technique currently exists. We describe a method for redox imaging of skeletal muscle using dynamic nuclear polarization magnetic resonance imaging (DNP-MRI), and apply this method to an animal model of local inflammation. Female C57/BL6 mice received injections of 0.5% bupivacaine into their gastrocnemius muscles. Plasma biomarkers, myeloperoxidase activity, and histological sections were assessed at 4 and 24h after bupivacaine injection to measure the inflammatory response. In vivo DNP-MRI was performed with the nitroxyl radicals carbamoyl-PROXYL (cell permeable) and carboxy-PROXYL (cell impermeable) as molecular imaging probes at 4 and 24h after bupivacaine administration. The images obtained after carbamoyl-PROXYL administration were confirmed with the results of L-band EPR spectroscopy. The plasma biomarkers, myeloperoxidase activity, and histological findings indicated that bupivacaine injection caused acute muscle damage and inflammation. DNP-MRI images of mice treated with carbamoyl-PROXYL or carboxy-PROXYL at 4 and 24h after bupivacaine injection showed similar increases in image intensity and decay rate was significantly increased at 24h. In addition, reduction rates in individual mice at 4h and 24h showed faster trends with bupivacaine injection than in their contralateral sides by image-based analysis. These findings indicate that in vivo DNP-MRI with nitroxyl radicals can non-invasively detect changes in the focal redox status of muscle resulting from locally-induced inflammation.

  6. A novel acute lethal liver injury mouse model with visualization of NF-κB activity for treatment of severe acute liver injury

    PubMed Central

    Liao, Huanjin; Cai, Jun; Zhang, Lifang; Peng, Yanxia; Wu, Ping; Xie, Tong; Pan, Qingjun

    2017-01-01

    Acute lethal inflammation, especially that related to liver injury, is an important clinical issue. To date, however, there is no model that can be used to assess this serious condition. This study was designed to establish a novel lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute lethal liver injury model in nuclear factor-κB (NF-κB) transgenic mice. The results show that a high dose of LPS (500 μg/kg) plus D-GalN (800 mg/kg) successfully established a novel mouse model of acute lethal liver injury with a lifespan of 8-10 h. Significantly increased NF-κB activity, detected with an in vivo imaging system (IVIS), peaked at approximately 4 h post-LPS/D-GalN challenge in NF-κB transgenic mice. Moreover, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 were significantly increased and peaked at approximately 4 h post-i.p. injection of LPS/D-GalN. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) also sharply increased. Correlation analyses showed that NF-κB activity was significantly correlated with serum levels of ALT and AST. The mouse model livers showed marked congestion and hemorrhage, and hematoxylin and eosin (H&E) staining confirmed the destruction of the lobular structure and severe hepatocyte necrosis and hemorrhage. None of these changes were observed in the control mice. In summary, a novel LPS/D-GalN-induced acute lethal liver injury model with visualization of NF-κB activity was established in NF-κB transgenic mice. This model will provide the technology for developing new therapeutic strategies for treatment of severe acute liver injury complicated by endotoxemia or septicemia. PMID:28386325

  7. Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model

    PubMed Central

    Öztürk Akcora, Büsra; Storm, Gert; Prakash, Jai; Bansal, Ruchi

    2017-01-01

    Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for idiopathic pulmonary fibrosis and advanced Hepatocellular carcinoma, but has not been explored for liver fibrosis yet. In this study, we aimed to investigate the therapeutic effects and mechanism of BIBF1120 in liver fibrogenesis. The effects of BIBF1120 were evaluated in TGFβ-activated mouse 3T3 fibroblasts, LX2 cells, primary human hepatic stellate cells (HSCs) and CCl4-induced liver fibrogenesis mouse model. Fibroblasts-conditioned medium studies were performed to assess the paracrine effects on macrophages and endothelial cells. In-vitro in TGFβ-activated fibroblasts, BIBF1120 significantly inhibited expression of major fibrotic parameters, wound-healing and contractility. In vivo in CCl4-induced acute liver injury model, post-disease BIBF1120 administration significantly attenuated collagen accumulation and HSC activation. Interestingly, BIBF1120 drastically inhibited intrahepatic inflammation and angiogenesis. To further elucidate the mechanism of action, 3T3-conditioned medium studies demonstrated increased 3T3-mediated macrophage chemotaxis and endothelial cells tube formation and activation, which was significantly decreased by BIBF1120. These results suggests that BIBF1120 can be a potential therapeutic approach for the treatment of liver fibrosis. PMID:28291245

  8. Specific inhibition of ICAM-1 effectively reduces bladder inflammation in a rat model of severe non-bacterial cystitis

    PubMed Central

    Zhang, Xiang; He, Hongchao; Lu, Guoliang; Xu, Tianyuan; Qin, Liang; Wang, Xianjin; Jin, Xingwei; Liu, Boke; Zhao, Zhonghua; Shen, Zhoujun; Shao, Yuan

    2016-01-01

    The development and progression of bladder pain syndrome/interstitial cystitis (BPS/IC) is closely related to bladder inflammation. Intercellular adhesion molecule 1 (ICAM-1) is associated with bladder inflammation in BPS/IC. We investigated the effect of specific inhibition of ICAM-1 using an anti-ICAM-1 antibody (AIA) on bladder inflammation in a rat model of severe non-bacterial cystitis (NBC) resembling BPS/IC by evaluating the bladder inflammation grade, mast cell infiltration and related cytokines and receptors. We also compared the effects of AIA with the COX-2 inhibitor celecoxib and the neurokinin-1 receptor (NK1R) inhibitor aprepitant. Our NBC model was established by intraperitoneal injection of cyclophosphamide combined with intravesical protamine/lipopolysaccharide, which resulted in severe bladder inflammation and increased mast cell infiltration, similar to the pathological changes of BPS/IC. Inhibition of ICAM-1 by AIA significantly decreased the bladder inflammation grade and mast cell counts, which was accompanied by a reduction of purinergic receptors (P2X2/P2X3), prostaglandin E2, EP1/EP2 receptors, TNF-α, NK1R, and ICAM-1. Moreover, AIA showed superior effects to those of celecoxib and aprepitant treatment in improving the bladder inflammatory response. Our results suggest that ICAM-1 may play a critical role in bladder inflammation in severe NBC and may be used as a novel therapeutic target in non-bacterial bladder inflammation such as BPS/IC. PMID:27782122

  9. Correlation between the serum and tissue levels of oxidative stress markers and the extent of inflammation in acute appendicitis

    PubMed Central

    Dumlu, Ersin Gürkan; Tokaç, Mehmet; Bozkurt, Birkan; Yildirim, Murat Baki; Ergin, Merve; Yalçin, Abdussamed; Kiliç, Mehmet

    2014-01-01

    OBJECTIVES: To determine the serum and tissue levels of markers of impaired oxidative metabolism and correlate these levels with the histopathology and Alvarado score of acute appendicitis patients. METHOD: Sixty-five acute appendicitis patients (mean age, 31.4±12.06 years; male/female, 30/35) and 30 healthy control subjects were studied. The Alvarado score was recorded. Serum samples were obtained before surgery and 12 hours postoperatively to examine the total antioxidant status, total oxidant status, paraoxonase, stimulated paraoxonase, arylesterase, catalase, myeloperoxidase, ceruloplasmin, oxidative stress markers (advanced oxidized protein products and total thiol level) and ischemia-modified albumin. Surgical specimens were also evaluated. RESULTS: The diagnoses were acute appendicitis (n = 37), perforated appendicitis (n = 8), phlegmonous appendicitis (n = 12), perforated+phlegmonous appendicitis (n = 4), or no appendicitis (n = 4). The Alvarado score of the acute appendicitis group was significantly lower than that of the perforated+phlegmonous appendicitis group (p = 0.004). The serum total antioxidant status, total thiol level, advanced oxidized protein products, total oxidant status, catalase, arylesterase, and ischemia-modified albumin levels were significantly different between the acute appendicitis and control groups. There was no correlation between the pathological extent of acute appendicitis and the tissue levels of the markers; additionally, there was no correlation between the tissue and serum levels of any of the parameters. CONCLUSIONS: The imbalance of oxidant/antioxidant systems plays a role in the pathogenesis acute appendicitis. The Alvarado score can successfully predict the presence and extent of acute appendicitis. PMID:25518019

  10. Anti-inflammatory modulation of chronic airway inflammation in the murine house dust mite model.

    PubMed

    Ulrich, Kristina; Hincks, Jennifer S; Walsh, Roddy; Wetterstrand, E M Caroline; Fidock, Mark D; Sreckovic, Sasha; Lamb, David J; Douglas, Garry J; Yeadon, Michael; Perros-Huguet, Christelle; Evans, Steven M

    2008-08-01

    Asthma affects 300 million people worldwide and continues to be a major cause of morbidity and mortality. Disease relevant animal models of asthma are required for benchmarking of novel therapeutic mechanisms in comparison to established clinical approaches. We demonstrate that chronic exposure of mice to house dust mite (HDM) extract results in allergic airway inflammation, that can be significantly attenuated by therapeutic intervention with phosphodiesterase 4 inhibition and corticosteroid treatment. Female BALB/c mice were administered intranasally with HDM (Dermatophagoides pteronyssinus) extract daily for five weeks, and therapeutic intervention with anti-inflammatory treatment (dexamethasone 1 mg/kg subcutaneous once daily, prednisolone 10mg/kg orally twice daily, fluticasone 3, 10 and 30 microg intranasally twice daily, roflumilast 10 mg/kg orally twice daily and intranasally 10 and 30 microg twice daily) was initiated after three weeks of exposure. Chronic HDM extract exposure resulted in significant airway inflammation, demonstrated by bronchoalveolar lavage cell infiltration and lung tissue inflammatory gene expression by TaqMan low density array. Chronic steroid treatment significantly inhibited these parameters. In addition, roflumilast caused a significant reduction in airway inflammatory cell infiltration. We have demonstrated that chronic HDM-induced allergic inflammation can be significantly ameliorated by steroid treatment, and that phosphodiesterase 4 inhibition modulates inflammatory cell infiltration. Therefore, the murine HDM model may be a useful tool for evaluating new targets for the treatment of asthma.

  11. Cocoa Procyanidins with Different Degrees of Polymerization Possess Distinct Activities in Models of Colonic Inflammation

    PubMed Central

    Bitzer, Zachary T.; Glisan, Shannon L.; Dorenkott, Melanie R.; Goodrich, Katheryn M.; Ye, Liyun; O’Keefe, Sean F.; Lambert, Joshua D.; Neilson, Andrew P.

    2015-01-01

    Procyanidins are available in the diet from sources such as cocoa and grapes. Procyanidins are unique in that they are comprised of repeating monomeric units and can exist in various degrees of polymerization. The degree of polymerization plays a role in determining the biological activities of procyanidins. However, generalizations cannot be made regarding the correlation between procyanidin structure and bioactivity, because the size-activity relationship appears to be system-dependent. Our aim was to screen fractions of procyanidins with differing degrees of polymerization in vitro for anti-inflammatory activities in models of colonic inflammation. Monomeric, oligomeric, and polymeric cocoa procyanidin fractions were screened using cell models of disrupted membrane integrity and inflammation in human colon cells. High molecular weight polymeric procyanidins were the most effective at preserving membrane integrity and reducing secretion of interleukin-8 in response to inflammatory stimuli. Conversely, oligomeric procyanidins appeared to be the least effective. These results suggest that polymeric cocoa procyanidins may be the most effective for preventing loss of gut barrier function and epithelial inflammation, which are critical steps in the pathogenesis of metabolic endotoxemia, inflammatory bowel disease, and colon cancer. Therefore, further investigations of the potential health-protective benefits of cocoa procyanidins with distinct degrees of polymerization, particularly high molecular weight procyanidins, are warranted. PMID:25869594

  12. Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model

    SciTech Connect

    Tafazoli, Shahrzad; Mashregi, Mariam; O'Brien, Peter J.

    2008-05-15

    Isoniazid is an anti-tuberculosis drug that can cause hepatotoxicity in 20% of patients that is usually associated with an inflammatory response. Hepatocytes when exposed to non-toxic levels of H{sub 2}O{sub 2}, to simulate H{sub 2}O{sub 2} formation by inflammatory cells, became twice as sensitive to isoniazid toxicity. Isoniazid cytotoxicity was prevented by 1-aminobenzotriazole, a non-selective P450 inhibitor or by bis-p-nitrophenyl phosphate (BNPP), an esterase inhibitor. Moreover, the cytotoxicity of hydrazine, the metabolite formed by amidase-catalyzed hydrolysis of isoniazid, was increased 16-fold by a non-toxic H{sub 2}O{sub 2}-generating system. The acetylhydrazine metabolite was found to be much less cytotoxic than hydrazine in this hepatocyte inflammation model. Hydrazine, therefore, seems to be the isoniazid reactive metabolite in this inflammation model. The molecular mechanism of hydrazine-induced cytotoxicity was attributed to oxidative stress as reactive oxygen species (ROS) and protein carbonyl formation occurred before the onset of hepatocyte toxicity. Hydrazine toxicity also involved significant production of endogenous H{sub 2}O{sub 2} which resulted in lysosomal membrane damage and leads to a collapse in mitochondrial membrane potential. These results implicated H{sub 2}O{sub 2}, a cellular mediator of inflammation, as a potential risk factor for the manifestation of adverse drug reactions, particularly those caused by hydrazine containing drugs.

  13. Herbal Formula, PM014, Attenuates Lung Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Lee, Hyojung; Kim, Youngeun; Kim, Hye Jin; Park, Soojin; Jang, Young Pyo; Jung, Sungki; Jung, Heejae; Bae, Hyunsu

    2012-01-01

    Chronic obstructive pulmonary disease (COPD), which is characterized by airway obstruction, leads to, as the two major forms of COPD, chronic bronchitis and emphysema. This study was conducted to evaluate the effects of herbal formula, PM014, in a murine model of COPD. Balb/c mice were treated once with each herb extract in PM014 or PM014 mixture via an oral injection. Lipopolysaccharide (LPS) or elastase/LPS were administrated to the mice to induce a disease that resembles COPD. PM014 treatment significantly attenuated the increased accumulation of immune cells in bronchoalveolar lavage fluid (BALF) compared to control mice. In addition, the TNF-α and IL-6 levels in BALF were decreased in the PM014 mice. Furthermore, histological analysis demonstrated that PM014 attenuated the hazardous effects of lung inflammation. These data suggest that PM014 exerts beneficial effects against forms of COPD such as lung inflammation. PMID:22778777

  14. Stretching of the back improves gait, mechanical sensitivity and connective tissue inflammation in a rodent model.

    PubMed

    Corey, Sarah M; Vizzard, Margaret A; Bouffard, Nicole A; Badger, Gary J; Langevin, Helene M

    2012-01-01

    The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy.

  15. Evaluation of Gastrointestinal Leakage in Multiple Enteric Inflammation Models in Chickens

    PubMed Central

    Kuttappan, Vivek A.; Vicuña, Eduardo A.; Latorre, Juan D.; Wolfenden, Amanda D.; Téllez, Guillermo I.; Hargis, Billy M.; Bielke, Lisa R.

    2015-01-01

    Enteric inflammation models can help researchers’ study methods to improve health and performance and evaluate various growth promoters and dietary formulations targeted to improve performance in poultry. Oral administration of fluorescein isothiocyanate-dextran (FITC-d; 3–5 kDa) and its pericellular mucosal epithelial leakage are an established marker to evaluate enteric inflammation in multiple species. The present study evaluated different methods to induce gut inflammation in poultry based on FITC-d leakage. Four independent experiments were completed with different inflammation treatment groups, and serum FITC-d and/or retention of FITC-d in GI tract were determined. In experiment 1 (n = 10 birds/treatment, broilers, processed at 14 days), groups included control (CON), dextran sodium sulfate (DSS; drinking water at 0.75%) and feed restriction (FRS; 24 h before processing). Experiment 2 (n = 14 birds/treatment, leghorns, processed at 7 days) included CON, DSS, FRS, and rye-based diet (RBD). In experiments 3 and 4 (n = 15 birds/treatment, broilers, processed at 7 days), groups were CON, DSS, high fat diet (HFD), FRS, and RBD. In all experiments, FRS and RBD treatments showed significantly higher serum FITC-d levels compared to the respective CON. This indicates that FRS and RBD results in disruption of the intact barrier of the gastrointestinal tract (GIT), resulting in increased gut permeability. DSS and HFD groups showed elevation of serum FITC-d levels although the magnitude of difference from respective CON was inconsistent between experiments. FRS was the only treatment which consistently showed elevated retention of FITC-d in GIT in all experiments. The results from present studies showed that FRS and RBD, based on serum FITC-d levels, can be robust models to induce gut leakage in birds in different age and species/strains. PMID:26697435

  16. Establishment of a coculture model for studying inflammation after pediatric cardiopulmonary bypass: from bench to bedside.

    PubMed

    Wollersheim, Sonja; Fedarava, Katisaryna; Huebler, Michael; Schneiderhan-Marra, Nicole; Berger, Felix; Miera, Oliver; Schmitt, Katharina R

    2012-06-01

    Cardiopulmonary bypass (CPB) has been known to induce an inflammatory response that is influenced by various factors. Hypothermia is supposed to reduce inflammation after CPB. We developed an in vitro coculture model for CPB and compared the effects of hypothermia on the inflammatory response in the coculture model with results from a clinical prospective randomized trial. The coculture model consisted of endothelial cells and monocytes. Cells were stimulated with tumor necrosis factor (TNF)-α and exposed to deep hypothermia (20°C) or normothermia (37°C). In the clinical trial, 20 patients undergoing CPB for ventricular septum defect receive either normothermic (37°C) or mild hypothermic (32°C) CPB. We observed a significant interleukin (IL)-6 and IL-8 release in the coculture model 2 and 24 h after the experimental start. In the clinical trial, cytokines were significantly increased directly after weaning from CPB and remained elevated until 24 h. IL-8 and IL-6 secretions were similar in the hypothermic and normothermic group of the coculture model and the patients after 24 h. These results demonstrate that the inflammatory reaction observed in our coculture model is comparable with the cytokine increase in the blood of children undergoing CPB. Our coculture model could be useful for studies on the mechanisms of CPB-induced inflammation.

  17. Variability in Ozone-Induced Pulmonary Injury and Inflammation in Healthy and Cardiovascular Compromised Rat Models

    EPA Science Inventory

    The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure depe...

  18. Different microRNA profiles in chronic epilepsy versus acute seizure mouse models.

    PubMed

    Kretschmann, Anita; Danis, Benedicte; Andonovic, Lidija; Abnaof, Khalid; van Rikxoort, Marijke; Siegel, Franziska; Mazzuferi, Manuela; Godard, Patrice; Hanon, Etienne; Fröhlich, Holger; Kaminski, Rafal M; Foerch, Patrik; Pfeifer, Alexander

    2015-02-01

    Epilepsy affects around 50 million people worldwide, and in about 65% of patients, the etiology of disease is unknown. MicroRNAs are small non-coding RNAs that have been suggested to play a role in the pathophysiology of epilepsy. Here, we compared microRNA expression patterns in the hippocampus using two chronic models of epilepsy characterised by recurrent spontaneous seizures (pilocarpine and self-sustained status epilepticus (SSSE)) and an acute 6-Hz seizure model. The vast majority of microRNAs deregulated in the acute model exhibited increased expression with 146 microRNAs up-regulated within 6 h after a single seizure. In contrast, in the chronic models, the number of up-regulated microRNAs was similar to the number of down-regulated microRNAs. Three microRNAs-miR-142-5p, miR-331-3p and miR-30a-5p-were commonly deregulated in all three models. However, there is a clear overlap of differentially expressed microRNAs within the chronic models with 36 and 15 microRNAs co-regulated at 24 h and at 28 days following status epilepticus, respectively. Pathway analysis revealed that the altered microRNAs are associated with inflammation, innate immunity and cell cycle regulation. Taken together, the identified microRNAs and the pathways they modulate might represent candidates for novel molecular approaches for the treatment of patients with epilepsy.

  19. Chlamydial heat shock protein 60 induces acute pulmonary inflammation in mice via the Toll-like receptor 4- and MyD88-dependent pathway.

    PubMed

    Bulut, Yonca; Shimada, Kenichi; Wong, Michelle H; Chen, Shuang; Gray, Pearl; Alsabeh, Randa; Doherty, Terence M; Crother, Timothy R; Arditi, Moshe

    2009-07-01

    Heat shock protein 60 derived from Chlamydia pneumoniae (cHSP60) activates Toll-like receptor 4 (TLR4) signaling through the MyD88 pathway in vitro, but it is not known how cHSP60 contributes to C. pneumoniae-induced lung inflammation. We treated wild-type (WT), TLR2(-/-), TLR4(-/-), or MyD88(-/-) mice intratracheally (i.t.) with recombinant cHSP60 (50 microg), UV-killed C. pneumoniae (UVCP; 5 x 10(6) inclusion-forming units/mouse), lipopolysaccharide (2 microg), or phosphate-buffered saline (PBS) and sacrificed mice 24 h later. Bronchoalveolar lavage (BAL) was obtained to measure cell counts and cytokine levels, lungs were analyzed for histopathology, and lung homogenate chemokine concentrations were determined. Bone marrow-derived dendritic cells (BMDDCs) were generated and stimulated with live C. pneumoniae (multiplicity of infection [MOI], 5), UVCP (MOI, 5), or cHSP60 for 24 h, and the expression of costimulatory molecules (CD80 and CD86) was measured by fluorescence-activated cell sorting. cHSP60 induced acute lung inflammation with the same intensity as that of UVCP-induced inflammation in WT mice but not in TLR4(-/-) or MyD88(-/-) mice. cHSP60- and UVCP-induced lung inflammation was associated with increased numbers of cells in BAL, increased neutrophil recruitment, and elevated BAL interleukin-6 (IL-6) levels. Both cHSP60 and UVCP induced IL-6 release and CD80 and CD86 expression in WT cells but not in MyD88(-/-) BMDDCs. cHSP60 stimulated DC activation in a TLR4- and MyD88-dependent manner with an intensity similar to that induced by UVCP. These data suggest that cHSP60 promotes lung inflammation and DC activation via TLR4 and MyD88 and therefore may play a significant role in the pathogenesis of C. pneumoniae-induced chronic inflammatory lung diseases.

  20. Novel Genetic Models to Study the Role of Inflammation in Brain Injury-Induced Alzheimer’s Pathology

    DTIC Science & Technology

    2015-12-01

    AWARD NUMBER: W81XWH-12-1-0629 TITLE: Novel Genetic Models to Study the Role of Inflammation in Brain Injury-Induced Alzheimer’s Pathology...30Sep2014 - 29Sep2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 12109018 TATRC Novel Genetic Models to Study the Role of Inflammation in Brain Injury...Academy of Engineering , the Institute of Medicine, and Case Western Reserve University. Dr. Kokiko-Cochran presented posters at many of these events and

  1. Targeting AMCase reduces esophageal eosinophilic inflammation and remodeling in a mouse model of egg induced eosinophilic esophagitis.

    PubMed

    Cho, Jae Youn; Rosenthal, Peter; Miller, Marina; Pham, Alexa; Aceves, Seema; Sakuda, Shohei; Broide, David H

    2014-01-01

    Studies of AMCase inhibition in mouse models of lung eosinophilic inflammation have produced conflicting results with some studies demonstrating inhibition of eosinophilic inflammation and others not. No studies have investigated the role of AMCase inhibition in eosinophilic esophagitis (EoE). We have used a mouse model of egg (OVA) induced EoE to determine whether pharmacologic inhibition of AMCase with allosamidin reduced eosinophilic inflammation and remodeling in the esophagus in EoE. Administration of intra-esophageal OVA for 6weeks to BALB/c mice induced increased levels of esophageal eosinophils, mast cells, and features of esophageal remodeling (fibrosis, basal zone hyperplasia, deposition of the extracellular matrix protein fibronectin). Administration of intraperitoneal (ip) allosamidin to BALB/c mice significantly inhibited AMCase enzymatic activity in the esophagus. Pharmacologic inhibition of AMCase with ip allosamidin inhibited both OVA induced increases in esophageal eosinophilic inflammation and OVA induced esophageal remodeling (fibrosis, epithelial basal zone hyperplasia, extracellular matrix deposition of fibronectin). This inhibition of eosinophilic inflammation in the esophagus by ip allosamidin was associated with reduced eotaxin-1 expression in the esophagus. Oral allosamidin inhibited eosinophilic inflammation in the epithelium but did not inhibit esophageal remodeling. These studies suggest that pharmacologic inhibition of AMCase results in inhibition of eosinophilic inflammation and remodeling in the esophagus in a mouse model of egg induced EoE partially through effects in the esophagus on reducing chemokines (i.e. eotaxin-1) implicated in the pathogenesis of EoE.

  2. Effect of choline chloride in allergen-induced mouse model of airway inflammation.

    PubMed

    Mehta, A K; Gaur, S N; Arora, N; Singh, B P

    2007-10-01

    The incidence of asthma has increased the world over, and current therapies for the disease suffer from potential side-effects. This has created an opportunity to develop novel therapeutic approaches. Here, the anti-inflammatory activity of choline was investigated in a mouse model of allergic airway inflammation. Choline (1 mg.kg(-1)) was administered via oral gavage or intranasally before and after ovalbumin (OVA) challenge in sensitised mice. Airway hyperresponsiveness (AHR) to methacholine was measured in the mice by whole-body plethysmography. Type-2 T-helper cell cytokine and leukotriene levels were estimated in bronchoalveolar lavage fluid (BALF) and spleen culture supernatant by ELISA. Eosinophil peroxidase activity was also determined in the BALF supernatant. Choline treatment in sensitised mice before OVA challenge via oral/intranasal routes significantly inhibited eosinophilic airway inflammation and eosinophil peroxidase activity. It also reduced immunoglobulin E and G1 production and inhibited the release of type-2 T-helper cell cytokines and leukotrienes. However, the development of AHR was prevented effectively by intranasal choline treatment. Most importantly, choline treatment after OVA challenge by both routes could reverse established asthmatic conditions in mice by inhibiting AHR, eosinophilic airway inflammation and other inflammatory parameters. This study provides a new therapeutic approach for controlling as well as preventing asthma exacerbations.

  3. Protease inhibitor reduces airway response and underlying inflammation in cockroach allergen-induced murine model.

    PubMed

    Saw, Sanjay; Arora, Naveen

    2015-04-01

    Protease(s) enhances airway inflammation and allergic cascade. In the present study, effect of a serine protease inhibitor was evaluated in mouse model of airway disease. Mice were sensitized with cockroach extract (CE) or Per a 10 and treated with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) 1 h before or after challenge to measure airway response. Mice were euthanized to collect bronchoalveolar lavage fluid (BALF), blood, and lung to evaluate inflammation. AEBSF treatment significantly reduced the AHR in allergen-challenged mice in dose-dependent manner (p≤ 0.01). IgE (p≤0.05) and Th2 cytokines (p≤0.05) were significantly reduced in treated mice. AEBSF treatment lowered total cell (p≤0.05), eosinophil (p≤0.05), and neutrophil (p≤0.05) in BALF and lung tissue. Oxidative stress parameters were impaired on treatment in allergen-challenged mice (p≤0.05). AEBSF had therapeutic effect in allergen-induced airway resistance and underling inflammation and had potential for combination or as add-on therapy for respiratory diseases.

  4. Canine pyometra: a model for the analysis of serum CXCL8 in inflammation

    PubMed Central

    HAAS, Melanie; KAUP, Franz-Josef; NEUMANN, Stephan

    2015-01-01

    Interleukin-8 (IL-8 or CXCL8) is a highly selective pro-inflammatory chemokine, that is elevated in sera of humans and animals with various inflammatory diseases. CXCL8 is possibly involved in uncontrolled inflammation and the development of a systemic inflammatory response syndrome (SIRS) and sepsis. Nevertheless, its behavior and precise properties in the course of inflammation are not fully understood. Thus, we used naturally occurring canine pyometra as a model of inflammation, in order to examine the behavior of serum CXCL8 in relation to the disease intensity and commonly analyzed inflammatory mediators. Using a commercially available canine ELISA kit, a significant increase of CXCL8 was determined in the serum of 23 dogs with pyometra compared with 35 healthy dogs. Interestingly, serum CXCL8 did not increase in severely diseased patients and behaved contrary to white blood cells (WBC), neutrophils and C-reactive protein (CRP). The measurement of serum CXCL8 may provide valuable information about the extent of ongoing lesions and could be a useful complement for existing laboratory tests. PMID:26522810

  5. Chrysin alleviates allergic inflammation and airway remodeling in a murine model of chronic asthma.

    PubMed

    Yao, Jing; Jiang, Mingzi; Zhang, Yunshi; Liu, Xing; Du, Qiang; Feng, Ganzhu

    2016-03-01

    Asthma is a chronic airway inflammatory disorder and progresses mainly due to airway remodeling. Chrysin, a natural flavonoid, has been reported to possess multiple biologic activities, including anti-inflammation, anti-oxidation and anti-proliferation. The present study aimed to investigate whether chrysin could relieve allergic airway inflammation and remodeling in a murine model of chronic asthma and the mechanism involved. The female BALB/c mice sensitized and challenged with ovalbumin (OVA) successfully developed airway hyperresponsiveness (AHR), inflammation and remodeling. The experimental data showed that chrysin could alleviate OVA-induced AHR. Chrysin could also reduce OVA-induced increases in the number of inflammatory cells, especially eosinophils, interleukin (IL) -4, and IL-13 in bronchoalveolar lavage fluid (BALF) and total IgE in serum. The decreased interferon-γ (IFN-γ) level in BALF was also upregulated by chrysin. In addition, inflammatory cell infiltration, goblet cell hyperplasia and the expression of α-smooth muscle actin (α-SMA) around bronchioles were suppressed by chrysin. Furthermore, the phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK) could be decreased by chrysin, which are associated with airway smooth muscle cell (ASMC) proliferation. These results indicate the promising therapeutic effect of chrysin on chronic asthma, especially the progression of airway remodeling.

  6. Canine pyometra: a model for the analysis of serum CXCL8 in inflammation.

    PubMed

    Haas, Melanie; Kaup, Franz-Josef; Neumann, Stephan

    2016-03-01

    Interleukin-8 (IL-8 or CXCL8) is a highly selective pro-inflammatory chemokine, that is elevated in sera of humans and animals with various inflammatory diseases. CXCL8 is possibly involved in uncontrolled inflammation and the development of a systemic inflammatory response syndrome (SIRS) and sepsis. Nevertheless, its behavior and precise properties in the course of inflammation are not fully understood. Thus, we used naturally occurring canine pyometra as a model of inflammation, in order to examine the behavior of serum CXCL8 in relation to the disease intensity and commonly analyzed inflammatory mediators. Using a commercially available canine ELISA kit, a significant increase of CXCL8 was determined in the serum of 23 dogs with pyometra compared with 35 healthy dogs. Interestingly, serum CXCL8 did not increase in severely diseased patients and behaved contrary to white blood cells (WBC), neutrophils and C-reactive protein (CRP). The measurement of serum CXCL8 may provide valuable information about the extent of ongoing lesions and could be a useful complement for existing laboratory tests.

  7. Berberine Attenuates Vascular Remodeling and Inflammation in a Rat Model of Metabolic Syndrome.

    PubMed

    Li, Xiao-Xing; Li, Chuan-Bao; Xiao, Jie; Gao, Hai-Qing; Wang, He-Wen; Zhang, Xin-Yu; Zhang, Cheng; Ji, Xiao-Ping

    2015-01-01

    Berberine is a natural product that shows benefits for metabolic syndrome (MS). However, the effects of berberine on the improvement of vascular inflammation and remodeling in MS remain unclear. This study aimed to investigate whether berberine could prevent vascular remodeling and inflammation in the MS condition. A rat model of MS was established, and MS rats were divided into two groups: MS group without berberine treatment, and MSB group with berberine treatment (each group n-10). Ten normal Wistar rats were used as controls (NC group). Vascular damage was examined by transmission electron microscopy and pathological staining. Compared to the NC group, the secretion of inflammatory factors was increased and the aortic wall thicker in the MS group. The MSB group exhibited decreased secretion of inflammatory factors and improved vascular remodeling, compared to the MS group. In addition, the levels of p38 mitogen-activated protein kinase (p38 MAPK), activating transcription factor 2 (ATF-2) and matrix metalloproteinase 2 (MMP-2) were significantly decreased in the MSB group compared to the MS group. In conclusion, our data show that berberine improves vascular inflammation and remodeling in the MS condition, and this is correlated with the ability of berberine to inhibit p38 MAPK activation, ATF-2 phosphorylation, and MMP-2 expression.

  8. Lack of anti-inflammatory effect of botulinum toxin type A in experimental models of inflammation.

    PubMed

    Bach-Rojecky, Lidija; Dominis, Mara; Lacković, Zdravko

    2008-10-01

    Botulinum toxin type A (BTX-A) has a long-lasting antinociceptive activity and less clear effect on inflammation. It was proposed that these two effects share the same mechanism--the inhibition of neurotransmitter exocytosis from peripheral nerve endings. However, till now possible anti-inflammatory action of BTX-A did not evoke much attention. In the present paper, we investigate possible anti-inflammatory action of the toxin in carrageenan and capsaicin models of inflammation in rats. BTX-A (5 and 10 U/kg) was injected into the plantar surface of the rat right hind-paw pad 5 days before the injection of the carrageenan (1%) or capsaicin (0.1%) at the same site. Carrageenan-induced paw oedema and capsaicin-induced protein extravasation were measured. Control, inflamed and BTX-A pretreated inflamed paws were photographed and histopathological analysis (haematoxylin & eosin) was performed. Pretreatment with BTX-A had no effect on the size of carrageenan-induced paw oedema, measured as paw volume and weight or capsaicin-induced plasma extravasations, measured by Evans blue as a marker of protein leakage. Neither macroscopic nor microscopic analysis showed a significant difference between BTX-A pretreated and control inflamed tissue. Results show dissociation between the effect of BTX-A on pain and inflammation thus questioning the validity of the suggested assumption about the common peripheral mechanism of action.

  9. Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation

    PubMed Central

    Juvet, Stephen; Scott, Jeremy A.; Chow, Chung-Wai

    2017-01-01

    Background Asthma is a chronic inflammatory disease characterized by airways hyper-responsiveness (AHR), reversible airway obstruction, and airway inflammation and remodeling. We previously showed that Syk modulates methacholine-induced airways contractility in naïve mice and in mice with allergic airways inflammation. We hypothesize that Syk plays a role in the pathogenesis of AHR; this was evaluated in a chronic 8-week mouse model of house dust mite (HDM)-induced allergic airways inflammation. Methods We used the Sykflox/flox//rosa26CreERT2 conditional Syk knock-out mice to assess the role of Syk prior to HDM exposure, and treated HDM-sensitized mice with the Syk inhibitor, GSK143, to evaluate its role in established allergic airways inflammation. Respiratory mechanics and methacholine (MCh)-responsiveness were assessed using the flexiVent® system. Lungs underwent bronchoalveolar lavage to isolate inflammatory cells or were frozen for determination of gene expression in tissues. Results MCh-induced AHR was observed following HDM sensitization in the Syk-intact (Sykflox/flox) and vehicle-treated BALB/c mice. MCh responsiveness was reduced to control levels in HDM-sensitized Sykdel/del mice and in BALB/c and Sykflox/flox mice treated with GSK143. Both Sykdel/del and GSK143-treated mice mounted appropriate immune responses to HDM, with HDM-specific IgE levels that were comparable to Sykflox/flox and vehicle-treated BALB/c mice. HDM-induced increases in bronchoalveolar lavage cell counts were attenuated in both Sykdel/del and GSK143-treated mice, due primarily to decreased neutrophil recruitment. Gene expression analysis of lung tissues revealed that HDM-induced expression of IL-17 and CXCL-1 was significantly attenuated in both Sykdel/del and GSK143-treated mice. Conclusion Syk inhibitors may play a role in the management of neutrophilic asthma. PMID:28107345

  10. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis

    PubMed Central

    Hammell, D.C.; Zhang, L.P.; Ma, F.; Abshire, S.M.; McIlwrath, S.L.; Stinchcomb, A.L.; Westlund, K.N.

    2015-01-01

    Background Current arthritis treatments often have side-effects attributable to active compounds as well as route of administration. Cannabidiol (CBD) attenuates inflammation and pain without side-effects, but CBD is hydrophobic and has poor oral bioavailability. Topical drug application avoids gastrointestinal administration, first pass metabolism, providing more constant plasma levels. Methods This study examined efficacy of transdermal CBD for reduction in inflammation and pain, assessing any adverse effects in a rat complete Freund’s adjuvant-induced monoarthritic knee joint model. CBD gels (0.6, 3.1, 6.2 or 62.3 mg/day) were applied for 4 consecutive days after arthritis induction. Joint circumference and immune cell invasion in histological sections were measured to indicate level of inflammation. Paw withdrawal latency (PWL) in response to noxious heat stimulation determined nociceptive sensitization, and exploratory behaviour ascertained animal’s activity level. Results Measurement of plasma CBD concentration provided by transdermal absorption revealed linearity with 0.6–6.2 mg/day doses. Transdermal CBD gel significantly reduced joint swelling, limb posture scores as a rating of spontaneous pain, immune cell infiltration and thickening of the synovial membrane in a dose-dependent manner. PWL recovered to near baseline level. Immunohistochemical analysis of spinal cord (CGRP, OX42) and dorsal root ganglia (TNFα) revealed dose-dependent reductions of pro-inflammatory biomarkers. Results showed 6.2 and 62 mg/day were effective doses. Exploratory behaviour was not altered by CBD indicating limited effect on higher brain function. Conclusions These data indicate that topical CBD application has therapeutic potential for relief of arthritis pain-related behaviours and inflammation without evident side-effects. PMID:26517407

  11. Recombinant erythroid differentiation regulator 1 inhibits both inflammation and angiogenesis in a mouse model of rosacea.

    PubMed

    Kim, Miri; Kim, Kyung-Eun; Jung, Haw Young; Jo, Hyunmu; Jeong, Seo-Won; Lee, Jahyung; Kim, Chang Han; Kim, Heejong; Cho, Daeho; Park, Hyun Jeong

    2015-09-01

    The erythroid differentiation regulator 1 (Erdr1), which is a novel and highly conserved factor, was recently reported to be negatively regulated by IL-18 and to play a crucial role as an antimetastatic factor. IL-18 is a proinflammatory cytokine that functions as an angiogenic mediator in inflammation. Rosacea is a chronic inflammatory skin disorder that is characterized by abnormal inflammation an