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Sample records for acute colonic inflammation

  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. 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.

  3. Inflammation and colon cancer.

    PubMed

    Terzić, Janos; Grivennikov, Sergei; Karin, Eliad; Karin, Michael

    2010-06-01

    The connection between inflammation and tumorigenesis is well-established and in the last decade has received a great deal of supporting evidence from genetic, pharmacological, and epidemiological data. Inflammatory bowel disease is an important risk factor for the development of colon cancer. Inflammation is also likely to be involved with other forms of sporadic as well as heritable colon cancer. The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and could differ between colitis-associated and other forms of colorectal cancer. Recent work has elucidated the role of distinct immune cells, cytokines, and other immune mediators in virtually all steps of colon tumorigenesis, including initiation, promotion, progression, and metastasis. These mechanisms, as well as new approaches to prevention and therapy, are discussed in this review.

  4. 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.

  5. Relationship between methylation and colonic inflammation in inflammatory bowel disease

    PubMed Central

    Lobatón, Triana; Azuara, Daniel; Rodríguez-Moranta, Francisco; Loayza, Carolina; Sanjuan, Xavier; de Oca, Javier; Fernández-Robles, Ana; Guardiola, Jordi; Capellá, Gabriel

    2014-01-01

    AIM: To investigate the relationship between the methylation status in the SLIT2 and TGFB2 promoters and colonic inflammation in inflammatory bowel disease patients. METHODS: We evaluated the methylation status of 2 genes (SLIT2 and TGFB2) in 226 biopsies taken from 62 colonoscopies of 38 patients (29 ulcerative colitis and 9 Crohn’s colitis) using methylation-specific melting curve analysis. The relationships between methylation status and clinical, biological, endoscopic and histological activities were evaluated. Twenty-three of the 38 patients had a second colonoscopy and were included in a longitudinal analysis. Numerical results were given as the means ± SD of the sample and range, except when specified. Student t analysis, U Mann Whitney and ANOVA factor were used to compare the means. Qualitative results were based on the χ2 test. RESULTS: SLIT2 methylation was more frequent in samples with endoscopic activity than with endoscopic remission (55% vs 18%, P < 0.001). SLIT2 methylation was also higher in samples with acute inflammation (56.5%) than in samples with chronic (24%) or absent inflammation (15%) (P < 0.001). For TGFB2 methylation, the correlation was only significant with endoscopic activity. Methylation was higher in the distal colon for both genes (P < 0.001 for SLIT2 and P = 0.022 for TGFB2). In the multivariate analysis, only inflammation status (and not disease duration or extension) was independently associated with SLIT2 methylation [OR = 6.6 (95%CI: 1.65-27.36), P = 0.009]. In the longitudinal analysis, the maintenance of endoscopic remission was protective for methylation. CONCLUSION: Endoscopic and histological inflammation are predictive for SLIT2 methylation. PMID:25132780

  6. Angiopoietin-like 4 Mediates Colonic Inflammation by Regulating Chemokine Transcript Stability via Tristetraprolin

    PubMed Central

    Phua, Terri; Sng, Ming Keat; Tan, Eddie Han Pin; Chee, Dickson Shao Liang; Li, Yinliang; Wee, Jonathan Wei Kiat; Teo, Ziqiang; Chan, Jeremy Soon Kiat; Lim, Maegan Miang Kee; Tan, Chek Kun; Zhu, Pengcheng; Arulampalam, Velmurugesan; Tan, Nguan Soon

    2017-01-01

    Many gastrointestinal diseases exhibit a protracted and aggravated inflammatory response that can lead to hypercytokinaemia, culminating in extensive tissue damage. Recently, angiopoietin-like 4 (ANGPTL4) has been implicated in many inflammation-associated diseases. However, how ANGPTL4 regulates colonic inflammation remains unclear. Herein, we show that ANGPTL4 deficiency in mice (ANGPTL4−/−) exacerbated colonic inflammation induced by dextran sulfate sodium (DSS) or stearic acid. Microbiota was similar between the two genotypes prior DSS challenge. A microarray gene expression profile of the colon from DSS-treated ANGPTL4−/− mice was enriched for genes involved in leukocyte migration and infiltration, and showed a close association to inflamed ulcerative colitis (UC), whereas the profile from ANGPTL4+/+ littermates resembled that of non-inflamed UC biopsies. Bone marrow transplantation demonstrates the intrinsic role of colonic ANGPTL4 in regulating leukocyte infiltration during DSS-induced inflammation. Using immortalized human colon epithelial cells, we revealed that the ANGPTL4-mediated upregulation of tristetraprolin expression operates through CREB and NF-κB transcription factors, which in turn, regulates the stability of chemokines. Together, our findings suggest that ANGPTL4 protects against acute colonic inflammation and that its absence exacerbates the severity of inflammation. Our findings emphasize the importance of ANGPTL4 as a novel target for therapy in regulating and attenuating inflammation. PMID:28287161

  7. Angiopoietin-like 4 Mediates Colonic Inflammation by Regulating Chemokine Transcript Stability via Tristetraprolin.

    PubMed

    Phua, Terri; Sng, Ming Keat; Tan, Eddie Han Pin; Chee, Dickson Shao Liang; Li, Yinliang; Wee, Jonathan Wei Kiat; Teo, Ziqiang; Chan, Jeremy Soon Kiat; Lim, Maegan Miang Kee; Tan, Chek Kun; Zhu, Pengcheng; Arulampalam, Velmurugesan; Tan, Nguan Soon

    2017-03-13

    Many gastrointestinal diseases exhibit a protracted and aggravated inflammatory response that can lead to hypercytokinaemia, culminating in extensive tissue damage. Recently, angiopoietin-like 4 (ANGPTL4) has been implicated in many inflammation-associated diseases. However, how ANGPTL4 regulates colonic inflammation remains unclear. Herein, we show that ANGPTL4 deficiency in mice (ANGPTL4(-/-)) exacerbated colonic inflammation induced by dextran sulfate sodium (DSS) or stearic acid. Microbiota was similar between the two genotypes prior DSS challenge. A microarray gene expression profile of the colon from DSS-treated ANGPTL4(-/-) mice was enriched for genes involved in leukocyte migration and infiltration, and showed a close association to inflamed ulcerative colitis (UC), whereas the profile from ANGPTL4(+/+) littermates resembled that of non-inflamed UC biopsies. Bone marrow transplantation demonstrates the intrinsic role of colonic ANGPTL4 in regulating leukocyte infiltration during DSS-induced inflammation. Using immortalized human colon epithelial cells, we revealed that the ANGPTL4-mediated upregulation of tristetraprolin expression operates through CREB and NF-κB transcription factors, which in turn, regulates the stability of chemokines. Together, our findings suggest that ANGPTL4 protects against acute colonic inflammation and that its absence exacerbates the severity of inflammation. Our findings emphasize the importance of ANGPTL4 as a novel target for therapy in regulating and attenuating inflammation.

  8. Neurological and cellular regulation of visceral hypersensitivity induced by chronic stress and colonic inflammation in rats.

    PubMed

    Chen, J; Winston, J H; Sarna, S K

    2013-09-17

    The role of inflammation in inducing visceral hypersensitivity (VHS) in ulcerative colitis patients remains unknown. We tested the hypothesis that acute ulcerative colitis-like inflammation does not induce VHS. However, it sets up molecular conditions such that chronic stress following inflammation exaggerates single-unit afferent discharges to colorectal distension. We used dextran sodium sulfate (DSS) to induce ulcerative colitis-like inflammation and a 9-day heterotypic chronic stress protocol in rats. DSS upregulated Nav1.8 mRNA in colon-responsive dorsal root ganglion (DRG) neurons, TRPV1 in colonic muscularis externae (ME) and BDNF in spinal cord without affecting the spike frequency in spinal afferents or VMR to CRD. By contrast, chronic stress did not induce inflammation but it downregulated Kv1.1 and Kv1.4 mRNA in DRG neurons, and upregulated TRPA1 and nerve growth factor in ME, which mediated the increase of spike frequency and VMR to CRD. Chronic stress following inflammation exacerbated spike frequency in spinal afferent neurons. TRPA1 antagonist suppressed the sensitization of afferent neurons. DSS-inflammation did not affect the composition or excitation thresholds of low-threshold and high-threshold fibers. Chronic stress following inflammation increased the percent composition of high-threshold fibers and lowered the excitation threshold of both types of fibers. We conclude that not all types of inflammation induce VHS, whereas chronic stress induces VHS in the absence of inflammation.

  9. 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.

  10. 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.

  11. 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

  12. 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

  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. 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.

  15. 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

  16. A Novel Role of Spred2 in the Colonic Epithelial Cell Homeostasis and Inflammation

    PubMed Central

    Takahashi, Sakuma; Yoshimura, Teizo; Ohkura, Takahiro; Fujisawa, Masayoshi; Fushimi, Soichiro; Ito, Toshihiro; Itakura, Junya; Hiraoka, Sakiko; Okada, Hiroyuki; Yamamoto, Kazuhide; Matsukawa, Akihiro

    2016-01-01

    Rapid and adequate mucosal healing is important for a remission of ulcerative colitis (UC) patients. Here, we examined whether Spred2, a member of the Sprouty-related EVH1-domain-containing proteins that inhibit the Ras/Raf/ERK pathway, plays a role in colonic mucosal homeostasis and inflammation by using Spred2 knockout (KO) mice. We first detected increased epithelial cell proliferation and cadherin 1 expression in the colon of naïve Spred2 KO mice compared to wild-type mice. Interestingly, Spred2 KO mice were resistant to dextran sulfate sodium (DSS)-induced acute colitis as indicated by lower levels of body weight loss and disease activity index. Histologically, epithelial cell injury and inflammation were milder in the colonic mucosa of Spred2 KO mice on day 3 and almost undetectable by day 8. Experiments with bone chimeric mice indicated that Spred2-deficiency in non-hematopoietic cells was responsible for the reduced sensitivity to DSS. Finally, Spred2 KO mice developed significantly fewer tumors in response to azoxymethane plus DSS. Taken together, our results demonstrate, for the first time, that Spred2 plays an important role in the regulation of colonic epithelial cell proliferation and inflammation by potentially down-regulating the activation of ERK. Thus, Spred2 may be a new therapeutic target for the treatment of UC. PMID:27869219

  17. 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

  18. 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

  19. Dietary Iron Enhances Colonic Inflammation and IL-6/IL-11-Stat3 Signaling Promoting Colonic Tumor Development in Mice

    PubMed Central

    Ho, Desiree S.; Fu, S. Kristine; Forrest, Cynthia H.; Croft, Kevin D.; Olynyk, John K.; Lawrance, Ian C.; Trinder, Debbie

    2013-01-01

    Chronic intestinal inflammation and high dietary iron are associated with colorectal cancer development. The role of Stat3 activation in iron-induced colonic inflammation and tumorigenesis was investigated in a mouse model of inflammation-associated colorectal cancer. Mice, fed either an iron-supplemented or control diet, were treated with azoxymethane and dextran sodium sulfate (DSS). Intestinal inflammation and tumor development were assessed by endoscopy and histology, gene expression by real-time PCR, Stat3 phosphorylation by immunoblot, cytokines by ELISA and apoptosis by TUNEL assay. Colonic inflammation was more severe in mice fed an iron-supplemented compared with a control diet one week post-DSS treatment, with enhanced colonic IL-6 and IL-11 release and Stat3 phosphorylation. Both IL-6 and ferritin, the iron storage protein, co-localized with macrophages suggesting iron may act directly on IL-6 producing-macrophages. Iron increased DSS-induced colonic epithelial cell proliferation and apoptosis consistent with enhanced mucosal damage. DSS-treated mice developed anemia that was not alleviated by dietary iron supplementation. Six weeks post-DSS treatment, iron-supplemented mice developed more and larger colonic tumors compared with control mice. Intratumoral IL-6 and IL-11 expression increased in DSS-treated mice and IL-6, and possibly IL-11, were enhanced by dietary iron. Gene expression of iron importers, divalent metal transporter 1 and transferrin receptor 1, increased and iron exporter, ferroportin, decreased in colonic tumors suggesting increased iron uptake. Dietary iron and colonic inflammation synergistically activated colonic IL-6/IL-11-Stat3 signaling promoting tumorigenesis. Oral iron therapy may be detrimental in inflammatory bowel disease since it may exacerbate colonic inflammation and increase colorectal cancer risk. PMID:24223168

  20. Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis.

    PubMed

    Kobayashi, Tetsuro; Glatz, Martin; Horiuchi, Keisuke; Kawasaki, Hiroshi; Akiyama, Haruhiko; Kaplan, Daniel H; Kong, Heidi H; Amagai, Masayuki; Nagao, Keisuke

    2015-04-21

    Staphylococcus aureus skin colonization is universal in atopic dermatitis and common in cancer patients treated with epidermal growth factor receptor inhibitors. However, the causal relationship of dysbiosis and eczema has yet to be clarified. Herein, we demonstrate that Adam17(fl/fl)Sox9-(Cre) mice, generated to model ADAM17-deficiency in human, developed eczematous dermatitis with naturally occurring dysbiosis, similar to that observed in atopic dermatitis. Corynebacterium mastitidis, S. aureus, and Corynebacterium bovis sequentially emerged during the onset of eczematous dermatitis, and antibiotics specific for these bacterial species almost completely reversed dysbiosis and eliminated skin inflammation. Whereas S. aureus prominently drove eczema formation, C. bovis induced robust T helper 2 cell responses. Langerhans cells were required for eliciting immune responses against S. aureus inoculation. These results characterize differential contributions of dysbiotic flora during eczema formation, and highlight the microbiota-host immunity axis as a possible target for future therapeutics in eczematous dermatitis.

  1. Dysbiosis and Staphylococcus aureus colonization drives inflammation in atopic dermatitis

    PubMed Central

    Kobayashi, Tetsuro; Glatz, Martin; Horiuchi, Keisuke; Kawasaki, Hiroshi; Akiyama, Haruhiko; Kaplan, Daniel H.; Kong, Heidi H.; Amagai, Masayuki; Nagao, Keisuke

    2015-01-01

    Summary Staphylococcus aureus skin colonization is universal in atopic dermatitis and common in cancer patients treated with epidermal growth factor receptor inhibitors. However, the causal relationship of dysbiosis and eczema has yet to be clarified. Herein, we demonstrate that Adam17fl/flSox9-Cre mice, generated to model ADAM17-deficiency in human, developed eczematous dermatitis with naturally occurring dysbiosis, similar to that observed in atopic dermatitis. Corynebacterium mastitidis, S. aureus, and Corynebacterium bovis sequentially emerged during the onset of eczematous dermatitis, and antibiotic specific for these bacterial species almost completely reversed dysbiosis and eliminated skin inflammation. Whereas S. aureus prominently drove eczema formation, C. bovis induced robust T helper 2 cell responses. Langerhans cells were required for eliciting immune responses against S. aureus inoculation. These results characterize differential contributions of dysbiotic flora during eczema formation, and highlight the microbiota-host immunity axis as a possible target for future therapeutics in eczematous dermatitis. PMID:25902485

  2. Nicotine suppresses acute colitis and colonic tumorigenesis associated with chronic colitis in mice.

    PubMed

    Hayashi, Shusaku; Hamada, Takayuki; Zaidi, Syed Faisal; Oshiro, Momoe; Lee, Jaemin; Yamamoto, Takeshi; Ishii, Yoko; Sasahara, Masakiyo; Kadowaki, Makoto

    2014-11-15

    Ulcerative colitis is a chronic inflammatory disease that frequently progresses to colon cancer. The tumor-promoting effect of inflammation is now widely recognized and understood. Recent studies have revealed that treatment with nicotine ameliorates colitis in humans and experimental murine models, whereas the effect of nicotine on colitis-associated colonic tumorigenesis remains unclear. In the present study, we examined the effect of nicotine on the development of acute colitis and colitis-associated cancer (CAC). The acute colitis model was induced by treatment with 3% dextran sulfate sodium (DSS) for 7 days, whereas the CAC model was induced by a combination of azoxymethane and repeated DSS treatment. Nicotine and a selective agonist of the α7-nicotinic acetylcholine receptor (α7-nAChR) reduced the severity of DSS-induced acute colonic inflammation. In addition, the suppressive effect of nicotine on acute colitis was attenuated by an antagonist of α7-nAChR. Furthermore, nicotine inhibited the IL-6 production of CD4 T cells in the DSS-induced inflamed colonic mucosa. We found that nicotine significantly reduced the number and size of colonic tumors in mice with CAC. Nicotine markedly inhibited the elevation of TNF-α and IL-6 mRNA as well as phosphorylated signal transducer and activator of transcription (Stat) 3 expression in the colons of the tumor model mice. These results demonstrate that nicotine suppresses acute colitis and colitis-associated tumorigenesis, and this effect may be associated with the activation of α7-nAChR. Furthermore, it is presumed that nicotine downregulates the expression of inflammatory mediators such as IL-6/Stat3 and TNF-α, thereby reducing the colonic tumorigenesis associated with chronic colitis.

  3. 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.

  4. Acute paraquat exposure impairs colonic motility by selectively attenuating nitrergic signalling in the mouse.

    PubMed

    Diss, Lucy; Dyball, Sarah; Ghela, Tina; Golding, Jonathan; Morris, Rachel; Robinson, Stephen; Tucker, Rosemary; Walter, Talia; Young, Paul; Allen, Marcus; Fidalgo, Sara; Gard, Paul; Mabley, Jon; Patel, Bhavik; Chatterjee, Prabal; Yeoman, Mark

    2016-02-01

    Paraquat, a common herbicide, is responsible for large numbers of deaths worldwide through both deliberate and accidental ingestion. Previous studies have eluded that the bioavailability of paraquat increases substantially with increasing dose and that these changes may in part be due to the effects that these high concentrations have on the gastrointestinal tract (GI tract). To date, the actions of acute, high concentrations (20mM for 60 min) of paraquat on the GI tract, particularly the colon which is a major site of paraquat absorption, are unknown. This study examined the effects of acute paraquat administration on colonic motility in the C57BL/6 mouse. Acute paraquat exposure decreased colonic motility and the amplitude of colonic migrating motor complexes (CMMCs), which are major motor patterns involved in faecal pellet propulsion. In isolated segments of distal colon, paraquat increased resting tension and markedly attenuated electrical field stimulation-evoked relaxations. Pharmacological dissection of paraquat's mechanism of action on both the CMMCs and field stimulated tissue using the nitric oxide synthase inhibitor NG-nitro-L-arginine and direct measurement of NO release from the myenteric plexus, demonstrated that paraquat selectively attenuates nitrergic signalling pathways. These changes did not appear to be due to alterations in colonic oxidative stress, inflammation or complex 1 activity, but were most likely caused by paraquat's ability to act as a redox couple. In summary, these data demonstrate that acute paraquat exposure attenuates colonic transit. These changes may facilitate the absorption of paraquat into the circulation and so facilitate its toxicity.

  5. Phosphodiesterase-5 inhibition suppresses colonic inflammation-induced tumorigenesis via blocking the recruitment of MDSC

    PubMed Central

    Lin, Shiyong; Wang, Jing; Wang, Lihui; Wen, Jing; Guo, Yandong; Qiao, Weiguang; Zhou, Jieqiong; Xu, Guoliang; Zhi, Fachao

    2017-01-01

    Phosphodiesterase 5 (PDE-5) is a major isoform of cGMP phosphodiesterase in diverse tissues and plays a critical role in regulating intracellular cGMP concentrations. However, the distribution and expression of PDE-5 in colitis-related colon cancer was still unclear, not even the function and mechanism. Western blotting and ELISA were performed to detect colonic PDE-5 expression in AOM/DSS-induced tumorigenesis model. Sildenafil, a specific PDE-5 inhibitor, was used to treat AOM/DSS-induced and AOM-induced colonic tumorigenesis model and DSS-induced colitis model. The leukocyte infiltration in colonic tissue was examined by flow cytometry and immunofluorescence staining. Further matrigel-based invasion assay was employed to determine the effects of Sildenafil on myeloid-derived suppressor cell (MDSC) in vitro. We first demonstrated the upregulation of colonic PDE-5 expression and the prevention role of PDE-5 inhibition in AOM/DSS-induced tumorigenesis model. More importantly, PDE-5 inhibitor Sildenafil inhibited colonic tumorigenesis dependent on inflammation and suppressed DSS-induced colitis. Molecular mechanism investigation indicated that Sildenafil regulated inflammation microenvironment via directly inhibiting MDSC infiltration in colonic tissue. The study provides solid evidence for the use of PDE-5 inhibitor in preventing and treating colonic inflammation-related tumorigenesis. PMID:28123846

  6. Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation.

    PubMed

    Sharma, Manoranjan; Mohapatra, Jogeswar; Wagh, Akshaya; Patel, Hiren M; Pandey, Dheerendra; Kadam, Shekhar; Argade, Anil; Deshpande, Shrikalp S; Shah, Gourang B; Chatterjee, Abhijit; Jain, Mukul R

    2014-03-01

    TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation. Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.

  7. Bardoxolone Methyl Prevents High-Fat Diet-Induced Colon Inflammation in Mice

    PubMed Central

    Dinh, Chi H. L.; Yu, Yinghua; Szabo, Alexander; Zhang, Qingsheng; Zhang, Peng; Huang, Xu-Feng

    2016-01-01

    Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora. PMID:26920068

  8. Bardoxolone Methyl Prevents High-Fat Diet-Induced Colon Inflammation in Mice.

    PubMed

    Dinh, Chi H L; Yu, Yinghua; Szabo, Alexander; Zhang, Qingsheng; Zhang, Peng; Huang, Xu-Feng

    2016-04-01

    Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora.

  9. 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.

  10. 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

  11. Roles for Inflammation and Regulatory T Cells in Colon Cancer

    PubMed Central

    Erdman, Susan E.; Poutahidis, Theofilos

    2014-01-01

    Risk for developing cancer rises substantially as a result of poorly regulated inflammatory responses to pathogenic bacterial infections. Anti-inflammatory CD4+ regulatory cells (TREG) function to restore immune homeostasis during chronic inflammatory disorders. It seems logical that TREG cells would function to reduce risk of inflammation-associated cancer in the bowel by down-regulating inflammation. It is widely believed, however, that TREG function in cancer mainly to suppress protective anticancer inflammatory responses. Thus roles for inflammation, TREG cells, and gut bacteria in cancer are paradoxical and are the subject of controversy. Our accumulated data build upon the “hygiene hypothesis” model in which gastrointestinal (GI) infections lead to changes in TREG that reduce inflammation-associated diseases. Ability of TREG to inhibit or suppress cancer depends upon gut bacteria and IL-10, which serve to maintain immune balance and a protective anti-inflammatory TREG phenotype. However, under poorly regulated pro-inflammatory conditions, TREG fail to inhibit and may instead contribute to a T helper (Th)-17-driven procarcinogenic process, a cancer state that is reversible by down-regulation of inflammation and interleukin (IL)-6. Consequently, hygienic individuals with a weakened IL-10– and TREG–mediated inhibitory loop are highly susceptible to the carcinogenic consequences of elevated inflammation and show more frequent inflammation-associated cancers. Taken together, these data help explain the paradox of inflammation and TREG in cancer and indicate that targeted stimulation of TREG may promote health and significantly reduce risk of cancer. PMID:20019355

  12. 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.

  13. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice

    PubMed Central

    Meira, Lisiane B.; Bugni, James M.; Green, Stephanie L.; Lee, Chung-Wei; Pang, Bo; Borenshtein, Diana; Rickman, Barry H.; Rogers, Arlin B.; Moroski-Erkul, Catherine A.; McFaline, Jose L.; Schauer, David B.; Dedon, Peter C.; Fox, James G.; Samson, Leona D.

    2008-01-01

    Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium–induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis. PMID:18521188

  14. Protective effect of sugar cane extract against dextran sulfate sodium-induced colonic inflammation in mice.

    PubMed

    Wang, Bin; Li, Yansen; Mizu, Masami; Furuta, Toma; Li, ChunMei

    2017-02-01

    Sugar cane extract (SCE) exhibits various biological effects and has been reported to enhance animal growth performance. However, the effect of SCE on inflammation in animals is still obscure. To study the effects and underlying mechanism of SCE on dextran sulfate sodium (DSS)-induced colonic inflammation, forty female ICR mice (26.63±0.19g, 6-week-old) were assigned into four groups: a control group (Cont), a DSS-challenged group (DSS), a SCE-supplemented group (SCE), and a DSS+SCE group (DSS+SCE). Mice in Cont group and DSS group were fed basic diet and other mice received 1% SCE supplemented in basic diet from 6-week to 8-week-old. Mice in DSS and DSS+SCE groups were also given a 4% DSS solution from 7-week to 8-week-old via drinking water to induce colonic inflammation. After 2 weeks, mice were sacrificed and samples were collected. The results showed that dietary SCE alleviated DSS induced growth suppression, splenic damage, colonic histological changes, colonic inflammation, oxidative stress, and colonic dysfunction of tight junctions. Meanwhile, the DSS exposure activated nuclear transcription factor kappa B p65 and inhibited nuclear factor E2-related factor 2 (Nrf2), while SCE markedly attenuated the DSS-promoted effect on the p65 nuclear accumulation and the DSS-inhibited effect on the Nrf2 nuclear accumulation. In conclusion, SCE conferred a protective role in the DSS-induced inflammation and the mechanism might be associated with the activated signals of the nuclear factor kappa B p65 and Nrf2.

  15. Initiation of antiretroviral therapy before detection of colonic infiltration by HIV reduces viral reservoirs, inflammation and immune activation

    PubMed Central

    Crowell, Trevor A; Fletcher, James LK; Sereti, Irini; Pinyakorn, Suteeraporn; Dewar, Robin; Krebs, Shelly J; Chomchey, Nitiya; Rerknimitr, Rungsun; Schuetz, Alexandra; Michael, Nelson L; Phanuphak, Nittaya; Chomont, Nicolas; Ananworanich, Jintanat

    2016-01-01

    Introduction Colonic infiltration by HIV occurs soon after infection, establishing a persistent viral reservoir and a barrier to cure. We investigated virologic and immunologic correlates of detectable colonic HIV RNA during acute HIV infection (AHI) and their response to antiretroviral treatment (ART). Methods From 49,458 samples screened for HIV, 74 participants were enrolled during AHI and 41 consented to optional sigmoidoscopy, HIV RNA was categorized as detectable (≥50 copies/mg) or undetectable in homogenized colon biopsy specimens. Biomarkers and HIV burden in blood, colon and cerebrospinal fluid were compared between groups and after 24 weeks of ART. Results Colonic HIV RNA was detectable in 31 participants (76%) and was associated with longer duration since HIV exposure (median 16 vs. 11 days, p=0.02), higher median plasma levels of cytokines and inflammatory markers (CXCL10 476 vs. 148 pg/mL, p=0.02; TNF-RII 1036 vs. 649 pg/mL, p<0.01; neopterin 2405 vs. 1368 pg/mL, p=0.01) and higher levels of CD8+ T cell activation in the blood (human leukocyte antigen - antigen D related (HLA-DR)/CD38 expression 14.4% vs. 7.6%, p <0.01) and colon (8.9% vs. 4.5%, p=0.01). After 24 weeks of ART, participants with baseline detectable colonic HIV RNA demonstrated persistent elevations in total HIV DNA in colonic mucosal mononuclear cells (CMMCs) (median 61 vs. 0 copies/106 CMMCs, p=0.03) and a trend towards higher total HIV DNA in peripheral blood mononuclear cells (PBMC) (41 vs. 1.5 copies/106 PBMCs, p=0.06). There were no persistent differences in immune activation and inflammation. Conclusions The presence of detectable colonic HIV RNA at the time of ART initiation during AHI is associated with higher levels of proviral DNA after 24 weeks of treatment. Seeding of HIV in the gut may have long-lasting effects on the size of persistent viral reservoirs and may represent an important therapeutic target in eradication strategies. PMID:27637172

  16. 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

  17. Role of TRPV1 in high-threshold rat colonic splanchnic afferents is revealed by inflammation.

    PubMed

    Phillis, Benjamin D; Martin, Chris M; Kang, Daiwu; Larsson, Håkan; Lindström, Erik A; Martinez, Vicente; Blackshaw, L Ashley

    2009-08-07

    The vanilloid-1 receptor TRPV1 is known to play a role in extrinsic gastrointestinal afferent function. We investigated the role of TRPV1 in mechanosensitivity in afferents from normal and inflamed tissue. Colonic mechanosensitivity was determined in an in vitro rat colon preparation by recording from attached splanchnic nerves. Recordings were made from serosal/mesenteric afferents responding only at high thresholds to graded mechanical stimulation with von Frey probes. Colonic inflammation was induced by adding 5% dextran sulphate sodium (DSS) to the drinking water for 5 days, and was confirmed by histopathology. The selective TRPV1 antagonist, SB-750364 (10(-8) to 10(-6)M), was tested on mechanosensory stimulus response functions of afferents from normal and inflamed preparations (N=7 each). Mechanosensory responses had thresholds of 1-2g, and maximal responses were observed at 12 g. The stimulus response function was not affected by DSS-induced colitis. SB-750364 had no effect on stimulus response functions in normal preparations, but reduced (up to 60%) in a concentration-dependent manner those in inflammation (2-way ANOVA, p<0.05). Moreover, in inflamed tissue, spontaneous afferent activity showed a dose-dependent trend toward reduction with SB-750364. We conclude that mechanosensitivity of high-threshold serosal colonic splanchnic afferents to graded stimuli is unaffected during DSS colitis. However, there is a positive influence of TRPV1 in mechanosensitivity in inflammation, suggesting up-regulation of excitatory TRPV1-mediated mechanisms.

  18. [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.

  19. Acute Appendicitis as Complication of Colon Transit Time Study; A Case Report

    PubMed Central

    Ghahramani, Leila; Roshanravan, Reza; Khodaei, Shahin; Rahimi Kazerooni, Salar; Moslemi, Sam

    2015-01-01

    Colon transit time study with radio opaque markers is a simple method for assessment of colon motility disorder in patients with chronic idiopathic constipation. We report a case of acute appendicitis that was induced by impaction of radio opaque markers after colon transit time study. We think that this case report is first significant complication of colon transit time study until now PMID:26396723

  20. 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.

  1. 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

  2. Type I IFN induces protein ISGylation to enhance cytokine expression and augments colonic inflammation

    PubMed Central

    Fan, Jun-Bao; Miyauchi-Ishida, Sayuri; Arimoto, Kei-ichiro; Liu, Dan; Yan, Ming; Liu, Chang-Wei; Győrffy, Balázs; Zhang, Dong-Er

    2015-01-01

    Type I IFNs have broad activity in tissue inflammation and malignant progression that depends on the expression of IFN-stimulated genes (ISGs). ISG15, one such ISG, can form covalent conjugates to many cellular proteins, a process termed “protein ISGylation.” Although type I IFNs are involved in multiple inflammatory disorders, the role of protein ISGylation during inflammation has not been evaluated. Here we report that protein ISGylation exacerbates intestinal inflammation and colitis-associated colon cancer in mice. Mechanistically, we demonstrate that protein ISGylation negatively regulates the ubiquitin–proteasome system, leading to increased production of IFN-induced reactive oxygen species (ROS). The increased cellular ROS then enhances LPS-induced activation of p38 MAP kinase and the expression of inflammation-related cytokines in macrophages. Thus our studies reveal a regulatory role for protein ISGylation in colonic inflammation and its related malignant progression, indicating that targeting ubiquitin-activating enzyme E1 homolog has therapeutic potential in treating inflammatory diseases. PMID:26515094

  3. Mechanisms of Motility Change on Trinitrobenzenesulfonic Acid-Induced Colonic Inflammation in Mice

    PubMed Central

    Cheon, Gab Jin; Cui, Yuan; Yeon, Dong-Soo; Kwon, Seong-Chun

    2012-01-01

    Ulcerative colitis is an inflammatory bowel disease (IBD) characterized by recurrent episodes of colonic inflammation and tissue degeneration in human or animal models. The contractile force generated by the smooth muscle is significantly attenuated, resulting in altered motility leading to diarrhea or constipation in IBD. The aim of this study is to clarify the altered contractility of circular and longitudinal smooth muscle layers in proximal colon of trinitrobenzen sulfonic acid (TNBS)-induced colitis mouse. Colitis was induced by direct injection of TNBS (120 mg/kg, 50% ethanol) in proximal colon of ICR mouse using a 30 G needle anesthetized with ketamin (50 mg/kg), whereas animals in the control group were injected of 50% ethanol alone. In TNBS-induced colitis, the wall of the proximal colon is diffusely thickened with loss of haustration, and showed mucosal and mucular edema with inflammatory infiltration. The colonic inflammation is significantly induced the reduction of colonic contractile activity including spontaneous contractile activity, depolarization-induced contractility, and muscarinic acetylcholine receptor-mediated contractile response in circular muscle layer compared to the longitudinal muscle layer. The inward rectification of currents, especially, important to Ca2+ and Na+ influx-induced depolarization and contraction, was markedly reduced in the TNBS-induced colitis compared to the control. The muscarinic acetylcholine-mediated contractile responses were significantly attenuated in the circular and longitudinal smooth muscle strips induced by the reduction of membrane expression of canonical transient receptor potential (TRPC) channel isoforms from the proximal colon of the TNBS-induced colitis mouse than the control. PMID:23269907

  4. Helicobacter Infection Is Required for Inflammation and Colon Cancer in Smad3-Deficient Mice

    PubMed Central

    Maggio-Price, Lillian; Treuting, Piper; Zeng, Weiping; Tsang, Mark; Bielefeldt-Ohmann, Helle; Iritani, Brian M.

    2017-01-01

    Accumulating evidence suggests that intestinal microbial organisms may play an important role in triggering and sustaining inflammation in individuals afflicted with inflammatory bowel disease (IBD). Moreover, individuals with IBD are at increased risk for developing colorectal cancer, suggesting that chronic inflammation may initiate genetic or epigenetic changes associated with cancer development. We tested the hypothesis that bacteria may contribute to the development of colon cancer by synergizing with defective transforming growth factor-β (TGF-β) signaling, a pathway commonly mutated in human colon cancer. Although others have reported that mice deficient in the TGF-β signaling molecule SMAD3 develop colon cancer, we found that SMAD3-deficient mice maintained free of the Gram-negative enterohepatic bacteria Helicobacter spp. for up to 9 months do not develop colon cancer. Furthermore, infection of SMAD3−/− mice with Helicobacter triggers colon cancer in 50% to 66% of the animals. Using real-time PCR, we found that Helicobacter organisms concentrate in the cecum, the preferred site of tumor development. Mucinous adenocarcinomas develop 5 to 30 weeks after infection and are preceded by an early inflammatory phase, consisting of increased proliferation of epithelial cells; increased numbers of cyclooxygenase-2–positive cells, CD4+ T cells, macrophages; and increased MHC class II expression. Colonic tissue revealed increased transcripts for the oncogene c-myc and the proinflammatory cytokines interleukin-1α (IL-1α), IL-1β, IL-6, IFN-γ, and tumor necrosis factor-α, some of which have been implicated in colon cancer. These results suggest that bacteria may be important in triggering colorectal cancer, notably in the context of gene mutations in the TGF-β signaling pathway, one of the most commonly affected cellular pathways in colorectal cancer in humans. PMID:16424015

  5. Non-cell autonomous effects of targeting inducible PGE2 synthesis during inflammation-associated colon carcinogenesis.

    PubMed

    Nakanishi, Masako; Perret, Christine; Meuillet, Emmanuelle J; Rosenberg, Daniel W

    2015-04-01

    Microsomal PGE2 synthase-1 (mPGES-1), the terminal enzyme in the formation of inducible PGE2, represents a potential target for cancer chemoprevention. We have previously shown that genetic abrogation of mPGES-1 significantly suppresses tumorigenesis in two preclinical models of intestinal cancer. In this study, we examined the role of mPGES-1 during colon tumorigenesis in the presence of dextran sulfate sodium (DSS)-induced inflammatory microenvironment. Using Apc (Δ14/+) in which the mPGES-1 gene is either wild-type (D14:WT) or deleted (D14:KO), we report that mPGES-1 deficiency enhances sensitivity to acute mucosal injury. As a result of the increased epithelial damage, protection against adenoma formation is unexpectedly compromised in the D14:KO mice. Examining the DSS-induced acute injury, cryptal structures are formed within inflamed areas of colonic mucosa of both genotypes that display the hallmarks of early neoplasia. When acute epithelial injury is balanced by titration of DSS exposures, however, these small cryptal lesions progress rapidly to adenomas in the D14:WT mice. Given that mPGES-1 is highly expressed within the intestinal stroma under the inflammatory conditions of DSS-induced ulceration, we propose a complex and dual role for inducible PGE2 synthesis within the colonic mucosa. Our data suggest that inducible PGE2 is critical for the maintenance of an intact colonic epithelial barrier, while promoting epithelial regeneration. This function is exploited during neoplastic transformation in Apc (Δ14/+) mice as PGE2 contributes to the growth and expansion of the early initiated cryptal structures. Taken together, inducible PGE2 plays a complex role in inflammation-associated cancers that requires further analysis. Inducible PGE2 production by mPGES-1 is critical for the colonic mucosal homeostasis. This function is exploited in the presence of the neoplastic transformation in Apc (Δ14/+) mice as PGE2 contributes to the growth and expansion of

  6. Non-cell autonomous effects of targeting inducible PGE2 synthesis during inflammation-associated colon carcinogenesis

    PubMed Central

    Nakanishi, Masako; Perret, Christine; Meuillet, Emmanuelle J.; Rosenberg, Daniel W.

    2015-01-01

    Microsomal PGE2 synthase-1 (mPGES-1), the terminal enzyme in the formation of inducible PGE2, represents a potential target for cancer chemoprevention. We have previously shown that genetic abrogation of mPGES-1 significantly suppresses tumorigenesis in two preclinical models of intestinal cancer. In this study, we examined the role of mPGES-1 during colon tumorigenesis in the presence of dextran sulfate sodium (DSS)-induced inflammatory microenvironment. Using Apc Δ14/+ in which the mPGES-1 gene is either wild-type (D14:WT) or deleted (D14:KO), we report that mPGES-1 deficiency enhances sensitivity to acute mucosal injury. As a result of the increased epithelial damage, protection against adenoma formation is unexpectedly compromised in the D14:KO mice. Examining the DSS-induced acute injury, cryptal structures are formed within inflamed areas of colonic mucosa of both genotypes that display the hallmarks of early neoplasia. When acute epithelial injury is balanced by titration of DSS exposures, however, these small cryptal lesions progress rapidly to adenomas in the D14:WT mice. Given that mPGES-1 is highly expressed within the intestinal stroma under the inflammatory conditions of DSS-induced ulceration, we propose a complex and dual role for inducible PGE2 synthesis within the colonic mucosa. Our data suggest that inducible PGE2 is critical for the maintenance of an intact colonic epithelial barrier, while promoting epithelial regeneration. This function is exploited during neoplastic transformation in Apc Δ14/+ mice as PGE2 contributes to the growth and expansion of the early initiated cryptal structures. Taken together, inducible PGE2 plays a complex role in inflammation-associated cancers that requires further analysis. Inducible PGE2 production by mPGES-1 is critical for the colonic mucosal homeostasis. This function is exploited in the presence of the neoplastic transformation in Apc Δ14/+ mice as PGE2 contributes to the growth and expansion of the

  7. 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

  8. Interaction of dietary fatty acids with tumour necrosis factor family cytokines during colon inflammation and cancer.

    PubMed

    Hofmanová, Jiřina; Straková, Nicol; Vaculová, Alena Hyršlová; Tylichová, Zuzana; Safaříková, Barbora; Skender, Belma; Kozubík, Alois

    2014-01-01

    Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF- α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NF κ B activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined.

  9. Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

    PubMed Central

    Straková, Nicol; Vaculová, Alena Hyršlová; Tylichová, Zuzana; Šafaříková, Barbora; Kozubík, Alois

    2014-01-01

    Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF-α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NFκB activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined. PMID:24876678

  10. Differential responsiveness to contractile agents of isolated smooth muscle cells from human colons as a function of age and inflammation.

    PubMed

    Boyer, J C; Guitton, C; Pignodel, C; Cuq, P; Moussu, P; Pouderoux, P; Christen, M O; Balmes, J L; Bali, J P

    1997-11-01

    To study the involvement of age and inflammation in motor colonic activity in man, contractile responses to CCK, carbachol, and KCl of isolated colonic smooth muscle cells (SMC) from normal and inflamed human colons were evaluated; the incidence of sex and smoking on contraction was also analyzed. Contractile responses to the three agonists were significantly lower in tissues with a low degree of inflammation than in tissues with high level of inflammation or normal tissues. This reduction in cell responsiveness appears to be nonspecific and nonreceptor mediated. A positive correlation of the contractile responses to the three stimulants with the age of patients was observed. In contrast, no association was found between sex, smoking, and cell contraction. In conclusion, contractions of SMC due to CCK, carbachol, and KCl were significantly modified during life; inflammation of the colon led to a loss of SMC responsiveness.

  11. 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.

  12. 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

  13. Structural environment built by AKAP12+ colon mesenchymal cells drives M2 macrophages during inflammation recovery.

    PubMed

    Yang, Jun-Mo; Lee, Hye Shin; Seo, Ji Hae; Park, Ji-Hyeon; Gelman, Irwin H; Lo, Eng H; Kim, Kyu-Won

    2017-02-16

    Macrophages exhibit phenotypic plasticity, as they have the ability to switch their functional phenotypes during inflammation and recovery. Simultaneously, the mechanical environment actively changes. However, how these dynamic alterations affect the macrophage phenotype is unknown. Here, we observed that the extracellular matrix (ECM) constructed by AKAP12+ colon mesenchymal cells (CMCs) generated M2 macrophages by regulating their shape during recovery. Notably, rounded macrophages were present in the linear and loose ECM of inflamed colons and polarized to the M1 phenotype. In contrast, ramified macrophages emerged in the contracted ECM of recovering colons and mainly expressed M2 macrophage markers. These contracted structures were not observed in the inflamed colons of AKAP12 knockout (KO) mice. Consequently, the proportion of M2 macrophages in inflamed colons was lower in AKAP12 KO mice than in WT mice. In addition, clinical symptoms and histological damage were more severe in AKAP12 KO mice than in WT mice. In experimentally remodeled collagen gels, WT CMCs drove the formation of a more compacted structure than AKAP12 KO CMCs, which promoted the polarization of macrophages toward an M2 phenotype. These results demonstrated that tissue contraction during recovery provides macrophages with the physical cues that drive M2 polarization.

  14. Structural environment built by AKAP12+ colon mesenchymal cells drives M2 macrophages during inflammation recovery

    PubMed Central

    Yang, Jun-Mo; Lee, Hye Shin; Seo, Ji Hae; Park, Ji-Hyeon; Gelman, Irwin H.; Lo, Eng H.; Kim, Kyu-Won

    2017-01-01

    Macrophages exhibit phenotypic plasticity, as they have the ability to switch their functional phenotypes during inflammation and recovery. Simultaneously, the mechanical environment actively changes. However, how these dynamic alterations affect the macrophage phenotype is unknown. Here, we observed that the extracellular matrix (ECM) constructed by AKAP12+ colon mesenchymal cells (CMCs) generated M2 macrophages by regulating their shape during recovery. Notably, rounded macrophages were present in the linear and loose ECM of inflamed colons and polarized to the M1 phenotype. In contrast, ramified macrophages emerged in the contracted ECM of recovering colons and mainly expressed M2 macrophage markers. These contracted structures were not observed in the inflamed colons of AKAP12 knockout (KO) mice. Consequently, the proportion of M2 macrophages in inflamed colons was lower in AKAP12 KO mice than in WT mice. In addition, clinical symptoms and histological damage were more severe in AKAP12 KO mice than in WT mice. In experimentally remodeled collagen gels, WT CMCs drove the formation of a more compacted structure than AKAP12 KO CMCs, which promoted the polarization of macrophages toward an M2 phenotype. These results demonstrated that tissue contraction during recovery provides macrophages with the physical cues that drive M2 polarization. PMID:28205544

  15. 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.

  16. 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.

  17. 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.

  18. Imaging inflammation in mouse colon using a rapid stage-scanning confocal fluorescence microscope

    NASA Astrophysics Data System (ADS)

    Saldua, Meagan A.; Olsovsky, Cory A.; Callaway, Evelyn S.; Chapkin, Robert S.; Maitland, Kristen C.

    2012-01-01

    Large area confocal microscopy may provide fast, high-resolution image acquisition for evaluation of tissue in pre-clinical studies with reduced tissue processing in comparison to histology. We present a rapid beam and stage-scanning confocal fluorescence microscope to image cellular and tissue features along the length of the entire excised mouse colon. The beam is scanned at 8,333 lines/sec by a polygon scanning mirror while the specimen is scanned in the orthogonal axis by a motorized translation stage with a maximum speed of 7 mm/sec. A single 1×60 mm2 field of view image spanning the length of the mouse colon is acquired in 10 s. Z-projection images generated from axial image stacks allow high resolution imaging of the surface of non-flat specimens. In contrast to the uniform size, shape, and distribution of colon crypts in confocal images of normal colon, confocal images of chronic bowel inflammation exhibit heterogeneous tissue structure with localized severe crypt distortion.

  19. Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation

    PubMed Central

    Li, Qingjie; Winston, John H.

    2015-01-01

    Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus. PMID:26608656

  20. Bioavailability of lemon verbena (Aloysia triphylla) polyphenols in rats: impact of colonic inflammation.

    PubMed

    Felgines, Catherine; Fraisse, Didier; Besson, Catherine; Vasson, Marie-Paule; Texier, Odile

    2014-05-28

    Lemon verbena (Aloysia triphylla) infusion, a widely consumed herbal tea, contains significant amounts of polyphenols such as flavone diglucuronides and phenylpropanoid glycosides (mainly verbascoside). We have recently shown that lemon verbena infusion offers beneficial effects against dextran sodium sulphate (DSS)-induced colonic inflammation in rats. The present study aimed to evaluate the bioavailability and intestinal absorption of polyphenols derived from lemon verbena infusion in both healthy and colitic rats. For this purpose, lemon verbena infusion was given to rats ad libitum for 14 d, and then 4 % DSS was added to the infusion for 7 d. Before and after DSS administration, 24 h urinary excretion of polyphenols was determined. Flavones were excreted in the urine as conjugated aglycones, and their excretion was not significantly altered by colonic inflammation. Only trace amounts of verbascoside were excreted in the urine, but various metabolites (hydroxycinnamic acids) were detected. The urinary excretion of hydroxycinnamic acids, particularly that of caffeic acid, increased after DSS administration (P< 0·05). Only flavone aglycones (luteolin and diosmetin) were excreted in the faeces in small proportions (3·2 % of ingested flavones). Intestinal absorption of lemon verbena polyphenols was examined using an in situ intestinal perfusion model. Intestinal absorption of verbascoside and flavone diglucuronides did not significantly differ between the healthy and colitic rats. Collectively, these results show that intestinal absorption and urinary excretion of lemon verbena flavone diglucuronides were not altered by colonic inflammation, but that urinary excretion of hydroxycinnamic acids derived from verbascoside was affected in a colitic situation.

  1. Salvia miltiorrhiza (dan shen) significantly ameliorates colon inflammation in dextran sulfate sodium induced colitis.

    PubMed

    Wen, Xiao-Dong; Wang, Chong-Zhi; Yu, Chunhao; Zhang, Zhiyu; Calway, Tyler; Wang, Yunwei; Li, Ping; Yuan, Chun-Su

    2013-01-01

    Inflammatory bowel disease increases the risks of human colorectal cancer. In this study, the effects of Salvia miltiorrhiza extract (SME) on chemically-induced colitis in a mouse model were evaluated. Chemical composition of SME was determined by HPLC analysis. A/J mice received a single injection of AOM 7.5 mg/kg. After one week, these mice received 2.5% DSS for eight days, or DSS plus SME (25 or 50 mg/kg). DSS-induced colitis was scored with the disease activity index (DAI). Body weight and colon length were also measured. The severity of inflammatory lesions was further evaluated by colon tissue histological assessment. HPLC assay showed that the major constituents in the tested SME were danshensu, protocatechuic aldehyde, salvianolic acid D, and salvianolic acid B. In the model group, the DAI score reached its highest level on Day 8, while the SME group on both doses showed a significantly reduced DAI score (both p < 0.01). As an objective index of the severity of inflammation, colon length was significantly shorter in the model group than the vehicle group. Treatment with 25 and 50 mg/kg of SME inhibited the shortening of colon in a dose-related manner (p < 0.05 and p < 0.01, respectively). SME groups also significantly reduced weight reduction (p < 0.05). Colitis histological data supported the pharmacological observations. Thus, Salvia miltiorrhiza could be a promising candidate in preventing and treating colitis and in reducing the risks of inflammation-associated colorectal cancer.

  2. 1,25(OH)2D3 Deficiency Induces Colon Inflammation via Secretion of Senescence-Associated Inflammatory Cytokines

    PubMed Central

    Zhi, Chunchun; Shen, Ming; Sun, Weiwei; Miao, Dengshun; Yuan, Xiaoqin

    2016-01-01

    Epidemiological studies showed that 1,25-Dihydroxyvitamin D[1,25(OH)2D3] insufficiency appears to be associated with aging and colon cancer while underlying biological mechanisms remain largely unknown. Inflammatory bowel disease is one of the risk factors for colon cancer. In this study, we investigated whether 1,25(OH)2D3 deficiency has an impact on the colon of 25-hydroxyvitamin D 1α-hydroxylase knockout [Cyp27b1−/−] mice fed on a rescue diet (high calcium, phosphate, and lactose) from weaning to 10 months of age. We found that 1,25(OH)2D3 deficient mice displayed significant colon inflammation phenotypes including shortened colon length, thinned and disordered mucosal structure, and inflammatory cell infiltration. DNA damage, cellular senescence and the production of senescence-associated inflammatory cytokines were also increased significantly in the colon of Cyp27b1−/−mice. Furthermore, the levels of ROS in the colon were increased significantly, whereas the expression levels of antioxidative genes were down-regulated dramatically in the colon of Cyp27b1−/−mice. Taken together, our results demonstrated that 1,25(OH)2D3 deficiency could induce colon inflammation, which may result from increased oxidative stress and DNA damage, subsequently, induced cell senescence and overproduction of senescence-associated secretory factors. Therefore, our findings suggest that 1,25(OH)2D3 may play an important role in preventing the development and progression of colon inflammation and colon cancer. PMID:26790152

  3. Dietary Supplementation with Fresh Pineapple Juice Decreases Inflammation and Colonic Neoplasia in IL-10-deficient Mice with Colitis

    PubMed Central

    Hale, Laura P.; Chichlowski, Maciej; Trinh, Chau T.; Greer, Paula K.

    2010-01-01

    Background Bromelain, a mixture of proteolytic enzymes typically derived from pineapple stem, decreases production of pro-inflammatory cytokines and leukocyte homing to sites of inflammation. We previously showed that short-term oral treatment with bromelain purified from pineapple stem decreased the severity of colonic inflammation in C57BL/6 Il10−/− mice with chronic colitis. Since fresh pineapple fruit contains similar bromelain enzymes but at different proportions, this study aimed to determine whether long-term dietary supplementation with pineapple (supplied as juice) could decrease colon inflammation and neoplasia in Il10−/− mice with chronic colitis as compared with bromelain derived from stem. Results Experimental mice readily consumed fresh pineapple juice at a level that generated mean stool proteolytic activities equivalent to 16 mg bromelain purified from stem, while control mice received boiled juice with inactive enzymes. Survival was increased in the group supplemented with fresh rather than boiled juice (p = 0.01). Mice that received fresh juice also had decreased histologic colon inflammation scores and a lower incidence of inflammation-associated colonic neoplasia (35% vs. 66%; p< 0.02), with fewer neoplastic lesions/colon (p = 0.05). Flow cytometric analysis of murine splenocytes exposed to fresh pineapple juice in vitro demonstrated proteolytic removal of cell surface molecules that can affect leukocyte trafficking and activation. Conclusions These results demonstrate that long-term dietary supplementation with fresh or unpasteurized frozen pineapple juice with proteolytically active bromelain enzymes is safe and decreases inflammation severity and the incidence and multiplicity of inflammation-associated colonic neoplasia in this commonly used murine model of inflammatory bowel disease. PMID:20848493

  4. Inflammation does not precede or accompany the induction of preneoplastic lesions in the colon of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-fed rats.

    PubMed

    Kühnel, Dana; Taugner, Felicitas; Scholtka, Bettina; Steinberg, Pablo

    2009-08-01

    Heterocyclic aromatic amines (HCAs) are formed in meat cooked at high temperatures for a long time or over an open flame. In this context 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant HCA in cooked meat, has been suggested to be involved in colon and prostate carcinogenesis. In the latter case it has been reported that: (1) roughly 50% of Fischer F344 male rats treated with PhIP develop carcinomas in the ventral prostate lobe at 1 year of age; (2) inflammation precedes prostatic intraepithelial neoplasia in PhIP-fed rats; (3) inflammation specifically occurs in the ventral prostate lobe of PhIP-fed rats. To test whether PhIP by itself leads to inflammation in the colon and whether a human-relevant concentration of PhIP is able to induce preneoplastic lesions in the colon, male F344 rats were fed 0.1 or 100 ppm PhIP for up to 10 months and thereafter the colon tissue was analyzed histochemically. In none of the experimental groups signs of acute or chronic colonic inflammation were observed. 0.1 ppm PhIP leads to the development of hyperplastic and dysplastic lesions in the colon of single animals, but the incidence of these lesions does not reach a statistical significance. In contrast, in rats fed 100 ppm PhIP for 10 months hyperplastic and dysplastic colonic lesions were induced in a statistically significant number of animals. It is concluded that: (1) the induction of preneoplastic lesions in rat colon by PhIP is not preceded or accompanied by an inflammatory process; (2) a human-relevant concentration of PhIP alone is not sufficient to initiate colon carcinogenesis in rats.

  5. 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.

  6. 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

  7. Glucosinolates from pak choi and broccoli induce enzymes and inhibit inflammation and colon cancer differently.

    PubMed

    Lippmann, Doris; Lehmann, Carsten; Florian, Simone; Barknowitz, Gitte; Haack, Michael; Mewis, Inga; Wiesner, Melanie; Schreiner, Monika; Glatt, Hansruedi; Brigelius-Flohé, Regina; Kipp, Anna P

    2014-06-01

    High consumption of Brassica vegetables is considered to prevent especially colon carcinogenesis. The content and pattern of glucosinolates (GSLs) can highly vary among different Brassica vegetables and may, thus, affect the outcome of Brassica intervention studies. Therefore, we aimed to feed mice with diets containing plant materials of the Brassica vegetables broccoli and pak choi. Further enrichment of the diets by adding GSL extracts allowed us to analyze the impact of different amounts (GSL-poor versus GSL-rich) and different patterns (broccoli versus pak choi) of GSLs on inflammation and tumor development in a model of inflammation-triggered colon carcinogenesis (AOM/DSS model). Serum albumin adducts were analyzed to confirm the up-take and bioactivation of GSLs after feeding the Brassica diets for four weeks. In agreement with their high glucoraphanin content, broccoli diets induced the formation of sulforaphane-lysine adducts. Levels of 1-methoxyindolyl-3-methyl-histidine adducts derived from neoglucobrassicin were the highest in the GSL-rich pak choi group. In the colon, the GSL-rich broccoli and the GSL-rich pak choi diet up-regulated the expression of different sets of typical Nrf2 target genes like Nqo1, Gstm1, Srxn1, and GPx2. GSL-rich pak choi induced the AhR target gene Cyp1a1 but did not affect Ugt1a1 expression. Both colitis and tumor number were drastically reduced after feeding the GSL-rich pak choi diet while the other three diets had no effect. GSLs can act anti-inflammatory and anti-carcinogenic but both effects depend on the specific amount and pattern of GSLs within a vegetable. Thus, a high Brassica consumption cannot be generally considered to be cancer-preventive.

  8. 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

  9. 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.

  10. 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

  11. Impact of bacterial colonization on the severity, and accompanying airway inflammation, of virus-induced wheezing in children.

    PubMed

    Yu, D; Wei, L; Zhengxiu, L; Jian, L; Lijia, W; Wei, L; Xiqiang, Y; Xiaodong, Z; Zhou, F; Enmei, L

    2010-09-01

    It is reported that bacterial colonization of the airway in neonates affects the likelihood and severity of subsequent wheezing in childhood. This study aimed to explore the impact of bacterial colonization on the severity of virus-induced wheezing, and accompanying airway inflammation. Nasopharyngeal aspirates (NPAs) from 68 hospitalized children with bronchiolitis and 85 children with recurrent wheezing were obtained. Eleven common respiratory viruses were sought by PCR and/or direct fluorescence assay. Bacteria were isolated from NPAs by routine culture methods. Cell numbers and concentrations of cytokines/chemokines in the NPAs were measured, and nucleated cells were characterized. The frequency of bacterial colonization in children with recurrent wheezing was significantly higher than in children with an initial attack of bronchiolitis. Bacterial colonization accompanying virus infection had no effect on clinical manifestations, duration of hospitalization, concentrations of cytokines/chemokines (except interleukin-10 (IL-10)) or cellularity in the children with bronchiolitis; however, among the children with recurrent wheezing, those who had coexistent non-invasive bacterial colonization and virus infection presented more frequent cyanosis, longer duration of hospitalization, a higher concentration of IL-10 and a higher percentage of neutrophils in NPAs than those with virus infection but without bacterial colonization. Bacterial colonization was common in children with virus-induced wheezing, particularly in the situation of recurrent wheezing. To some extent, bacterial colonization accompanying virus infection may contribute to the severity of the wheezing because of its impact on airway inflammation.

  12. 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

  13. Translocator Protein-Mediated Stabilization of Mitochondrial Architecture during Inflammation Stress in Colonic Cells

    PubMed Central

    Issop, Leeyah; Ostuni, Mariano A.; Lee, Sunghoon; Laforge, Mireille; Péranzi, Gabriel; Rustin, Pierre; Benoist, Jean-François; Estaquier, Jérome; Papadopoulos, Vassilios; Lacapère, Jean-Jacques

    2016-01-01

    Chronic inflammation of the gastrointestinal tract increasing the risk of cancer has been described to be linked to the high expression of the mitochondrial translocator protein (18 kDa; TSPO). Accordingly, TSPO drug ligands have been shown to regulate cytokine production and to improve tissue reconstruction. We used HT-29 human colon carcinoma cells to evaluate the role of TSPO and its drug ligands in tumor necrosis factor (TNF)-induced inflammation. TNF-induced interleukin (IL)-8 expression, coupled to reactive oxygen species (ROS) production, was followed by TSPO overexpression. TNF also destabilized mitochondrial ultrastructure, inducing cell death by apoptosis. Treatment with the TSPO drug ligand PK 11195 maintained the mitochondrial ultrastructure, reducing IL-8 and ROS production and cell death. TSPO silencing and overexpression studies demonstrated that the presence of TSPO is essential to control IL-8 and ROS production, so as to maintain mitochondrial ultrastructure and to prevent cell death. Taken together, our data indicate that inflammation results in the disruption of mitochondrial complexes containing TSPO, leading to cell death and epithelia disruption. Significance: This work implicates TSPO in the maintenance of mitochondrial membrane integrity and in the control of mitochondrial ROS production, ultimately favoring tissue regeneration. PMID:27054921

  14. 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

  15. Acute experimental distal colitis alters colonic transit in rats.

    PubMed

    Myers, B S; Dempsey, D T; Yasar, S; Martin, J S; Parkman, H P; Ryan, J P

    1997-04-01

    Data from humans with active distal colitis suggest that the proximal colon exhibits increased contractile activity and delayed transit, whereas the distal colon shows decreased contractile activity and rapid transit. The present study used the acetic acid rat model of experimental colitis to determine the effect of distal colitis on total and regional colonic transit in vivo and on the in vitro contractility of circular smooth muscle from the proximal and distal colon. Distal colitis was induced in rats by intracolonic administration of 4% acetic acid; sham control rats received saline enemas. Control and colitic rats were studied 2 days postenemas. Total colon transit was determined by calculating the geometric center of distribution of a radiolabeled marker (51Cr) instilled into the proximal colon. Regional transit was assessed by expressing the radioactivity in the cecum, proximal and distal colon, and excreted stool as a percent of total radioactivity. Muscle strips from the proximal and distal colon were stimulated with 100 microM acetylcholine (ACh) and 60 mM KCl and the tension was expressed as kilograms per square centimeter. Distal colitis was characterized by decreased total colon transit, increased retention of marker in the cecum and proximal colon, and decreased retention of marker in the distal colon. In vitro contractility studies revealed that distal colitis increased proximal colon circular smooth muscle contractility and decreased distal colon circular smooth muscle contractility to both ACh and potassium. Distal colitis is associated with regional differences in colonic circular smooth muscle contractility, which may contribute to delayed transit in the proximal colon and rapid transit in the distal colon.

  16. 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

  17. 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.

  18. WSES Guidelines for the management of acute left sided colonic diverticulitis in the emergency setting.

    PubMed

    Sartelli, Massimo; Catena, Fausto; Ansaloni, Luca; Coccolini, Federico; Griffiths, Ewen A; Abu-Zidan, Fikri M; Di Saverio, Salomone; Ulrych, Jan; Kluger, Yoram; Ben-Ishay, Ofir; Moore, Frederick A; Ivatury, Rao R; Coimbra, Raul; Peitzman, Andrew B; Leppaniemi, Ari; Fraga, Gustavo P; Maier, Ronald V; Chiara, Osvaldo; Kashuk, Jeffry; Sakakushev, Boris; Weber, Dieter G; Latifi, Rifat; Biffl, Walter; Bala, Miklosh; Karamarkovic, Aleksandar; Inaba, Kenji; Ordonez, Carlos A; Hecker, Andreas; Augustin, Goran; Demetrashvili, Zaza; Melo, Renato Bessa; Marwah, Sanjay; Zachariah, Sanoop K; Shelat, Vishal G; McFarlane, Michael; Rems, Miran; Gomes, Carlos Augusto; Faro, Mario Paulo; Júnior, Gerson Alves Pereira; Negoi, Ionut; Cui, Yunfeng; Sato, Norio; Vereczkei, Andras; Bellanova, Giovanni; Birindelli, Arianna; Di Carlo, Isidoro; Kok, Kenneth Y; Gachabayov, Mahir; Gkiokas, Georgios; Bouliaris, Konstantinos; Çolak, Elif; Isik, Arda; Rios-Cruz, Daniel; Soto, Rodolfo; Moore, Ernest E

    2016-01-01

    Acute left sided colonic diverticulitis is one of the most common clinical conditions encountered by surgeons in acute setting. A World Society of Emergency Surgery (WSES) Consensus Conference on acute diverticulitis was held during the 3rd World Congress of the WSES in Jerusalem, Israel, on July 7th, 2015. During this consensus conference the guidelines for the management of acute left sided colonic diverticulitis in the emergency setting were presented and discussed. This document represents the executive summary of the final guidelines approved by the consensus conference.

  19. MODEL OF COLONIC INFLAMMATION: IMMUNE MODULATORY MECHANISMS IN INFLAMMATORY BOWEL DISEASE

    PubMed Central

    Wendelsdorf, Katherine; Bassaganya-Riera, Josep; Hontecillas, Raquel; Eubank, Stephen

    2010-01-01

    Inflammatory Bowel Disease (IBD) is an immunoinflammatory illness of the gut initiated by an immune response to bacteria in the microflora. The resulting immunopathogenesis leads to lesions in epithelial lining of the colon through which bacteria may infiltrate the tissue causing recurring bouts of diarrhea, rectal bleeding, and mal-nutrition. In healthy individuals such immunopathogenesis is avoided by the presence of regulatory cells that inhibit the inflammatory pathway. Highly relevant to the search for treatment strategies is the identification of components of the inflammatory pathway that allow regulatory mechanisms to be overridden and immunopathogenesis to proceed. In vitro techniques have identified cellular interactions involved in inflammation-regulation crosstalk. However, tracing immunological mechanisms discovered at the cellular level confidently back to an in vivo context of multiple, simultaneous interactions has met limited success. To explore the impact of specific interactions, we have constructed a system of 29 ordinary differential equations representing different phenotypes of T-cells, macrophages, dendritic cells, and epithelial cells as they move and interact with bacteria in the lumen, lamina propria, and lymphoid tissue of the colon. Simulations revealed the positive inflammatory feedback loop formed by inflammatory M1 macrophage activation of T-cells as a driving force underlying the immunopathology of IBD. Furthermore, strategies that remove M1 from the site of infection, by either i) increasing its potential to switch to a regulatory M2 phenotype or ii) increasing the rate of reversion (for M1 and M2 alike) to a resting state, cease immunopathogenesis even as bacteria are eliminated by other inflammatory cells. Based on these results, we identify macrophages and their mechanisms of plasticity as key targets for mucosal inflammation intervention strategies. In addition, we propose that the primary mechanism behind the association of

  20. 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.

  1. Altered expression of Butyrophilin (BTN) and BTN‐like (BTNL) genes in intestinal inflammation and colon cancer

    PubMed Central

    Lebrero‐Fernández, Cristina; Wenzel, Ulf Alexander; Akeus, Paulina; Wang, Ying; Strid, Hans; Simrén, Magnus; Gustavsson, Bengt; Börjesson, Lars G.; Cardell, Susanna L.; Öhman, Lena; Quiding‐Järbrink, Marianne

    2016-01-01

    Abstract Several Butyrophilin (BTN) and Btn‐like (BTNL) molecules control T lymphocyte responses, and are genetically associated with inflammatory disorders and cancer. In this study, we present a comprehensive expression analysis of human and murine BTN and BTNL genes in conditions associated with intestinal inflammation and cancer. Using real‐time PCR, expression of human BTN and BTNL genes was analyzed in samples from patients with ulcerative colitis, irritable bowel syndrome, and colon tumors. Expression of murine Btn and Btnl genes was examined in mouse models of spontaneous colitis (Muc2 −/−) and intestinal tumorigenesis (Apc Min/+). Our analysis indicates a strong association of several of the human genes with ulcerative colitis and colon cancer; while especially BTN1A1, BTN2A2, BTN3A3, and BTNL8 were significantly altered in inflammation, colonic tumors exhibited significantly decreased levels of BTNL2, BTNL3, BTNL8, and BTNL9 as compared to unaffected tissue. Colonic inflammation in Muc2 −/− mice significantly down‐regulated the expression of particularly Btnl1, Btnl4, and Btnl6 mRNA, and intestinal polyps derived from Apc Min/+ mice displayed altered levels of Btn1a1, Btn2a2, and Btnl1 transcripts. Thus, our data present an association of BTN and BTNL genes with intestinal inflammation and cancer and represent a valuable resource for further studies of this gene family. PMID:27957327

  2. Quantification of inflammation in colonic tissue sections and wound healing in-vitro with digital holographic microscopy

    NASA Astrophysics Data System (ADS)

    Bettenworth, Dominik; Lenz, Philipp; Krausewitz, Philipp; Brückner, Markus; Ketelhut, Steffi; von Bally, Gert; Domagk, Dirk; Kemper, Björn

    2013-06-01

    We show that the tissue refractive index, obtained from quantitative digital holographic microscopy (DHM) phase contrast images of unstained histological colonic sections, is directly related to the degree of inflammation in experimental colitis. In addition, it is demonstrated that quantitative DHM phase contrast is capable to quantify in-vitro wound healing assays.

  3. ApoE deficiency promotes colon inflammation and enhances the inflammatory potential of oxidized-LDL and TNF-α in primary colon epithelial cells

    PubMed Central

    El-Bahrawy, Ali H.; Tarhuni, Abdelmetalab; Kim, Hogyoung; Subramaniam, Venkat; Benslimane, Ilyes; Elmajeed, Zakaria Y. Abd; Okpechi, Samuel C.; Ghonim, Mohamed A.; Hemeida, Ramadan A.M.; Abo-yousef, Amira M.; El-Sherbiny, Gamal A.; Abdel-Raheem, Ihab T.; Kim, Jong; Naura, Amarjit S.; Boulares, A. Hamid

    2016-01-01

    Although deficiency in Apolipoprotein E (ApoE) is linked to many diseases, its effect on colon homoeostasis remains unknown. ApoE appears to control inflammation by regulating nuclear factor-κB (NF-κB). The present study was designed to examine whether ApoE deficiency affects factors of colon integrity in vivo and given the likelihood that ApoE deficiency increases oxidized lipids and TNF-α, the present study also examined whether such deficiency enhances the inflammatory potential of oxidized-LDL (oxLDL) and TNF-α in colon epithelial cells (CECs), in vitro. Here we show that ApoE deficiency is associated with chronic inflammation systemically and in colonic tissues as assessed by TNF-α levels. Increased colon TNF-α mRNA coincided with a substantial increase in cyclooxygenase (COX)-2. ApoE deficiency enhanced the potential of oxLDL and TNF-α to induce COX-2 expression as well as several other inflammatory factors in primary CECs. Interestingly, oxLDL enhanced TGF-β expression only in ApoE−/−, but not in wild-type, epithelial cells. ApoE deficiency appears to promote COX-2 expression enhancement through a mechanism that involves persistent NF-κB nuclear localization and PI3 and p38 MAP kinases but independently of Src. In mice, ApoE deficiency promoted a moderate increase in crypt length, which was associated with opposing effects of an increase in cell proliferation and apoptosis at the bottom and top of the crypt respectively. Our results support the notion that ApoE plays a central role in colon homoeostasis and that ApoE deficiency may constitute a risk factor for colon pathologies. PMID:27538678

  4. Lactate dehydrogenase inhibitors can reverse inflammation induced changes in colon cancer cells.

    PubMed

    Manerba, Marcella; Di Ianni, Lorenza; Govoni, Marzia; Roberti, Marinella; Recanatini, Maurizio; Di Stefano, Giuseppina

    2017-01-01

    The inflammatory microenvironment is an essential component of neoplastic lesions and can significantly impact on tumor progression. Besides facilitating invasive growth, inflammatory cytokines were also found to reprogram cancer cell metabolism and to induce aerobic glycolysis. Previous studies did not consider the possible contribution played in these changes by lactate dehydrogenase (LDH). The A isoform of LDH (LDH-A) is the master regulator of aerobic glycolysis; it actively reduces pyruvate and causes enhanced lactate levels in tumor tissues. In cancer cells, lactate was recently found to directly increase migration ability; moreover, when released in the microenvironment, it can facilitate matrix remodeling. In this paper, we illustrate that treatment of human colon adenocarcinoma cells with TNF-α and IL-17, two pro-inflammatory cytokines, modifies LDH activity, causing a shift toward the A isoform which results in increased lactate production. At the same time, the two cytokines appeared to induce features of epithelial-mesenchymal transition in the treated cells, such as reduction of E-cadherin levels and increased secretion of metalloproteinases. Noteworthy, oxamate and galloflavin, two inhibitors of LDH activity which reduce lactate production in cells, were found to relieve the inflammation-induced effects. These results suggest LDH-A and/or lactate as common elements at the cross-road between cancer cell metabolism, tumor progression and inflammation. At present, LDH inhibitors suitable for clinical use are actively searched as possible anti-proliferative agents; our data lead to hypothesize for these compounds a wider potential in anticancer treatment.

  5. Acute colonic pseudo-obstruction (Ogilvie's syndrome) with caecal perforation after caesarean section

    PubMed Central

    Khajehnoori, Masoomeh; Nagra, Sonal

    2016-01-01

    Ogilvie syndrome or acute colonic pseudo-obstruction is characterized by acute dilatation of the colon usually involving caecum and right hemi-colon in the absence of any mechanical obstruction. It is usually associated with an underlying severe illness/infection or surgery, mostly caesarean section and rarely occurs spontaneously. Identification of this condition is important due to the increased risk of bowel ischaemia and perforation particularly with caecal diameter >9 cm. This is a case report of bowel perforation following caesarean section leading to urgent laparotomy. PMID:27554827

  6. American ginseng suppresses Western diet-promoted tumorigenesis in model of inflammation-associated colon cancer: role of EGFR

    PubMed Central

    2011-01-01

    Background Western diets increase colon cancer risk. Epidemiological evidence and experimental studies suggest that ginseng can inhibit colon cancer development. In this study we asked if ginseng could inhibit Western diet (20% fat) promoted colonic tumorigenesis and if compound K, a microbial metabolite of ginseng could suppress colon cancer xenograft growth. Methods Mice were initiated with azoxymethane (AOM) and, two weeks later fed a Western diet (WD, 20% fat) alone, or WD supplemented with 250-ppm ginseng. After 1 wk, mice received 2.5% dextran sulfate sodium (DSS) for 5 days and were sacrificed 12 wks after AOM. Tumors were harvested and cell proliferation measured by Ki67 staining and apoptosis by TUNEL assay. Levels of EGF-related signaling molecules and apoptosis regulators were determined by Western blotting. Anti-tumor effects of intraperitoneal compound K were examined using a tumor xenograft model and compound K absorption measured following oral ginseng gavage by UPLC-mass spectrometry. Effects of dietary ginseng on microbial diversity were measured by analysis of bacterial 16S rRNA. Results Ginseng significantly inhibited colonic inflammation and tumorigenesis and concomitantly reduced proliferation and increased apoptosis. The EGFR cascade was up-regulated in colonic tumors and ginseng significantly reduced EGFR and ErbB2 activation and Cox-2 expression. Dietary ginseng altered colonic microbial diversity, and bacterial suppression with metronidazole reduced serum compound K following ginseng gavage. Furthermore, compound K significantly inhibited tumor xenograft growth. Conclusions Ginseng inhibited colonic inflammation and tumorigenesis promoted by Western diet. We speculate that the ginseng metabolite compound K contributes to the chemopreventive effects of this agent in colonic tumorigenesis. PMID:22070864

  7. 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

  8. Colonic gene silencing using siRNA-loaded calcium phosphate/PLGA nanoparticles ameliorates intestinal inflammation in vivo.

    PubMed

    Frede, Annika; Neuhaus, Bernhard; Klopfleisch, Robert; Walker, Catherine; Buer, Jan; Müller, Werner; Epple, Matthias; Westendorf, Astrid M

    2016-01-28

    Cytokines and chemokines are predominant players in the progression of inflammatory bowel diseases. While systemic neutralization of these players with antibodies works well in some patients, serious contraindications and side effects have been reported. Therefore, the local interference of cytokine signaling mediated by siRNA-loaded nanoparticles might be a promising new therapeutic approach. In this study, we produced multi-shell nanoparticles consisting of a calcium phosphate (CaP) core coated with siRNA directed against pro-inflammatory mediators, encapsulated into poly(d,l-lactide-co-glycolide acid) (PLGA), and coated with a final outer layer of polyethyleneimine (PEI), for the local therapeutic treatment of colonic inflammation. In cell culture, siRNA-loaded CaP/PLGA nanoparticles exhibited a rapid cellular uptake, almost no toxicity, and an excellent in vitro gene silencing efficiency. Importantly, intrarectal application of these nanoparticles loaded with siRNA directed against TNF-α, KC or IP-10 to mice suffering from dextran sulfate sodium (DSS)-induced colonic inflammation led to a significant decrease of the target genes in colonic biopsies and mesenteric lymph nodes which was accompanied with a distinct amelioration of intestinal inflammation. Thus, this study provides evidence that the specific and local modulation of the inflammatory response by CaP/PLGA nanoparticle-mediated siRNA delivery could be a promising approach for the treatment of intestinal inflammation.

  9. Identification of urinary biomarkers of colon inflammation in IL10-/- mice using Short-Column LCMS metabolomics.

    PubMed

    Otter, Don; Cao, Mingshu; Lin, Hui-Ming; Fraser, Karl; Edmunds, Shelley; Lane, Geoff; Rowan, Daryl

    2011-01-01

    The interleukin-10-deficient (IL10(-/-)) mouse develops colon inflammation in response to normal intestinal microflora and has been used as a model of Crohn's disease. Short-Column LCMS metabolite profiling of urine from IL10(-/-) and wild-type (WT) mice was used, in two independent experiments, to identify mass spectral ions differing in intensity between these two genotypes. Three differential metabolites were identified as xanthurenic acid and as the glucuronides of xanthurenic acid and of α-CEHC (2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman). The significance of several differential metabolites as potential biomarkers of colon inflammation was evaluated in an experiment which compared metabolite concentrations in IL10(-/-) and WT mice housed, either under conventional conditions and dosed with intestinal microflora, or maintained under specific pathogen-free (SPF) conditions. Concentrations of xanthurenic acid, α-CEHC glucuronide, and an unidentified metabolite m/z 495(-)/497(+) were associated with the degree of inflammation in IL10(-/-) mice and may prove useful as biomarkers of colon inflammation.

  10. SHP-2 Phosphatase Prevents Colonic Inflammation by Controlling Secretory Cell Differentiation and Maintaining Host-Microbiota Homeostasis

    PubMed Central

    Coulombe, Geneviève; Langlois, Ariane; De Palma, Giada; Langlois, Marie-Josée; Mccarville, Justin L.; Gagné-Sanfaçon, Jessica; Perreault, Nathalie; Feng, Gen-Sheng; Bercik, Premysl; Boudreau, François; Verdu, Elena F.; Rivard, Nathalie

    2017-01-01

    Polymorphisms in the PTPN11 gene encoding for the tyrosine phosphatase SHP-2 were described in patients with ulcerative colitis. We have recently demonstrated that mice with an intestinal epithelial cell-specific deletion of SHP-2 (SHP-2IEC-KO) develop severe colitis 1 month after birth. However, the mechanisms by which SHP-2 deletion induces colonic inflammation remain to be elucidated. We generated SHP-2IEC-KO mice lacking Myd88 exclusively in the intestinal epithelium. The colonic phenotype was histologically analyzed and cell differentiation was determined by electron microscopy and lysozyme or Alcian blue staining. Microbiota composition was analyzed by 16S sequencing. Results show that innate defense genes including those specific to Paneth cells were strongly up-regulated in SHP-2-deficient colons. Expansion of intermediate cells (common progenitors of the Goblet and Paneth cell lineages) was found in the colon of SHP-2IEC-KO mice whereas Goblet cell number was clearly diminished. These alterations in Goblet/intermediate cell ratio were noticed 2 weeks after birth, before the onset of inflammation and were associated with significant alterations in microbiota composition. Indeed, an increase in Enterobacteriaceae and a decrease in Firmicutes were observed in the colon of these mice, indicating that dysbiosis also occurred prior to inflammation. Importantly, loss of epithelial Myd88 expression inhibited colitis development in SHP-2IEC-KO mice, rescued Goblet/intermediate cell ratio, and prevented NFκB hyperactivation and inflammation. These data indicate that SHP-2 is functionally important for the maintenance of appropriate barrier function and host-microbiota homeostasis in the large intestine. PMID:27100271

  11. LZ-207, a Newly Synthesized Flavonoid, Induces Apoptosis and Suppresses Inflammation-Related Colon Cancer by Inhibiting the NF-κB Signaling Pathway.

    PubMed

    Sun, Jie; Li, Fanni; Zhao, Yue; Zhao, Li; Qiao, Chen; Li, Zhiyu; Guo, Qinglong; Lu, Na

    2015-01-01

    Flavonoids and flavonoid derivatives, which have significant biological and pharmacological activities, including antitumor and anti-inflammatory activities, have been widely used in human healthcare. To design a more effective flavonoid antitumor agent, we altered the flavonoid backbone with substitutions of piperazine and methoxy groups to synthesize a novel flavonoid derivative, LZ-207. The anticancer effect of LZ-207 against HCT116 colon cancer cells and the underlying mechanism of this effect were explored in this study. Specifically, LZ-207 exhibited inhibitory effects on growth and viability in several human colon cancer cell lines and induced apoptosis in HCT116 cells both in vitro and in vivo. LZ-207 treatment also suppressed the nuclear translocation of NF-κB and the phosphorylation of IκB and IKKα/β in a dose-dependent manner in both HCT116 cells and human acute monocytic leukemia THP-1 cells. Moreover, LZ-207 also reduced the secretion of the pro-inflammatory cytokine interleukin-6 (IL-6) in LPS-induced THP-1 cells, and this effect was confirmed at the transcriptional level. Furthermore, LZ-207 significantly inhibited HCT116 cell proliferation that was elicited by LPS-induced THP-1 cells in a co-culture system. These findings elucidated some potential molecular mechanisms for preventing inflammation-driven colon cancer using the newly synthesized flavonoid LZ-207 and suggested the possibility of further developing novel therapeutic agents derived from flavonoids.

  12. 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

  13. 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.

  14. Tumor necrosis factor (TNF)-neuropeptide Y (NPY) crosstalk regulates inflammation, epithelial barrier functions and colonic motility

    PubMed Central

    Chandrasekharan, Bindu; Jeppsson, Sabrina; Pienkowski, Stefan; Belsham, Denise D; Sitaraman, Shanthi V.; Merlin, Didier; Kokkotou, Efi; Nusrat, Asma; Tansey, Malu G.; Srinivasan, Shanthi

    2014-01-01

    Background Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is up regulated in the enteric nervous system (ENS) during murine colitis, and that NPY knockout mice exhibit reduced inflammation. Here we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main pro-inflammatory cytokine. Methods Utilizing primary enteric neurons and colon explant cultures from WT and NPY knockout (NPY−/−) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, utilizing the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only). Results We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY−/− mice produced less TNF compared to WT. Further, TNF activated NPY promoter in enteric neurons via phospho-c-jun. NPY−/− mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability via phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF-inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared to etanercept. Conclusions We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF maybe a better therapeutic option than using anti-TNF antibodies. PMID:24108115

  15. Campylobacter jejuni Colonization Is Associated with a Dysbiosis in the Cecal Microbiota of Mice in the Absence of Prominent Inflammation

    PubMed Central

    Lone, Abdul G.; Selinger, L. Brent; Uwiera, Richard R. E.; Xu, Yong; Inglis, G. Douglas

    2013-01-01

    Background Campylobacter jejuni causes enterocolitis in humans, but does not incite disease in asymptomatic carrier animals. To survive in the intestine, C. jejuni must successfully compete with the microbiota and overcome the host immune defense. Campylobacter jejuni colonization success varies considerably amongst individual mice, and we examined the degree to which the intestinal microbiota was affected in mice (i.e. a model carrier animal) colonized by C. jejuni at high relative to low densities. Methods Mice were inoculated with C. jejuni or buffer, and pathogen shedding and intestinal colonization were measured. Histopathologic scoring and quantification of mRNA expression for α-defensins, toll-like receptors, and cytokine genes were conducted. Mucosa-associated bacterial communities were characterized by two approaches: multiplexed barcoded pyrosequencing and terminal restriction fragment length polymorphism analysis. Results Two C. jejuni treatments were established based on the degree of cecal and colonic colonization; C. jejuni Group A animals were colonized at high cell densities, and C. jejuni Group B animals were colonized at lower cell densities. Histological examination of cecal and colonic tissues indicated that C. jejuni did not incite visible pathologic changes. Although there was no significant difference among treatments in expression of mRNA for α-defensins, toll-like receptors, or cytokine genes, a trend for increased expression of toll-like receptors and cytokine genes was observed for C. jejuni Group A. The results of the two methods to characterize bacterial communities indicated that the composition of the cecal microbiota of C. jejuni Group A mice differed significantly from C. jejuni Group B and Control mice. This difference was due to a reduction in load, diversity and richness of bacteria associated with the cecal mucosa of C. jejuni Group A mice. Conclusions High density colonization by C. jejuni is associated with a dysbiosis in

  16. Acute and chronic effects of rat colon after photodynamic therapy and radiotherapy: a comparative study

    NASA Astrophysics Data System (ADS)

    Sassy, T.; Breiter, N.; Sroka, Ronald; Ernst, Helmut

    1994-03-01

    After clinical photodynamic therapy (PDT) and radiotherapy (RT) of the colon carcinoma acute and late damages on adjacent normal tissue were seen. Therefore it was the aim of this experimental study to investigate these damages on normal colon tissue of rats after PDT in comparison with RT. Within the first hours after PDT the endoscopic examination showed a severe acute damage. The histopathological examination showed that the acute ulceration depends on the energy density applied within the first three days. This study indicates different progresses of acute effects after PDT and RT, respectively. Late damages were observed only by RT in contrast to PDT. Synthetic diet prevents acute damages after PDT. However, the synthetic diet after RT can prevent the late damage for the duration of the diet administration.

  17. Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis

    PubMed Central

    Aherne, CM; Saeedi, B; Collins, CB; Masterson, JC; McNamee, EN; Perrenoud, L; Rapp, CR; Curtis, VF; Bayless, A; Fletcher, A; Glover, LE; Evans, CM; Jedlicka, P; Furuta, GT; de Zoeten, EF; Colgan, SP; Eltzschig, HK

    2015-01-01

    Central to inflammatory bowel disease (IBD) pathogenesis is loss of mucosal barrier function. Emerging evidence implicates extracellular adenosine signaling in attenuating mucosal inflammation. We hypothesized that adenosine-mediated protection from intestinal barrier dysfunction involves tissue-specific signaling through the A2B adenosine receptor (Adora2b) at the intestinal mucosal surface. To address this hypothesis, we combined pharmacologic studies and studies in mice with global or tissue-specific deletion of the Adora2b receptor. Adora2b−/− mice experienced a significantly heightened severity of colitis, associated with a more acute onset of disease and loss of intestinal epithelial barrier function. Comparison of mice with Adora2b deletion on vascular endothelial cells (Adora2bfl/flVeCadCre+) or intestinal epithelia (Adora2bfl/flVillinCre+) revealed a selective role for epithelial Adora2b signaling in attenuating colonic inflammation. In vitro studies with Adora2b knockdown in intestinal epithelial cultures or pharmacologic studies highlighted Adora2b-driven phosphorylation of vasodilator-stimulated phosphoprotein (VASP) as a specific barrier repair response. Similarly, in vivo studies in genetic mouse models or treatment studies with an Adora2b agonist (BAY 60-6583) recapitulate these findings. Taken together, our results suggest that intestinal epithelial Adora2b signaling provides protection during intestinal inflammation via enhancing mucosal barrier responses. PMID:25850656

  18. 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.

  19. Association between chronic liver and colon inflammation during the development of murine syngeneic graft-versus-host disease

    PubMed Central

    Brandon, J. Anthony; Perez, Jacqueline; Jennings, C. Darrell; Cohen, Donald A.; Sindhava, V. J.; Bondada, S.; Kaplan, Alan M.

    2010-01-01

    The murine model of cyclosporine A (CsA)-induced syngeneic graft-versus-host disease (SGVHD) is a bone marrow (BM) transplantation model that develops chronic colon inflammation identical to other murine models of CD4+ T cell-mediated colitis. Interestingly, SGVHD animals develop chronic liver lesions that are similar to the early peribiliary inflammatory stages of clinical chronic liver disease, which is frequently associated with inflammatory bowel disease (IBD). Therefore, studies were initiated to investigate the chronic liver inflammation that develops in the SGVHD model. To induce SGVHD, mice were lethally irradiated, reconstituted with syngeneic BM, and treated with CsA. All of the SGVHD animals that developed colitis also develop chronic liver inflammation. Liver samples from control and SGVHD animals were monitored for tissue pathology, RNA for inflammatory mediators, and phenotypic analysis and in vitro reactivity of the inflammatory infiltrate. Diseased animals developed lesions of intrahepatic and extrahepatic bile ducts. Elevated levels of mRNA for molecules associated with chronic liver inflammation, including mucosal cellular adhesion molecule −1, the chemokines CCL25, CCL28, CCR9, and TH1- and TH17-associated cytokines were observed in livers of SGVHD mice. CD4+ T cells were localized to the peribiliary region of the livers of diseased animals, and an enhanced proliferative response of liver-associated mononuclear cells against colonic bacterial antigens was observed. The murine model of SGVHD colitis may be a valuable tool to study the entero-hepatic linkage between chronic colon inflammation and inflammatory liver disease. PMID:20634434

  20. Soy protein concentrate mitigates markers of colonic inflammation and loss of gut barrier function in vitro and in vivo.

    PubMed

    Bitzer, Zachary T; Wopperer, Amy L; Chrisfield, Benjamin J; Tao, Ling; Cooper, Timothy K; Vanamala, Jairam; Elias, Ryan J; Hayes, John E; Lambert, Joshua D

    2017-02-01

    Whereas a number of studies have examined the effects of soy isoflavones and tocopherols on colonic inflammation, few have examined soy protein. We determined the radical scavenging and cytoprotective effects of soy protein concentrate (SPC) in vitro and its anti-inflammatory effects in dextran sulfate sodium (DSS)-treated mice. Cotreatment with SPC protected Caco-2 human colon cells from H2O2-induced cell death and mitigated intracellular oxidative stress. Treatment of differentiated Caco-2 cells with SPC blunted DSS-induced increases in monolayer permeability. Pepsin/pancreatin-digested SPC had reduced radical scavenging activity, but retained the monolayer protective effects of SPC. In vivo, 1.5% DSS caused body weight loss, colon shortening, and splenomegaly in CF-1 mice. Co-treatment with 12% SPC mitigated DSS-induced body weight loss and splenomegaly. DSS increased colonic interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1 expression. The levels of these markers were significantly lower in mice co-treated with SPC. SPC prevented DSS-mediated reductions in colonic glucagon-like peptide 2 levels, suggesting that SPC can prevent loss of gut barrier function, but no significant effect on claudin 1 and occludin mRNA levels of was observed. SPC-treated mice had lower colonic mRNA expression of toll-like receptor 4 and nucleotide-binding oligomerization domain-containing protein-like receptor family, pyrin domain containing protein 3 (NLRP3), and lower caspase-1 enzyme activity than DSS-treated mice. In summary, SPC exerted antioxidant and cytoprotective effects in vitro and moderated the severity of DSS-induced inflammation and loss of gut barrier function in vivo. These effects appear to be mediated in part through reduced NLRP3 expression and caspase 1 activity.

  1. Management of acute perioperative myocardial infarction: a case report of concomitant acute myocardial infarction and tumor bleeding in the transverse colon

    PubMed Central

    Li, Yu-Feng; Gao, Wen-Qian; Li, Yuan-Xin; Feng, Quan-Zhou; Zhu, Ping

    2016-01-01

    Acute myocardial infarction complicated by bleeding colon tumor is problematic with regard to management, and appropriate balance of antiplatelet or anticoagulation therapy and hemostasis or surgery is crucial for effective treatment. Here, we present a case of concomitant acute myocardial infarction and bleeding tumor in the transverse colon, and share our experience of successfully balancing anticoagulation therapy and hemostasis. PMID:26937182

  2. 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.

  3. 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

  4. 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.

  5. White and dark kidney beans reduce colonic mucosal damage and inflammation in response to dextran sodium sulfate.

    PubMed

    Monk, Jennifer M; Zhang, Claire P; Wu, Wenqing; Zarepoor, Leila; Lu, Jenifer T; Liu, Ronghua; Pauls, K Peter; Wood, Geoffrey A; Tsao, Rong; Robinson, Lindsay E; Power, Krista A

    2015-07-01

    Common beans are a rich source of nondigestible fermentable components and phenolic compounds that have anti-inflammatory effects. We assessed the gut-health-promoting potential of kidney beans in healthy mice and their ability to attenuate colonic inflammation following dextran sodium sulphate (DSS) exposure (via drinking water, 2% DSS w/v, 7 days). C57BL/6 mice were fed one of three isocaloric diets: basal diet control (BD), or BD supplemented with 20% cooked white (WK) or dark red kidney (DK) bean flour for 3 weeks. In healthy mice, anti-inflammatory microbial-derived cecal short chain fatty acid (SCFA) levels (acetate, butyrate and propionate), colon crypt height and colonic Mucin 1 (MUC1) and Resistin-like Molecule beta (Relmβ) mRNA expression all increased in WK- and DK-fed mice compared to BD, indicative of enhanced microbial activity, gut barrier integrity and antimicrobial defense response. During colitis, both bean diets reduced (a) disease severity, (b) colonic histological damage and (c) increased mRNA expression of antimicrobial and barrier integrity-promoting genes (Toll-like Receptor 4 (TLR4), MUC1-3, Relmβ and Trefoil Factor 3 (TFF3)) and reduced proinflammatory mediator expression [interleukin (IL)-1β, IL-6, interferon (IFN)γ, tumor necrosis factor (TNF)α and monocyte chemoattractant protein-1], which correlated with reduced colon tissue protein levels. Further, bean diets exerted a systemic anti-inflammatory effect during colitis by reducing serum levels of IL-17A, IFNγ, TNFα, IL-1β and IL-6. In conclusion, both WK and DK bean-supplemented diets enhanced microbial-derived SCFA metabolite production, gut barrier integrity and the microbial defensive response in the healthy colon, which supported an anti-inflammatory phenotype during colitis. Collectively, these data demonstrate a beneficial colon-function priming effect of bean consumption that mitigates colitis severity.

  6. 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.

  7. Colonization of CF patients' upper airways with S. aureus contributes more decisively to upper airway inflammation than P. aeruginosa.

    PubMed

    Janhsen, Wibke Katharina; Arnold, Christin; Hentschel, Julia; Lehmann, Thomas; Pfister, Wolfgang; Baier, Michael; Böer, Klas; Hünniger, Kerstin; Kurzai, Oliver; Hipler, Uta-Christina; Mainz, Jochen Georg

    2016-10-01

    In cystic fibrosis (CF) patients' airways, inflammatory processes decisively contribute to remodeling and pulmonary destruction. The aims of this study were to compare upper airway (UAW) inflammation in the context of Staphylococcus aureus and Pseudomonas aeruginosa colonization in a longitudinal setting, and to examine further factors influencing UAW inflammation. Therefore, we analyzed soluble inflammatory mediators in noninvasively obtained nasal lavage (NL) of CF patients together with microbiology, medication, and relevant clinical parameters. NL, applying 10 mL of isotonic saline per nostril, was serially performed in 74 CF patients (326 samples). Concentrations of the inflammatory mediators' interleukin (IL)-1β, IL-6, IL-8, matrix metalloproteinase (MMP)-9, and its anti-protease TIMP-1 were quantified by bead-based multiplexed assay, neutrophil elastase (NE) via ELISA. Culture-based microbiology of the upper and lower airways (LAW), as well as serological and clinical findings, were compiled. Our results indicate that UAW colonization with S. aureus significantly impacts the concentration of all measured inflammatory mediators in NL fluid except TIMP-1, whereas these effects were not significant for P. aeruginosa. Patients with S. aureus colonization of both the UAW and LAW showed significantly increased concentrations of IL-1β, IL-6, IL-8, MMP-9, and slightly elevated concentrations of NE in NL fluid compared to non-colonized patients. This work elaborates a survey on S. aureus' virulence factors that may contribute to this underestimated pathology. Serial assessment of epithelial lining fluid by NL reveals that colonization of the UAW with S. aureus contributes more to CF airway inflammatory processes than hitherto expected.

  8. [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.

  9. New Trends in Acute Management of Colonic Diverticular Bleeding

    PubMed Central

    Cirocchi, Roberto; Grassi, Veronica; Cavaliere, Davide; Renzi, Claudio; Tabola, Renata; Poli, Giulia; Avenia, Stefano; Farinella, Eleonora; Arezzo, Alberto; Vettoretto, Nereo; D’Andrea, Vito; Binda, Gian Andrea; Fingerhut, Abe

    2015-01-01

    Abstract Colonic diverticular disease is the most common cause of lower gastrointestinal bleeding. In the past, this condition was usually managed with urgent colectomy. Recently, the development of endoscopy and interventional radiology has led to a change in the management of colonic diverticular bleeding. The aim of this systematic review is to define the best treatment for colonic diverticular bleeding. A systematic bibliographic research was performed on the online databases for studies (randomized controlled trials [RCTs], observational trials, case series, and case reports) published between 2005 and 2014, concerning patients admitted with a diagnosis of diverticular bleeding according to the PRISMA methodology. The outcomes of interest were: diagnosis of diverticulosis as source of bleeding; incidence of self-limiting diverticular bleeding; management of non self-limiting bleeding (endoscopy, angiography, surgery); and recurrent diverticular bleeding. Fourteen studies were retrieved for analysis. No RCTs were found. Eleven non-randomized clinical controlled trials (NRCCTs) were included in this systematic review. In all studies, the definitive diagnosis of diverticular bleeding was always made by urgent colonoscopy. The colonic diverticular bleeding stopped spontaneously in over 80% of the patients, but a re-bleeding was not rare. Recently, interventional endoscopy and angiography became the first-line approach, thus relegating emergency colectomy to patients presenting with hemodynamic instability or as a second-line treatment after failure or complications of hemostasis with less invasive treatments. Colonoscopy is effective to diagnose diverticular bleeding. Nowadays, interventional endoscopy and angiographic treatment have gained a leading role and colectomy should only be entertained in case of failure of the former. PMID:26554768

  10. Toxic Megacolon and Acute Ischemia of the Colon due to Sigmoid Stenosis Related to Diverticulitis

    PubMed Central

    Antonopoulos, P.; Almyroudi, M.; Kolonia, V.; Kouris, S.; Troumpoukis, N.; Economou, N.

    2013-01-01

    We present a rare case of toxic megacolon accompanied by necrosis of the colon due to chronic dilation caused by stenosis of the sigmoid colon as a complication of diverticulitis. The patient presented at the emergency department with diffuse abdominal pain, fever (38.8°C) and tachycardia (120 beats/min). Physical examination revealed distension and tenderness on deep palpation on the left lower quadrant without peritoneal signs. Abdominal computed tomography showed located stenosis in the sigmoid colon and marked dilation of the descending (12 cm diameter) and transverse (7.5 cm diameter) colon. A few hours later, the patient developed severe septic shock with electrolyte abnormalities. He had a history of two prior admissions to our hospital due to crises of acute diverticulitis. Based on Jalan's criteria the diagnosis was compatible with toxic megacolon. The patient's condition deteriorated suddenly and an emergency colectomy was performed. The operative findings revealed a necrotic colon. Histology examination confirmed the diagnosis of ischemia of the colon. To our knowledge this is the first published report in the literature which refers to a rare complication of diverticulitis, namely chronic stenosis which complicated to colonic ischemia and toxic megacolon. PMID:24163654

  11. Hypokalemia associated with acute colonic pseudo-obstruction in an ESRD patient.

    PubMed

    Boobés, Khaled; Rosa, Robert M; Batlle, Daniel

    2017-03-01

    Ogilvie's syndrome, or acute colonic pseudo-obstruction, is characterized by massive dilation of the colon without mechanical obstruction. Water and electrolytes often can be sequestered in the dilated intestinal loops resulting in profuse and watery diarrhea as well as hypokalemia. We report an anuric, end-stage renal disease (ESRD) patient undergoing peritoneal dialysis (PD) who developed acute colonic pseudo-obstruction causing a prolonged hospitalization. He also developed severe hypokalemia with a serum potassium (K+) as low as 2.4 mEq/L and required 180 - 240 mEq of potassium chloride per day for more than a month to correct it. While PD K+ losses often contribute to hypokalemia, the PD K+ loss was estimated to be only 39 mEq/day. Therefore, PD could only contribute modestly to the recalcitrant hypokalemia observed during the episode of pseudo-obstruction. It has been shown, however, that patients with colonic pseudo-obstruction have enhanced colonic K+ secretion. In addition, experimental studies in patients with chronic kidney disease (CKD) have demonstrated that colonic K+ excretion can be up to 3 times greater than in individuals with normal renal function. This increase may involve an upregulation of the large conductance K+ channel (maxi-K), also known as the BK channel, in the apical border of the colonocytes. We suggest that ESRD may have placed our patient at a greater risk of developing hypokalemia as his colon may have already adapted to secrete more K+. Clinicians should be aware of this extrarenal K+ wasting etiology in patients with colonic pseudo-obstruction, particularly in those with CKD where such a severe K+ deficit is not anticipated and, therefore, may inhibit more rigorous K+ replacement.

  12. Acute abdomen secondary to complete tubular colonic duplication

    PubMed Central

    Castejón-Casado, Javier; Muñoz Miguelsanz, MA; Diaz, E. Moreno; Gomez, M. Garcia; Garcia, MA Padilla; Valade, R. Fernandez

    2014-01-01

    We report the case of a 6-month-old infant who presented with a complete duplication of the large intestine, debuting clinically with acute abdomen and severe metabolic disorders. We discuss the pathogenesis and morphology of the lesions, diagnostic difficulties and peculiarities of surgical treatment. PMID:25197196

  13. 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.

  14. 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

  15. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression.

    PubMed

    Neufert, Clemens; Becker, Christoph; Neurath, Markus F

    2007-01-01

    Colorectal cancer is a life-threatening disease that can develop spontaneously or as a complication of inflammatory bowel diseases. Mouse models are essential tools for the preclinical testing of novel therapeutic options in vivo. Here, we provide a highly reliable protocol for an experimental mouse model to study the development of colon cancers. It is based on the mutagenic agent azoxymethane (AOM), which exerts colonotropic carcinogenicity. Repeated intraperitoneal administration of AOM results in the development of spontaneous tumors within 30 weeks. As an alternative option, inflammation-dependent tumor growth can be investigated by combining the administration of AOM with the inflammatory agent dextran sodium sulfate in drinking water, which causes rapid growth of multiple colon tumors per mouse within 10 weeks. Different scoring systems including number of tumors and tumor size identify factors promoting or inhibiting tumor initiation and/or tumor progression, respectively.

  16. Retroperitoneal abscess and acute acalculous cholecystitis after iatrogenic colon injury: report of a case

    PubMed Central

    Dong, Chengwei; Wang, Yuxu; Hu, Sanyuan; Du, Futian; Ding, Wei

    2015-01-01

    Acute acalculous cholecystitis has a high mortality rate due to the difficulties in early diagnosis and high rate of complications like empyema, gangrene and perforation. We report a case of 20-year-old male with acute severe pancreatitis, acute renal failure and acute peripancreatic fluid collection who was transferred to our department after blood filtration treatment in ICU. After percutaneous catheter drainage for 20 hours, the patient got a high fever. Computed tomography revealed retroperitoneal colon injury. In this case, percutaneous catheter drainage was performed again and the pus cavity was flushed regularly, after which the patient’s state gradually improved. Unpredictably, septic shock appeared on the 51st day. Repeated computed tomography revealed acute acalculous cholecystitis and abscess formation. After percutaneous transhepatic gallbladder catheterization and drainage, the patient got better gradually. Three months later the retroperitoneal catheter was removed. Four months later, ultrasound examination showed normal gallbladder and the catheter was removed. PMID:26131252

  17. Voluntary exercise prevents colonic inflammation in high-fat diet-induced obese mice by up-regulating PPAR-γ activity

    SciTech Connect

    Liu, Wei-Xin; Wang, Ting; Zhou, Feng; Wang, Ying; Xing, Jun-Wei; Zhang, Shen; Gu, Shou-Zhi; Sang, Li-Xuan; Dai, Cong; Wang, Hai-Lan

    2015-04-10

    Obesity is associated with increased colonic inflammation, which elevates the risk of colon cancer. Although exercise exerts anti-inflammatory actions in multiple chronic diseases associated with inflammation, it is unknown whether this strategy prevents colonic inflammation in obesity. We hypothesized that voluntary exercise would suppress colonic inflammation in high-fat diet (HFD)-induced obesity by modulation of peroxisome proliferator-activated receptor (PPAR)-γ. Male C57Bl/6J mice fed either a control diet (6.5% fat, CON) or a high-fat diet (24% fat, HFD) were divided into sedentary, voluntary exercise or voluntary exercise with PPAR-γ antagonist GW9662 (10 mg/kg/day). All interventions took place for 12 weeks. Compared with CON-sedentary group, HFD-sedentary mice gained significantly more body weight and exhibited metabolic disorders. Molecular studies revealed that HFD-sedentary mice had increased expression of inflammatory mediators and activation of nuclear factor (NF)-κB in the colons, which were associated with decreased expression and activity of PPAR-γ. Voluntary exercise markedly attenuated body weight gain, improved metabolic disorders, and normalized the expression of inflammatory mediators and activation of NF-κB in the colons in HFD-mice while having no effects in CON-animals. Moreover, voluntary exercise significantly increased expression and activity of PPAR-γ in the colons in both HFD- and CON-animals. However, all of these beneficial effects induced by voluntary exercise were abolished by GW9662, which inhibited expression and activity of PPAR-γ. The results suggest that decreased PPAR-γ activity in the colon of HFD-induced obesity may facilitate the inflammatory response and colon carcinogenesis. Voluntary exercise prevents colonic inflammation in HFD-induced obesity by up-regulating PPAR-γ activity. - Highlights: • Obesity down-regulates PPAR-γ in the colon. • Down-regulated colonic PPAR-γ may facilitate inflammatory

  18. Influence of NleH effector expression, host genetics, and inflammation on Citrobacter rodentium colonization of mice.

    PubMed

    Feuerbacher, Leigh Ann; Hardwidge, Philip R

    2014-05-01

    The Escherichia coli NleH1 and NleH2 virulence proteins differentially regulate host transcription of innate immunity genes. The mouse pathogen Citrobacter rodentium encodes one NleH protein, which functions equivalently to E. coli NleH1. We examined the impact of host genetics and intestinal inflammation on the contribution of NleH to C. rodentium colonization of mice differing in LPS responsiveness. NleH expression was detrimental to C. rodentium in C57BL/10ScNJ mice, which do not mount LPS-induced inflammatory responses. This phenotype was reversed if inflammation was induced by chemical means. C. rodentium that expressed both E. coli NleH1 and NleH2 was hypervirulent in C3H/HeJ mice.

  19. Acute on chronic pancreatitis causing a highway to the colon with subsequent road closure: pancreatic colonic fistula presenting as a large bowel obstruction treated with pancreatic duct stenting.

    PubMed

    Cochrane, Justin; Schlepp, Greg

    2015-01-01

    Context. Colonic complications associated with acute pancreatitis have a low incidence but carry an increased risk of mortality with delayed diagnosis and treatment. Pancreatic colonic fistula is most commonly associated with walled off pancreatic necrosis or abscess formation and rarely forms spontaneously. Classic clinical manifestations for pancreatic colonic fistula include diarrhea, hematochezia, and fever. Uncommonly pancreatic colonic fistula presents as large bowel obstruction. Case. We report a case of a woman with a history of recurrent episodes of acute pancreatitis who presented with large bowel obstruction secondary to pancreatic colonic fistula. Resolution of large bowel obstruction and pancreatic colonic fistula was achieved with pancreatic duct stenting. Conclusion. Pancreatic colonic fistula can present as large bowel obstruction. Patients with resolved acute pancreatitis who have radiographic evidence of splenic flexure obstruction, but without evidence of mechanical obstruction on colonoscopy, should be considered for ERCP to evaluate for PCF. PCF not associated with walled off pancreatic necrosis or peritoneal abscess can be treated conservatively with pancreatic duct stenting.

  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. Phosalone-induced inflammation and oxidative stress in the colon: Evaluation and treatment

    PubMed Central

    Ghasemi-Niri, Seyedeh Farnaz; Maqbool, Faheem; Baeeri, Maryam; Gholami, Mahdi; Abdollahi, Mohammad

    2016-01-01

    AIM: To investigate the side effects of phosalone on intestinal cells and to evaluate benefits of ellagic acid (EA) as a remedy. METHODS: In order to conduct an in vivo study, a rat model was used. The rats were divided into ten groups based on the materials used in the experiment and their dosage. The first group was fed normally. The second group was administered EA through gavage. Next Four groups were given (1/3, 1/5, 1/10, 1/20) LD50 phosalone; an organophosphorus compound. The last four groups received (1/3, 1/5, 1/10, 1/20) LD50 phosalone and of EA. After one month, the rats were sacrificed and their colon cells were examined to evaluate the level of inflammation, proteins and oxidative stress markers. RESULTS: The results of this research show that phosalone elevates oxidative stress and changes the level of tumor necrosis factor-a (TNF-α), interlukin-6β (IL-6β) and nuclear factor (NF)-κB proteins. EA administration reduced phosalone toxicity and changed oxidative stress and inflammatory markers for all phosalone doses. Overall changes in reduction of TNF-α (230.47 ± 16.55 pg/mg protein vs 546.43 ± 45.24 pg/mg protein, P < 0.001), IL-6β (15.85 ± 1.03 pg/mg protein vs 21.55 ± 1.3 pg/mg protein, P < 0.05), and NF-κB (32.47 ± 4.85 pg/mg protein vs 51.41 ± 0.71 pg/mg protein, P < 0.05) manifest that the efficacy of EA is more viable for 1/3 LD50 dose of phosalone. Furthermore, EA is effective to counteract the negative outcomes of oxidative stress. When EA was used to treat 1/3 LD50 of phosalone’s side effects, it improved the level of AChE activity (48.5% ± 6% vs 25% ± 7%, P < 0.05), TTM (0.391 ± 0.008 mmol/L vs 0.249 ± 0.032 mmol/L, P < 0.05), FRAP (46.04 ± 5.005 μmol/L vs 18.22 ± 1.9 μmol/L, P < 0.01) and MPO (0.222 ± 0.019 U/mg protein vs 0.387 ± 0.04 U/mg protein, P < 0.05). CONCLUSION: This research highlights that EA is effective to alleviate the side effects of phosalone by reducing the level of oxidative stress and inflammatory

  2. 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.

  3. Burden of meticillin-resistant Staphylococcus aureus colonization and infection in London acute hospitals: retrospective on a voluntary surveillance programme.

    PubMed

    Mumtaz, S; Bishop, L A; Wright, A L; Kanfoudi, L; Duckworth, G; Fraser, G G

    2011-12-01

    Although meticillin-resistant Staphylococcus aureus (MRSA) is recognized as an important cause of hospital and community healthcare-associated morbidity, and colonization as a precursor to infection, few studies have attempted to assess the burden of both colonization and infection across acute healthcare providers within a defined health economy. This study describes the prevalence and incidence of MRSA colonization and infection in acute London hospital Trusts participating in a voluntary surveillance programme in 2000-2001. Hospital infection control staff completed a weekly return including details on incident and prevalent colonizations, bacteraemias and other significant infections due to MRSA. Incidence and prevalence rates were calculated for hospitals with sufficient participation across both years. Colonizations accounted for 79% of incident MRSA cases reported; 4% were bacteraemias, and 17% other significant infections. There was no change in incidence of colonization of hospital patients between 2000 and 2001. By contrast, there was an unexplained 49% increase in prevalence of colonizations over this period. For any given month, prevalent colonizations outnumbered incident colonizations at least twofold. This MRSA surveillance programme was unusual for prospective ascertainment of incident and prevalent cases of both colonization and infection within an English regional health economy. Consistent with other studies, the incidence and prevalence of colonization substantially exceeded infection. Given the small contribution of bacteraemias to the overall MRSA burden, and the surveillance, screening and control interventions of recent years, it may be appropriate to review the present reliance on bacteraemia surveillance.

  4. 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

  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. 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. Pneumocystis colonization, airway inflammation, and pulmonary function decline in acquired immunodeficiency syndrome.

    PubMed

    Norris, Karen A; Morris, Alison; Patil, Sangita; Fernandes, Eustace

    2006-01-01

    As a result of improved diagnosis, treatment, and supportive care for HIV-infected patients, AIDS in developed countries has now become a chronic infection with prolonged survival time, but longterm complications are increasing contributors to morbidity and mortality. HIV-infected patients are at increased risk for the development of pulmonary complications, including chronic obstructive pulmonary disease (COPD); however, the mechanisms associated with this increased susceptibility have not been defined. Infectious agents may contribute to the development of COPD by upregulating inflammatory mediators in the lung that act in concert with cigarette smoke to promote lung pathology. Studies in human subjects and non-human primate models of AIDS suggest that the inflammatory response to asymptomatic carriage or colonization by the opportunistic pathogen, Pneumocystis sp. (Pc), is similar to that of COPD, which is characterized by influx of CD8+ T cells, neutrophils, and macrophages into the lungs. We have shown a high frequency of Pc colonization among asymptomatic HIV-infected subjects and in non-HIV infected subjects with COPD. To investigate the role of Pc in the progression of obstructive lung disease in HIV infections, we developed a non-human primate model of Pc colonizatoin and infection in simian immunodeficiency virus (SIV)-infected macaques. These animals develop a prolonged colonization state characterized by a persistent influx of CD8+ T cells and neutrophils, and local increases in IL-8, IFN-gamma, and TNF-alpha. SIV-infected Pc-colonized monkeys show progressive decline in pulmonary function compared to SIV-infected monkeys. We hypothesize that in the context of AIDS-immune dysfunction, Pc colonization induces inflammatory responses leading to changes in pulmonary function and architecture similar to that seen in emphysema. Information gained from these studies will lead to the development of interventions to prevent lung injury associated with Pc

  8. A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis.

    PubMed

    Deng, Lin; Zhou, Jin-Feng; Sellers, Rani S; Li, Jiu-Feng; Nguyen, Andrew V; Wang, Yubao; Orlofsky, Amos; Liu, Qiang; Hume, David A; Pollard, Jeffrey W; Augenlicht, Leonard; Lin, Elaine Y

    2010-02-01

    Inflammatory bowel disease (IBD) is a high-risk condition for human colorectal cancer. However, our mechanistic understanding of the link between inflammation and tumorigenesis in the colon is limited. Here we established a novel mouse model of colitis-associated cancer by genetically inactivating signal transducer and activator of transcription 3 (Stat3) in macrophages, with partial deletion in other myeloid and lymphoid cells. Inflammation developed in the colon of mutant mice spontaneously, and tumor lesions, including invasive carcinoma, arose in the inflamed region of the intestine with a frequency similar to that observed in human IBD patients. The development of both inflammation and tumors in the mutant mice required the presence of microflora. Indeed, inflammation was associated with disruption of colonic homeostasis, fulminant epithelial/tumor cell proliferation, and activation of the mammalian target of rapamycin (mTOR)-Stat3 pathway in epithelial and tumor cells. The activation of this pathway was essential for both the excess proliferation of epithelial/tumor cells and the disruption of colonic homeostasis in the mutant mice. Notably, a similar abnormal up-regulation of mTOR-Stat3 signaling was consistently observed in the colonic epithelial cells of human IBD patients with active disease. These studies demonstrate a novel mouse model of IBD-colorectal cancer progression in which disrupted immune regulation, mTOR-Stat3 signaling, and epithelial hyperproliferation are integrated and simultaneously linked to the development of malignancy.

  9. A Novel Mouse Model of Inflammatory Bowel Disease Links Mammalian Target of Rapamycin-Dependent Hyperproliferation of Colonic Epithelium to Inflammation-Associated Tumorigenesis

    PubMed Central

    Deng, Lin; Zhou, Jin-Feng; Sellers, Rani S.; Li, Jiu-Feng; Nguyen, Andrew V.; Wang, Yubao; Orlofsky, Amos; Liu, Qiang; Hume, David A.; Pollard, Jeffrey W.; Augenlicht, Leonard; Lin, Elaine Y.

    2010-01-01

    Inflammatory bowel disease (IBD) is a high-risk condition for human colorectal cancer. However, our mechanistic understanding of the link between inflammation and tumorigenesis in the colon is limited. Here we established a novel mouse model of colitis-associated cancer by genetically inactivating signal transducer and activator of transcription 3 (Stat3) in macrophages, with partial deletion in other myeloid and lymphoid cells. Inflammation developed in the colon of mutant mice spontaneously, and tumor lesions, including invasive carcinoma, arose in the inflamed region of the intestine with a frequency similar to that observed in human IBD patients. The development of both inflammation and tumors in the mutant mice required the presence of microflora. Indeed, inflammation was associated with disruption of colonic homeostasis, fulminant epithelial/tumor cell proliferation, and activation of the mammalian target of rapamycin (mTOR)-Stat3 pathway in epithelial and tumor cells. The activation of this pathway was essential for both the excess proliferation of epithelial/tumor cells and the disruption of colonic homeostasis in the mutant mice. Notably, a similar abnormal up-regulation of mTOR-Stat3 signaling was consistently observed in the colonic epithelial cells of human IBD patients with active disease. These studies demonstrate a novel mouse model of IBD-colorectal cancer progression in which disrupted immune regulation, mTOR-Stat3 signaling, and epithelial hyperproliferation are integrated and simultaneously linked to the development of malignancy. PMID:20042677

  10. 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

  11. Farnesol attenuates 1,2-dimethylhydrazine induced oxidative stress, inflammation and apoptotic responses in the colon of Wistar rats.

    PubMed

    Khan, Rehan; Sultana, Sarwat

    2011-07-15

    Colon cancer is the major health hazard related with high mortality and it is a pathological consequence of persistent oxidative stress and inflammation. Farnesol, an isoprenoid alcohol, has been shown to possess antioxidant, anti-inflammatory and chemopreventive properties. The present study was performed to evaluate the protective efficacy of farnesol against 1,2-dimethylhydrazine (DMH) induced oxidative stress, inflammatory response and apoptotic tissue damage. Farnesol was administered once daily for seven consecutive days at the doses of 50 and 100 mg/kg body weight in corn oil. On day 7, a single injection of DMH was given subcutaneously in the groin at the dose of 40 mg/kg body weight. Protective effects of farnesol were assessed by using caspase-3 activity, tissue lipid peroxidation (LPO) and antioxidant status as end point markers. Further strengthening was evident on histopathological observations used to assess the protective efficacy of farnesol. Prophylactic treatment with farnesol significantly ameliorates DMH induced oxidative damage by diminishing the tissue LPO accompanied by increase in enzymatic viz., superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and quinone reductase (QR) and non-enzymatic viz., reduced glutathione (GSH) antioxidant status. Farnesol supplementation significantly decreased caspase-3 activity in colonic tissue. Histological findings also revealed that pretreatment with farnesol significantly reduced the severity of submucosal edema, regional destruction of the mucosal layer and intense infiltration of the inflammatory cells in mucosal and submucosal layers of the colon. The data of the present study suggest that farnesol effectively suppress DMH induced colonic mucosal damage by ameliorating oxidative stress, inflammatory and apoptotic responses.

  12. Long-term outcomes of palliative colonic stenting versus emergency surgery for acute proximal malignant colonic obstruction: a multicenter trial

    PubMed Central

    Siddiqui, Ali; Cosgrove, Natalie; Yan, Linda H.; Brandt, Daniel; Janowski, Raymond; Kalra, Ankush; Zhan, Tingting; Baron, Todd H.; Repici, Allesandro; Taylor, Linda Jo; Adler, Douglas. G.

    2017-01-01

    Background and study aims Long-term data are limited regarding clinical outcomes of self-expanding metal stents as an alternative for surgery in the treatment of acute proximal MBO. The aim of this study was to compare the long-term outcomes of stenting to surgery for palliation in patients with incurable obstructive CRC for lesions proximal to the splenic flexure. Patients and methods Retrospective multicenter cohort study of obstructing proximal CRC patients with who underwent insertion of a SEMS (n = 69) or surgery (n = 36) from 1999 to 2014. The primary endpoint was relief of obstruction. Secondary endpoints included technical success, duration of hospital stay, early and late adverse events (AEs) and survival. Results Technical success was achieved in 62/69 (89.8 %) patients in the SEMS group and in 36 /36 (100 %) patients who underwent surgery (P = 0.09). In the SEMS group, 10 patients underwent stenting as a bridge to surgery and 59 underwent stent placement for palliation. Clinical relief was achieved in 78 % of patients with stenting and in 100 % of patients who underwent surgery (P < 0.001). Patients with SEMS had significantly less acute AEs compared to the surgery group (7.2 % vs. 30.5 %, P = 0.003). Hospital mortality for the SEMS group was 0 % compared to 5.6 % in the surgery group (P = 0.11). Patients in the SEMS group had a significantly shorter median hospital stay (4 days) as compared to the surgery group (8 days) (P < 0.01). Maintenance of decompression without the recurrence of bowel obstruction until death or last follow-up was lower in the SEMS group (73.9 %) than the surgery group (97.3 %; P = 0.003). SEMS placement was associated with higher long-term complication rates compared to surgery (21 % and 11 % P = 0.27). Late SEMS AEs included occlusion (10 %), migration (5 %), and colonic ulcer (6 %). At 120 weeks, survival in the SEMS group was 5.6 % vs. 0 % in the

  13. Comparison of sesion severity, distribution, and colonic mucin expression in pigs with acute swine dysentery following oral inoculation with "Brachyspira hampsonii" or Brachyspira hyodysenteriae.

    PubMed

    Wilberts, B L; Arruda, P H; Kinyon, J M; Madson, D M; Frana, T S; Burrough, E R

    2014-11-01

    Swine dysentery is classically associated with infection by Brachyspira hyodysenteriae, the only current officially recognized Brachyspira sp. that consistently imparts strong beta-hemolysis on blood agar. Recently, several strongly beta-hemolytic Brachyspira have been isolated from swine with clinical dysentery that are not identified as B. hyodysenteriae by PCR including the recently proposed species "Brachyspira hampsonii." In this study, 6-week-old pigs were inoculated with either a clinical isolate of "B. hampsonii" (EB107; n = 10) clade II or a classic strain of B. hyodysenteriae (B204; n = 10) to compare gross and microscopic lesions and alterations in colonic mucin expression in pigs with clinical disease versus controls (n = 6). Gross lesions were similar between infected groups. No histologic difference was observed between infected groups with regard to neutrophilic inflammation, colonic crypt depth, mucosal ulceration, or hemorrhage. Histochemical and immunohistochemical evaluation of the apex of the spiral colon revealed decreased expression of sulphated mucins, decreased expression of MUC4, and increased expression of MUC5AC in diseased pigs compared to controls. No difference was observed between diseased pigs in inoculated groups. This study reveals significant alterations in colonic mucin expression in pigs with acute swine dysentery and further reveals that these and other microscopic changes are similar following infection with "B. hampsonii" clade II or B. hyodysenteriae.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. SMAD4 haploinsufficiency associates with augmented colonic inflammation in select humans and mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    SMAD4 is a common mediator of the TGF-beta signaling pathway. One of the members of this pathway, TGF-beta 1, has an important role in controlling gut inflammation in relation to the continuous stimulation of the intestinal microbiota. SMAD4 haploinsufficiency in humans has been linked to juvenile p...

  1. 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.

  2. 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

  3. 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.

  4. Polyphenol metabolites from colonic microbiota exert anti-inflammatory activity on different inflammation models.

    PubMed

    Larrosa, Mar; Luceri, Cristina; Vivoli, Elisa; Pagliuca, Chiara; Lodovici, Maura; Moneti, Gloriano; Dolara, Piero

    2009-08-01

    The polyphenols in fruits and vegetables may be partly responsible for the health-promoting effects attributed to fruit and vegetable intake. Although their properties have been relatively well studied, the activity of their metabolites, produced after ingestion, has been poorly investigated. Thus, the aim of this work was to study the potential anti-inflammatory effect of 18 polyphenol metabolites, derived from colon microbiota. They were screened by measuring prostaglandin E(2) (PGE(2)) production by CCD-18 colon fibroblast cells stimulated with IL-1beta. Metabolites that inhibited more than 50% PGE(2) production were hydrocaffeic (HCAF), dihydroxyphenyl acetic (dOHPA), and hydroferulic acid (HFER), that subsequently were tested with the writhing and paw pressure test in rodents where all three compounds showed an anti-inflammatory effect. The effect of HCAF administered orally (50 mg/kg) was also tested in the dextran sodium sulfate (DSS)-induced colitis model. Weight loss and fecal water content were more pronounced in DSS rats than in DSS-HCAF treated rats. HCAF treatment diminished the expression of the cytokines IL-1beta, IL-8, and TNF-alpha, reduced malonyldialdehyde (MDA) levels and oxidative DNA damage (measured as 8-oxo-2'-deoxyguanosine levels) in distal colon mucosa. These results indicate that HCAF, dOHPA, and HFER have anti-inflammatory activity in vitro and in vivo.

  5. Erdosteine prevents colonic inflammation through its antioxidant and free radical scavenging activities.

    PubMed

    Sener, Göksel; Aksoy, Halil; Sehirli, Ozer; Yüksel, Meral; Aral, Cenk; Gedik, Nursal; Cetinel, Sule; Yeğen, Berrak C

    2007-09-01

    After intracolonic administration of trinitrobenzene sulphonic acid (TNBS), Sprague-Dawley rats were treated orally either with saline or erdosteine (100 mg/kg per day), a sulfhydryl-containing antioxidant, for 3 days. On the 4th day, rats were decapitated and distal colon was removed for the macroscopic and microscopic damage scoring, for the measurement of malondialdehyde (MDA), glutathione (GSH) and collagen levels, myeloperoxidase (MPO) activity, luminol and lucigenin chemiluminescence (CL) and DNA fragmentation. Lactate dehydrogenase (LDH) activity, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and antioxidant capacity were assayed in blood samples. Colitis caused significant increases in the colonic CL values, macroscopic and microscopic damage scores, MDA and collagen levels, MPO activity and DNA fragmentation, along with a significant decrease in tissue GSH level. Similarly, serum cytokines and LDH were elevated in the saline-treated colitis group as compared with the control group. On the other hand, erdosteine treatment reversed all these biochemical indices, and histopathologic alterations induced by TNBS, suggesting that erdosteine protects the colonic tissue via its radical scavenging and antioxidant activities.

  6. Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria.

    PubMed

    Turner, Natalie; Wong, Hui-Li; Templeton, Arnoud; Tripathy, Sagarika; Whiti Rogers, Te; Croxford, Matthew; Jones, Ian; Sinnathamby, Mathuranthakan; Desai, Jayesh; Tie, Jeanne; Bae, Susie; Christie, Michael; Gibbs, Peter; Tran, Ben

    2016-02-01

    In Stage II colon cancer, multiple independent studies have shown that a dense intratumoural immune infiltrate (local inflammation) is associated with improved outcomes, while systemic inflammation, measured by various markers, has been associated with poorer outcomes. However, previous studies have not considered the interaction between local and systemic inflammation, nor have they assessed the type of inflammatory response compared with standard clinicopathologic criteria. In order to evaluate the potential clinical utility of inflammatory markers in Stage II colon cancer, we examined local and systemic inflammation in a consecutive series of patients with resected Stage II colon cancer between 2000 and 2010 who were identified from a prospective clinical database. Increased intratumoural chronic inflammatory cell (CIC) density, as assessed by pathologist review of hematoxylin and eosin stained slides, was used to represent local inflammation. Neutrophil-to-lymphocyte ratio (NLR) >5, as calculated from pre-operative full blood counts, was used to represent systemic inflammation. In 396 eligible patients identified, there was a non-significant inverse relationship between local and systemic inflammation. Increased CIC density was significantly associated with improved overall (HR 0.45, p = 0.001) and recurrence-free survival (HR 0.37, p = 0.003). High NLR was significantly associated with poorer overall survival (HR 2.56, p < 0.001). The combination of these markers further stratified prognosis independent of standard high-risk criteria, with a dominant systemic inflammatory response (low CIC/high NLR) associated with the worst outcome (5-year overall survival 55.8%). With further validation this simple, inexpensive combined inflammatory biomarker might assist in patient selection for adjuvant chemotherapy in Stage II colon cancer.

  7. 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

  8. GEN-27, a Newly Synthetic Isoflavonoid, Inhibits the Proliferation of Colon Cancer Cells in Inflammation Microenvironment by Suppressing NF-κB Pathway.

    PubMed

    Wang, Yajing; Lu, Ping; Zhang, Weifeng; Du, Qianming; Tang, Jingjing; Wang, Hong; Lu, Jinrong; Hu, Rong

    2016-01-01

    Nonresolving inflammation is one of the consistent features of the tumor microenvironment in the intestine and plays a critical role in the initiation and development of colon cancer. Here we reported the inhibitory effects of GEN-27, a new derivative of genistein, on the inflammation-related colon cancer cell proliferation and delineated the mechanism of its action. The results indicated that GEN-27 inhibited the proliferation of human colon tumor HCT116 cells stimulated by culture supernatants of LPS-induced human monocytes THP-1 cells and significantly decreased LPS-induced secretion of proinflammatory cytokines interleukin-6 and interleukin-1β in THP-1 cells. The HCT116 cell proliferation elicited by THP-1-conditioned medium could be blocked by the interleukin-1 receptor antagonist (IL-1RA). Further mechanistic study revealed that GEN-27 remarkably inhibited the nuclear translocation of NF-κB and phosphorylation of IκB and IKKα/β in both HCT116 and THP-1 cells. In addition, GEN-27 markedly suppressed the HCT116 cell proliferation stimulated by IL-1β treatment, which was dependent on the inhibition of NF-κB/p65 nuclear localization, as verified by p65 overexpression and BAY 11-7082, an NF-κB inhibitor. Taken together, our findings established that GEN-27 modulated NF-κB signaling pathway involved in inflammation-induced cancer cells proliferation and therefore could be a potential chemopreventive agent against inflammation-associated colon cancer.

  9. Changes in composition of caecal microbiota associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species.

    PubMed

    Bassett, Shalome A; Young, Wayne; Barnett, Matthew P G; Cookson, Adrian L; McNabb, Warren C; Roy, Nicole C

    2015-03-11

    Human inflammatory bowel disease (IBD) is a chronic intestinal disease where the resident microbiota contributes to disease development, yet the specific mechanisms remain unclear. Interleukin-10 gene-deficient (Il10-/-) mice develop inflammation similar to IBD, due in part to an inappropriate response to commensal bacteria. We have previously reported changes in intestinal morphology and colonic gene expression in Il10-/- mice in response to oral bacterial inoculation. In this study, we aimed to identify specific changes in the caecal microbiota associated with colonic inflammation in these mice. The microbiota was evaluated using pyrotag sequencing, denaturing gradient gel electrophoresis (DGGE) and quantitative real-time PCR. Microbiota profiles were influenced by genotype of the mice and by bacterial inoculation, and a strong correlation was observed between the microbiota and colonic inflammation scores. Although un-inoculated Il10-/- and C57 mice had similar microbiota communities, bacterial inoculation resulted in different changes to the microbiota in Il10-/- and C57 mice. Inoculated Il10-/- mice had significantly less total bacteria than un-inoculated Il10-/- mice, with a strong negative correlation between total bacterial numbers, relative abundance of Escherichia/Shigella, microbiota diversity, and colonic inflammation score. Our results show a putative causative role for the microbiota in the development of IBD, with potentially key roles for Akkermansia, or for Bacteroides, Helicobacter, Parabacteroides, and Alistipes, depending on the composition of the bacterial inoculum. These data support the use of bacterially-inoculated Il10-/- mice as an appropriate model to investigate human IBD.

  10. Colonic inflammation and enhanced-beta-catenin signaling accompany an increase of the Lachnospiraceae/Streptococcaceae in the hind gut of high-fat diet-fed mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Consumption of an obesigenic / high-fat (HF) diet is associated with an increase of inflammation-related colon cancer risk and may alter the gut microbiota. To test the hypothesis that a HF feeding accelerates inflammatory processes and changes gut microbiome composition, C57BL/6 mice were fed a HF ...

  11. Apple Flavonoid Phloretin Inhibits Escherichia coli O157:H7 Biofilm Formation and Ameliorates Colon Inflammation in Rats ▿ †

    PubMed Central

    Lee, Jin-Hyung; Regmi, Sushil Chandra; Kim, Jung-Ae; Cho, Moo Hwan; Yun, Hyungdon; Lee, Chang-Soo; Lee, Jintae

    2011-01-01

    Pathogenic biofilms have been associated with persistent infections due to their high resistance to antimicrobial agents, while commensal biofilms often fortify the host's immune system. Hence, controlling biofilm formation of both pathogenic bacteria and commensal bacteria is important in bacterium-related diseases. We investigated the effect of plant flavonoids on biofilm formation of enterohemorrhagic Escherichia coli O157:H7. The antioxidant phloretin, which is abundant in apples, markedly reduced E. coli O157:H7 biofilm formation without affecting the growth of planktonic cells, while phloretin did not harm commensal E. coli K-12 biofilms. Also, phloretin reduced E. coli O157:H7 attachment to human colon epithelial cells. Global transcriptome analyses revealed that phloretin repressed toxin genes (hlyE and stx2), autoinducer-2 importer genes (lsrACDBF), curli genes (csgA and csgB), and dozens of prophage genes in E. coli O157:H7 biofilm cells. Electron microscopy confirmed that phloretin reduced fimbria production in E. coli O157:H7. Also, phloretin suppressed the tumor necrosis factor alpha-induced inflammatory response in vitro using human colonic epithelial cells. Moreover, in the rat model of colitis induced by trinitrobenzene sulfonic acid (TNBS), phloretin significantly ameliorated colon inflammation and body weight loss. Taken together, our results suggest that the antioxidant phloretin also acts as an inhibitor of E. coli O157:H7 biofilm formation as well as an anti-inflammatory agent in inflammatory bowel diseases without harming beneficial commensal E. coli biofilms. PMID:21930760

  12. Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease.

    PubMed

    Hale, Laura P; Greer, Paula K; Trinh, Chau T; Gottfried, Marcia R

    2005-08-01

    Bromelain is a mixture of proteinases derived from pineapple stem that is marketed in health food stores as a "digestive aid". Orally administered bromelain was anecdotally reported to induce clinical and endoscopic remission of ulcerative colitis in two patients whose disease was refractory to multi-agent conventional medical therapy. However, the potential efficacy of bromelain in colitis has not yet been tested rigorously in either animals or humans. In this study, the clinical and histologic severity of inflammatory bowel disease (IBD) was determined in IL-10-/- mice treated orally with bromelain in vivo. Daily treatment with oral bromelain beginning at age 5 weeks decreased the incidence and severity of spontaneous colitis in C57BL/6 IL-10-/- mice. Bromelain also significantly decreased the clinical and histologic severity of colonic inflammation when administered to piroxicam-exposed IL-10-/- mice with established colitis. Proteolytically active bromelain was required for anti-inflammatory effects in vivo. Adverse effects of dermatitis, hair loss, and weight loss due to mucositis were rare, dose related, and were not seen in wild-type mice treated orally with up to 1000 mg bromelain/kg/day for 18 weeks. Although the exact mechanisms by which exogenous proteinases affect bowel inflammation have not yet been determined, the results justify additional studies of this complementary biologically based approach to treatment of IBD.

  13. Association of TLR4 and Treg in Helicobacter pylori Colonization and Inflammation in Mice

    PubMed Central

    Jing, Lei; Liu, Dongsheng; Hu, Sijun; Liu, Wei; Zhou, Nanjin; Xie, Yong

    2016-01-01

    The host immune response plays an important role in the pathogenesis of Helicobacter pylori infection. The aim of this study was to clarify the immune pathogenic mechanism of Helicobacter pylori infection via TLR signaling and gastric mucosal Treg cells in mice. To discover the underlying mechanism, we selectively blocked the TLR signaling pathway and subpopulations of regulatory T cells in the gastric mucosa of mice, and examined the consequences on H. pylori infection and inflammatory response as measured by MyD88, NF-κB p65, and Foxp3 protein expression levels and the levels of Th1, Th17 and Th2 cytokines in the gastric mucosa. We determined that blocking TLR4 signaling in H. pylori infected mice decreased the numbers of Th1 and Th17 Treg cells compared to controls (P < 0.001–0.05), depressed the immune response as measured by inflammatory grade (P < 0.05), and enhanced H. pylori colonization (P < 0.05). In contrast, blocking CD25 had the opposite effects, wherein the Th1 and Th17 cell numbers were increased (P < 0.001–0.05), immune response was enhanced (P < 0.05), and H. pylori colonization was inhibited (P < 0.05) compared to the non-blocked group. In both blocked groups, the Th2 cytokine IL-4 remained unchanged, although IL-10 in the CD25 blocked group was significantly decreased (P < 0.05). Furthermore, MyD88, NF-κB p65, and Foxp3 in the non-blocked group were significantly lower than those in the TLR4 blocked group (P < 0.05), but significantly higher than those of the CD25 blocked group (P < 0.05). Together, these results suggest that there might be an interaction between TLR signaling and Treg cells that is important for limiting H. pylori colonization and suppressing the inflammatory response of infected mice. PMID:26901645

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. Acute Inflammation

    MedlinePlus

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  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. Inflammation increases NOTCH1 activity via MMP9 and is counteracted by Eicosapentaenoic Acid-free fatty acid in colon cancer cells.

    PubMed

    Fazio, Chiara; Piazzi, Giulia; Vitaglione, Paola; Fogliano, Vincenzo; Munarini, Alessandra; Prossomariti, Anna; Milazzo, Maddalena; D'Angelo, Leonarda; Napolitano, Manuela; Chieco, Pasquale; Belluzzi, Andrea; Bazzoli, Franco; Ricciardiello, Luigi

    2016-02-11

    Aberrant NOTCH1 signalling is critically involved in multiple models of colorectal cancer (CRC) and a prominent role of NOTCH1 activity during inflammation has emerged. Epithelial to Mesenchymal Transition (EMT), a crucial event promoting malignant transformation, is regulated by inflammation and Metalloproteinase-9 (MMP9) plays an important role in this process. Eicosapentaenoic Acid (EPA), an omega-3 polyunsaturated fatty acid, was shown to prevent colonic tumors in different settings. We recently found that an extra-pure formulation of EPA as Free Fatty Acid (EPA-FFA) protects from colon cancer development in a mouse model of Colitis-Associated Cancer (CAC) through modulation of NOTCH1 signalling. In this study, we exposed colon cancer cells to an inflammatory stimulus represented by a cytokine-enriched Conditioned Medium (CM), obtained from THP1-differentiated macrophages. We found, for the first time, that CM strongly up-regulated NOTCH1 signalling and EMT markers, leading to increased invasiveness. Importantly, NOTCH1 signalling was dependent on MMP9 activity, upon CM exposure. We show that a non-cytotoxic pre-treatment with EPA-FFA antagonizes the effect of inflammation on NOTCH1 signalling, with reduction of MMP9 activity and invasiveness. In conclusion, our data suggest that, in CRC cells, inflammation induces NOTCH1 activity through MMP9 up-regulation and that this mechanism can be counteracted by EPA-FFA.

  15. Inflammation increases NOTCH1 activity via MMP9 and is counteracted by Eicosapentaenoic Acid-free fatty acid in colon cancer cells

    PubMed Central

    Fazio, Chiara; Piazzi, Giulia; Vitaglione, Paola; Fogliano, Vincenzo; Munarini, Alessandra; Prossomariti, Anna; Milazzo, Maddalena; D’Angelo, Leonarda; Napolitano, Manuela; Chieco, Pasquale; Belluzzi, Andrea; Bazzoli, Franco; Ricciardiello, Luigi

    2016-01-01

    Aberrant NOTCH1 signalling is critically involved in multiple models of colorectal cancer (CRC) and a prominent role of NOTCH1 activity during inflammation has emerged. Epithelial to Mesenchymal Transition (EMT), a crucial event promoting malignant transformation, is regulated by inflammation and Metalloproteinase-9 (MMP9) plays an important role in this process. Eicosapentaenoic Acid (EPA), an omega-3 polyunsaturated fatty acid, was shown to prevent colonic tumors in different settings. We recently found that an extra-pure formulation of EPA as Free Fatty Acid (EPA-FFA) protects from colon cancer development in a mouse model of Colitis-Associated Cancer (CAC) through modulation of NOTCH1 signalling. In this study, we exposed colon cancer cells to an inflammatory stimulus represented by a cytokine-enriched Conditioned Medium (CM), obtained from THP1-differentiated macrophages. We found, for the first time, that CM strongly up-regulated NOTCH1 signalling and EMT markers, leading to increased invasiveness. Importantly, NOTCH1 signalling was dependent on MMP9 activity, upon CM exposure. We show that a non-cytotoxic pre-treatment with EPA-FFA antagonizes the effect of inflammation on NOTCH1 signalling, with reduction of MMP9 activity and invasiveness. In conclusion, our data suggest that, in CRC cells, inflammation induces NOTCH1 activity through MMP9 up-regulation and that this mechanism can be counteracted by EPA-FFA. PMID:26864323

  16. 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

  17. Cocoa polyphenols prevent inflammation in the colon of azoxymethane-treated rats and in TNF-α-stimulated Caco-2 cells.

    PubMed

    Rodríguez-Ramiro, Ildefonso; Ramos, Sonia; López-Oliva, Elvira; Agis-Torres, Angel; Bravo, Laura; Goya, Luis; Martín, Maria Angeles

    2013-07-28

    Numerous lines of evidence support a relationship between intestinal inflammation and cancer. Therefore, much attention has recently been focused on the identification of natural compounds with anti-inflammatory activities as a strategy to suppress the early stages of colorectal cancer. Because cocoa is a rich source of bioactive compounds, the present study investigated its anti-inflammatory properties in a rat model of azoxymethane (AOM)-induced colon carcinogenesis and in TNF-α-stimulated Caco-2 cells. A total of forty male rats were fed with control or cocoa-enriched diets (12 %) during 8 weeks and injected with saline or AOM (20 mg/kg body weight) during the third and fourth week (n 10 rats/group). At the end of the experiment, colon samples were evaluated for markers of inflammation. The anti-inflammatory activity of a cocoa polyphenolic extract (10 μg/ml) was examined in TNF-α-stimulated Caco-2 cells, an in vitro model of experimentally induced intestinal inflammation. The signalling pathways involved, including NF-κB and the mitogen-activated protein kinase family such as c-Jun NH₂-terminal kinases (JNK), extracellular signal-regulated kinases and p38, were also evaluated. The results show that the cocoa-rich diet decreases the nuclear levels of NF-κB and the expression of pro-inflammatory enzymes such as cyclo-oxygenase-2 and inducible NO synthase induced by AOM in the colon. Additionally, the experiments in Caco-2 cells confirm that cocoa polyphenols effectively down-regulate the levels of inflammatory markers induced by TNF-α by inhibiting NF-κB translocation and JNK phosphorylation. We conclude that cocoa polyphenols suppress inflammation-related colon carcinogenesis and could be promising in the dietary prevention of intestinal inflammation and related cancer development.

  18. Therapeutic targeting of inflammation and tryptophan metabolism in colon and gastrointestinal cancer.

    PubMed

    Santhanam, Srikanth; Alvarado, David M; Ciorba, Matthew A

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death in the United States. Cytotoxic therapies cause significant adverse effects for most patients and do not offer cure in many advanced cases of CRC. Immunotherapy is a promising new approach to harness the body's own immune system and inflammatory response to attack and clear the cancer. Tryptophan metabolism along the kynurenine pathway (KP) is a particularly promising target for immunotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) is the most well studied of the enzymes that initiate this pathway and it is commonly overexpressed in CRC. Herein, we provide an in-depth review of how tryptophan metabolism and KP metabolites shape factors important to CRC pathogenesis including the host mucosal immune system, pivotal transcriptional pathways of neoplastic growth, and luminal microbiota. This pathway's role in other gastrointestinal (GI) malignancies such as gastric, pancreatic, esophageal, and GI stromal tumors is also discussed. Finally, we highlight how currently available small molecule inhibitors and emerging methods for therapeutic targeting of IDO1 might be applied to colon, rectal, and colitis-associated cancer.

  19. Therapeutic targeting of inflammation and tryptophan metabolism in colon and gastrointestinal cancer

    PubMed Central

    Santhanam, Srikanth; Alvarado, David M.; Ciorba, Matthew A.

    2015-01-01

    Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death in the United States. Cytotoxic therapies cause significant side effects for most patients and do not offer cure in many advanced cases of CRC. Immunotherapies are a promising new approach to harness the body’s own immune system and inflammatory response to attack and clear the cancer. Tryptophan metabolism along the kynurenine pathway is a particularly promising target for immunotherapy. Indoleamine 2,3 dioxygenase 1 (IDO1) is the most well studied of the enzymes that initiate this pathway and it is commonly overexpressed in CRC. Herein, we provide an in-depth review of how tryptophan metabolism and kynurenine pathway metabolites shape factors important to CRC pathogenesis including the host mucosal immune system, pivotal transcriptional pathways of neoplastic growth and luminal microbiota. This pathway’s role in other gastrointestinal malignancies such as gastric, pancreatic, esophageal and gastrointestinal stromal tumors (GIST) is also discussed. Finally, we highlight how currently available small molecule inhibitors and emerging methods for therapeutic targeting of IDO1 might be applied to colon, rectal and colitis associated cancer. PMID:26297050

  20. 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.

  1. High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22

    PubMed Central

    Gulhane, Max; Murray, Lydia; Lourie, Rohan; Tong, Hui; Sheng, Yong H.; Wang, Ran; Kang, Alicia; Schreiber, Veronika; Wong, Kuan Yau; Magor, Graham; Denman, Stuart; Begun, Jakob; Florin, Timothy H.; Perkins, Andrew; Cuív, Páraic Ó.; McGuckin, Michael A.; Hasnain, Sumaira Z.

    2016-01-01

    Prolonged high fat diets (HFD) induce low-grade chronic intestinal inflammation in mice, and diets high in saturated fat are a risk factor for the development of human inflammatory bowel diseases. We hypothesized that HFD-induced endoplasmic reticulum (ER)/oxidative stress occur in intestinal secretory goblet cells, triggering inflammatory signaling and reducing synthesis/secretion of proteins that form the protective mucus barrier. In cultured intestinal cells non-esterified long-chain saturated fatty acids directly increased oxidative/ER stress leading to protein misfolding. A prolonged HFD elevated the intestinal inflammatory cytokine signature, alongside compromised mucosal barrier integrity with a decrease in goblet cell differentiation and Muc2, a loss in the tight junction protein, claudin-1 and increased serum endotoxin levels. In Winnie mice, that develop spontaneous colitis, HFD-feeding increased ER stress, further compromised the mucosal barrier and increased the severity of colitis. In obese mice IL-22 reduced ER/oxidative stress and improved the integrity of the mucosal barrier, and reversed microbial changes associated with obesity with an increase in Akkermansia muciniphila. Consistent with epidemiological studies, our experiments suggest that HFDs are likely to impair intestinal barrier function, particularly in early life, which partially involves direct effects of free-fatty acids on intestinal cells, and this can be reversed by IL-22 therapy. PMID:27350069

  2. 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

  3. 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

  4. 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.

  5. 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'.

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. Amelioration of 1,2 Dimethylhydrazine (DMH) induced colon oxidative stress, inflammation and tumor promotion response by tannic acid in Wistar rats.

    PubMed

    Hamiza, Oday O; Rehman, Muneeb U; Tahir, Mir; Khan, Rehan; Khan, Abdul Quaiyoom; Lateef, Abdul; Ali, Farrah; Sultana, Sarwat

    2012-01-01

    Colon cancer is the third most common malignant neoplasm in the world and it remains an important cause of death, especially in western countries. The toxic environmental pollutant, 1, 2-dimethylhydrazine (DMH), is also a colon-specific carcinogen. Tannic acid (TA) is reported to be effective against various types of chemically induced toxicity and also carcinogenesis. In the present study, we evaluated the chemopreventive efficacy of TA against DMH induced colon toxicity in a rat model. Efficacy of TA against the colon toxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, lipid peroxidation, histopathological changes and expression of early molecular markers of inflammation and tumor promotion. DMH treatment induced oxidative stress enzymes (p<0.001) and an early inflammatory and tumor promotion response in the colons of Wistar rats. TA treatment prevented deteriorative effects induced by DMH through a protective mechanism that involved reduction of oxidative stress as well as COX-2, i-NOS, PCNA protein expression levels and TNF-α(p<0.001) release. It could be concluded from our results that TA markedly protects against chemically induced colon toxicity and acts plausibly by virtue of its antioxidant, anti-inflammatory and antiproliferative activities.

  14. Expression and Polymorphism of Toll-Like Receptor 4 and Effect on NF-κB Mediated Inflammation in Colon Cancer Patients.

    PubMed

    Semlali, Abdelhabib; Reddy Parine, Narasimha; Arafah, Maha; Mansour, Lamjed; Azzi, Arezki; Al Shahrani, Omair; Al Amri, Abdullah; Shaik, Jilani P; Aljebreen, Abdulrahman M; Alharbi, Othman; Almadi, Majid A; Azzam, Nahla Ali; Kohailan, Muhammad; Rouabhia, Mahmoud; Alanazi, Mohammad Saud

    2016-01-01

    Our aim was to evaluate the association between the expression and the polymorphism of TLR4/NF-κB pathways and colon cancer. TLR4 (rs4986790, rs10759932, rs10759931 and rs2770150) were genotyped in blood samples from Colorectal patients and healthy controls. TLR4 and cytokines inflammatory expression were evaluated by real time PCR on 40 matching normal and colon tissues and the protein level by Immunohistochemistry. The high level of TLR4 expression in colon cancer tissues is mainly due to infections by bacteria in the human colon and leads to induction of an acute secretion of inflammatory cytokines mediated by NF-κB. Also, we report here a clear evidence for an association between TLR4 rs10759931 polymorphism (OR = 0.086, CI: 0.04-0.18, P = <0.00001). This polymorphism affects the entire population without being specific to either gender or to any age group. In contrast, the rs2770150 is associated with colon cancer in women aged over 50 years and is closely linked with the decreased levels of female sex hormones during the post-menopausal period (OR = 0.188, CI: 0.074-0.48, P = <0.00084). rs10759932 and rs4986790 appear to have any association with colon cancer. Our data suggest that TLR4 SNPs could possibly serve as biomarkers for decision making in colon cancer treatment.

  15. Expression and Polymorphism of Toll-Like Receptor 4 and Effect on NF-κB Mediated Inflammation in Colon Cancer Patients

    PubMed Central

    Semlali, Abdelhabib; Reddy Parine, Narasimha; Arafah, Maha; Mansour, Lamjed; Azzi, Arezki; Al Shahrani, Omair; Al Amri, Abdullah; Shaik, Jilani P.; Aljebreen, Abdulrahman M.; Alharbi, Othman; Almadi, Majid A.; Azzam, Nahla Ali; Kohailan, Muhammad; Rouabhia, Mahmoud; Alanazi, Mohammad Saud

    2016-01-01

    Our aim was to evaluate the association between the expression and the polymorphism of TLR4/NF-κB pathways and colon cancer. TLR4 (rs4986790, rs10759932, rs10759931 and rs2770150) were genotyped in blood samples from Colorectal patients and healthy controls. TLR4 and cytokines inflammatory expression were evaluated by real time PCR on 40 matching normal and colon tissues and the protein level by Immunohistochemistry. The high level of TLR4 expression in colon cancer tissues is mainly due to infections by bacteria in the human colon and leads to induction of an acute secretion of inflammatory cytokines mediated by NF-κB. Also, we report here a clear evidence for an association between TLR4 rs10759931 polymorphism (OR = 0.086, CI: 0.04–0.18, P = <0.00001). This polymorphism affects the entire population without being specific to either gender or to any age group. In contrast, the rs2770150 is associated with colon cancer in women aged over 50 years and is closely linked with the decreased levels of female sex hormones during the post-menopausal period (OR = 0.188, CI: 0.074–0.48, P = <0.00084). rs10759932 and rs4986790 appear to have any association with colon cancer. Our data suggest that TLR4 SNPs could possibly serve as biomarkers for decision making in colon cancer treatment. PMID:26771524

  16. Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

    PubMed Central

    Maggio-Price, Lillian; Treuting, Piper; Bielefeldt-Ohmann, Helle; Seamons, Audrey; Drivdahl, Rolf; Zeng, Weiping; Lai, LapHin; Huycke, Mark; Phelps, Susan; Brabb, Thea; Iritani, Brian M.

    2009-01-01

    Alterations in genes encoding transforming growth factor-β-signaling components contribute to colon cancer in humans. Similarly, mice deficient in the transforming growth factor-β signaling molecule, Smad3, develop colon cancer, but only after a bacterial trigger occurs, resulting in chronic inflammation. To determine whether Smad3-null lymphocytes contribute to increased cancer susceptibility, we crossed Smad3-null mice with mice deficient in both B and T lymphocytes (Rag2−/− mice). Helicobacter-infected Smad3/Rag2-double knockout (DKO) mice had more diffuse inflammation and increased incidence of adenocarcinoma compared with Helicobacter-infected Smad3−/− or Rag2−/− mice alone. Adoptive transfer of WT CD4+CD25+ T-regulatory cells provided significant protection of Smad3/Rag2-DKO from bacterial-induced typhlocolitis, dysplasia, and tumor development, whereas Smad3−/− T-regulatory cells provided no protection. Immunohistochemistry, real-time reverse transcriptase-polymerase chain reaction, and Western blot analyses of colonic tissues from Smad3/Rag2-DKO mice 1 week after Helicobacter infection revealed an influx of macrophages, enhanced nuclear factor-κB activation, increased BclXL/Bcl-2 expression, increased c-Myc expression, accentuated epithelial cell proliferation, and up-regulated IFN-γ, IL-1α, TNF-α, IL-1β, and IL-6 transcription levels. These results suggest that the loss of Smad3 increases susceptibility to colon cancer by at least two mechanisms: deficient T-regulatory cell function, which leads to excessive inflammation after a bacterial trigger; and increased expression of proinflammatory cytokines, enhanced nuclear factor-κB activation, and increased expression of both pro-oncogenic and anti-apoptotic proteins that result in increased cell proliferation/survival of epithelial cells in colonic tissues. PMID:19119184

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. Effects of konjac glucomannan, inulin and cellulose on acute colonic responses to genotoxic azoxymethane.

    PubMed

    Wu, Wen-Tzu; Yang, Lien-Chuan; Chen, Hsiao-Ling

    2014-07-15

    Mice were fed low-fibre, or that supplemented with soluble fibre (konjac glucomannan, KGM; inulin), or insoluble fibre (cellulose) to determine how these three fibres modulated the acute colonic responses to an azoxymethane (AOM) treatment. Results indicated that KGM and inulin exerted greater anti-genotoxic effects compared to cellulose and up-regulated the gene expressions of glutathione S-transferase and antioxidant enzymes. The apoptotic index in the distal colon was the greatest and the expression of Bcl-2 was the lowest in the KGM group 24h after the AOM treatment. On the other hand, the proliferative index and expression of Cyclin D1 were lower in all fibre groups. Furthermore, KGM increased cecal short-chain fatty acid contents, and both KGM and inulin increased fecal probiotic concentrations. This study suggested that soluble fibres were more effective than cellulose on ameliorating AOM-induced genotoxicity by up-regulating antioxidant enzyme genes, and enhancing epithelium apoptosis by down-regulating Bcl-2.

  4. Long-term vitamin D3 supplementation does not prevent colonic inflammation or modulate bone health in IL-10 knockout mice at young adulthood.

    PubMed

    Glenn, Andrea J; Fielding, Kristina A; Chen, Jianmin; Comelli, Elena M; Ward, Wendy E

    2014-09-22

    Inflammatory bowel disease (IBD) is an idiopathic disease that can impair bone metabolism. Low vitamin D status has been implicated in its progress. This study used interleukin (IL)-10 knockout (KO) mice, that develop an intestinal inflammation when housed in a non-sterile environment, to determine if supplementation with vitamin D3 throughout life could mitigate inflammation and attenuate the lower bone mineral content (BMC) and density (BMD), and bone strength. Female IL-10 KO mice were randomized 25 or 5000 IU vitamin D3/kg diet throughout pregnancy and lactation. At weaning, offspring received the same or opposite diet as their mother until age three months. Body weight growth was similar among groups within a sex. At three months of age, there were no differences in inflammation and gene expression in the colon of offspring. Male offspring exposed to continuous 25 IU vitamin D3/kg diet had lower (p < 0.001) colonic VDR expression and those exposed only to low vitamin D3 until weaning had higher serum IL-6. There were no differences in femur or vertebral BMC, BMD or bone strength. In summary, long-term exposure to vitamin D3 did not attenuate intestinal inflammation or preserve bone mineral or bone strength. Thus, supplementation with vitamin D3 does not exert anti-inflammatory effects in this mouse model that mimics human inflammatory bowel disease.

  5. Duration of Colonization With Klebsiella pneumoniae Carbapenemase-Producing Bacteria at Long-Term Acute Care Hospitals in Chicago, Illinois

    PubMed Central

    Haverkate, Manon R.; Weiner, Shayna; Lolans, Karen; Moore, Nicholas M.; Weinstein, Robert A.; Bonten, Marc J. M.; Hayden, Mary K.; Bootsma, Martin C. J.

    2016-01-01

    Background. High prevalence of Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae has been reported in long-term acute care hospitals (LTACHs), in part because of frequent readmissions of colonized patients. Knowledge of the duration of colonization with KPC is essential to identify patients at risk of KPC colonization upon readmission and to make predictions on the effects of transmission control measures. Methods. We analyzed data on surveillance isolates that were collected at 4 LTACHs in the Chicago region during a period of bundled interventions, to simultaneously estimate the duration of colonization during an LTACH admission and between LTACH (re)admissions. A maximum-likelihood method was used, taking interval-censoring into account. Results. Eighty-three percent of patients remained colonized for at least 4 weeks, which was the median duration of LTACH stay. Between LTACH admissions, the median duration of colonization was 270 days (95% confidence interval, 91–∞). Conclusions. Only 17% of LTACH patients lost colonization with KPC within 4 weeks. Approximately half of the KPC-positive patients were still carriers when readmitted after 9 months. Infection control practices should take prolonged carriage into account to limit transmission of KPCs in LTACHs. PMID:27747253

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. Rosmarinic acid suppresses colonic inflammation in dextran sulphate sodium (DSS)-induced mice via dual inhibition of NF-κB and STAT3 activation

    PubMed Central

    Jin, Bo-Ram; Chung, Kyung-Sook; Cheon, Se-Yun; Lee, Minho; Hwang, Soonjae; Noh Hwang, Sam; Rhee, Ki-Jong; An, Hyo-Jin

    2017-01-01

    Ulcerative colitis (UC), a type of inflammatory bowel disease (IBD), is a chronic inflammatory disorder of the colon. Although UC is generally treated with anti-inflammatory drugs or immunosuppressants, most of these treatments often prove to be inadequate. Rosmarinic acid (RA) is a phenolic ester included in various medicinal herbs such as Salvia miltiorrhiz and Perilla frutescens. Although RA has many biological and pharmacological activities, the anti-inflammatory effect of RA in colonic tissue remains unclear. In this study, we investigated the anti-inflammatory effects and underlying molecular mechanism of RA in mice with dextran sulphate sodium (DSS)-induced colitis. In the DSS-induced colitis model, RA significantly reduced the severity of colitis, as assessed by disease activity index (DAI) scores, colonic damage, and colon length. In addition, RA resulted in the reduction of the inflammatory-related cytokines, such as IL-6, IL-1β, and IL-22, and protein levels of COX-2 and iNOS in mice with DSS-induced colitis. Furthermore, RA effectively and pleiotropically inhibited nuclear factor-kappa B and signal transducer and activator of transcription 3 activation, and subsequently reduced the activity of pro-survival genes that depend on these transcription factors. These results demonstrate that RA has an ameliorative effect on colonic inflammation and thus a potential therapeutic role in colitis. PMID:28383063

  14. 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, ...

  15. Reduction of colonic inflammation in HLA-B27 transgenic rats by feeding Marie Ménard apples, rich in polyphenols.

    PubMed

    Castagnini, Cinzia; Luceri, Cristina; Toti, Simona; Bigagli, Elisabetta; Caderni, Giovanna; Femia, Angelo P; Giovannelli, Lisa; Lodovici, Maura; Pitozzi, Vanessa; Salvadori, Maddalena; Messerini, Luca; Martin, Rocio; Zoetendal, Erwin G; Gaj, Stan; Eijssen, Lars; Evelo, Chris T; Renard, Catherine M G C; Baron, Alain; Dolara, Piero

    2009-12-01

    Inflammatory bowel diseases (IBD) are immunomediated ailments affecting millions of individuals. Although diet is regarded as an important factor influencing IBD, there are no accepted dietary recommendations presently available. We administered 7.6 % lyophilised apples obtained from two cultivars (Golden Delicious and Marie Ménard, low and high in polyphenols, respectively) to HLA-B27 transgenic rats which develop spontaneous IBD. After 3 months feeding, rats fed Marie Ménard apples had reduced myeloperoxidase activity (3.6 (sem 0.3) v. 2.2 (sem 0.2) U/g tissue; P < 0.05) and reduced cyclo-oxygenase-2 (P < 0.05) and inducible NO synthase gene expression (P < 0.01) in the colon mucosa and significantly less diarrhoea (P < 0.05), compared with control rats. Cell proliferation in the colon mucosa was reduced significantly by feeding Golden Delicious apples, with a borderline effect of Marie Ménard apples. Gene expression profiling of the colon mucosa, analysed using the Whole Rat Genome 4 x 44 K Agilent Arrays, revealed a down-regulation of the pathways of PG synthesis, mitogen-activated protein kinase (MAPK) signalling and TNFalpha-NF-kappaB in Marie Ménard-fed rats. In the stools of the animals of this group we also measured a significant reduction of bacteria of the Bacteriodes fragilis group. In conclusion, the administration of Marie Ménard apples, rich in polyphenols and used at present only in the manufacturing of cider, ameliorates colon inflammation in transgenic rats developing spontaneous intestinal inflammation, suggesting the possible use of these and other apple varieties to control inflammation in IBD patients.

  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. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. Acute experimental colitis decreases colonic circular smooth muscle contractility in rats.

    PubMed

    Myers, B S; Martin, J S; Dempsey, D T; Parkman, H P; Thomas, R M; Ryan, J P

    1997-10-01

    Distal colitis decreases the contractility of the underlying circular smooth muscle. We examined how time after injury and lesion severity contribute to the decreased contractility and how colitis alters the calcium-handling properties of the affected muscle. Distal colitis was induced in rats by intrarectal administration of 4% acetic acid. Contractile responses to acetylcholine, increased extracellular potassium, and the G protein activator NaF were determined for circular muscle strips from sham control and colitic rats at days 1, 2, 3, 7, and 14 postenemas. Acetylcholine stimulation of tissues from day 3 colitic rats was performed in a zero calcium buffer, in the presence of nifedipine, and after depletion of intracellular stores of calcium. The colitis was graded macroscopically as mild, moderate, or severe. Regardless of agonist, maximal decrease in force developed 2 to 3 days posttreatment, followed by a gradual return to control by day 14. The inhibitory effect of colitis on contractility increased with increasing severity of inflammation. Limiting extracellular calcium influx had a greater inhibitory effect on tissues from colitic rats; intracellular calcium depletion had a greater inhibitory effect on tissues from control animals. The data suggest that both lesion severity and time after injury affect the contractile response of circular smooth muscle from the inflamed distal colon. Impaired utilization of intracellular calcium may contribute to the decreased contractility.

  4. Acute effect of substance P in immunologic vasculitis in the rat colon.

    PubMed

    Murthy, S N; DePace, D M; Shah, R S; Podell, R

    1991-01-01

    Substance P has been implicated as a neuronal mediator of inflammation in various inflammatory conditions. However, the exact role played by substance P in inflammatory bowel diseases or in experimental colonic vasculitis has not been clearly understood. In this study, we examined the effect of close superior mesenteric artery injection of substance P under prevailing inflammatory conditions induced by intravenous human albumin antialbumin immune complex followed by intracolonic perfusion of 2.5% formaldehyde in rats or intracolonic perfusion of 5% alcohol alone. The immune complex- and formaldehyde-treated rats showed severe microvascular changes such as microvascular plugging by red blood cells, endothelial breakage and extravasation of plasma proteins and red blood cells. The bolus injection of 10(-8) M substance P reduced extravasation of Evans blue dye by 50% and the tissue wet to dry ratio by 20% in immune complex- and formaldehyde-perfused rats. Myeloperoxidase activity was not changed. Substance P also significantly inhibited (44%) the extravasation in alcohol-perfused rats. Pretreatment of immune complex- and formaldehyde-treated rats with substance P antagonist reversed the effect of substance P. These findings suggest that the most immediate effect of substance P may be vasodilation and clearing of vascular plugs induced by immune complex and formaldehyde. This effect of substance P differs from its chronic effect, which causes vasodilation and extravasation.

  5. 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

  6. 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

  7. 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.

  8. The combination of high-fat diet-induced obesity and chronic ulcerative colitis reciprocally exacerbates adipose tissue and colon inflammation

    PubMed Central

    2011-01-01

    Background This study evaluated the relationship between ulcerative colitis and obesity, which are both chronic diseases characterized by inflammation and increases in immune cells and pro-inflammatory cytokines. Methods Mice with chronic ulcerative colitis induced by 2 cycles of dextran sodium sulfate (DSS) in the first and fourth week of the experiment were fed a high-fat diet (HFD) to induce obesity by 8 weeks. The animals were divided into 4 \\ groups (control, colitis, HFD and colitis + HFD). Results Obesity alone did not raise histopathology scores, but the combination of obesity and colitis worsened the scores in the colon compared to colitis group. Despite the reduction in weight gain, there was increased inflammatory infiltrate in both the colon and visceral adipose tissue of colitis + HFD mice due to increased infiltration of macrophages, neutrophils and lymphocytes. Intravital microscopy of VAT microvasculature showed an increase in leukocyte adhesion and rolling and overexpression of adhesion molecules compared to other groups. Moreover, circulating lymphocytes, monocytes and neutrophils in the spleen and cecal lymph nodes were increased in the colitis + HFD group. Conclusion Our results demonstrated the relationship between ulcerative colitis and obesity as aggravating factors for each disease, with increased inflammation in the colon and adipose tissue and systemic alterations observed in the spleen, lymph nodes and bloodstream. PMID:22073943

  9. Predictive value of the Diverticular Inflammation and Complication Assessment (DICA) endoscopic classification on the outcome of diverticular disease of the colon: An international study

    PubMed Central

    Brandimarte, Giovanni; Di Mario, Francesco; Annunziata, Maria L; Bafutto, Mauro; Bianco, Maria A; Colucci, Raffaele; Conigliaro, Rita; Danese, Silvio; De Bastiani, Rudi; Elisei, Walter; Escalante, Ricardo; Faggiani, Roberto; Ferrini, Luciano; Forti, Giacomo; Latella, Giovanni; Graziani, Maria G; Oliveira, Enio C; Papa, Alfredo; Penna, Antonio; Portincasa, Piero; Søreide, Kjetil; Spadaccini, Antonio; Usai, Paolo; Bonovas, Stefanos; Scarpignato, Carmelo; Picchio, Marcello; Lecca, Piera G; Zampaletta, Costantino; Cassieri, Claudio; Damiani, Alberto; Desserud, Kari F; Fiorella, Serafina; Landi, Rosario; Goni, Elisabetta; Lai, Maria A; Pigò, Flavia; Rotondano, Gianluca; Schiaccianoce, Giuseppe

    2015-01-01

    Background Diverticular Inflammation and Complication Assessment (DICA) endoscopic classification has been recently developed for patients suffering from diverticulosis and diverticular disease. Aims We assessed retrospectively the predictive value of DICA in patients for whom endoscopic data and clinical follow-up were available. Methods For each patient, we recorded: age, severity of DICA, presence of abdominal pain, C-reactive protein and faecal calprotectin test (if available) at the time of diagnosis; months of follow-up; therapy taken during the follow-up to maintain remission (if any); occurrence/recurrence of diverticulitis; need of surgery. Results We enrolled 1651 patients (793 M, 858 F, mean age 66.6 ± 11.1 years): 939 (56.9%) patients were classified as DICA 1, 501 (30.3%) patients as DICA 2 and 211 (12.8%) patients as DICA 3. The median follow-up was 24 (9–38) months. Acute diverticulitis (AD) occurred/recurred in 263 (15.9%) patients; surgery was necessary in 57 (21.7%) cases. DICA was the only factor significantly associated to the occurrence/recurrence of diverticulitis and surgery either at univariate (χ2 = 405.029; p < 0.0001) or multivariate analysis (hazard ratio = 4.319, 95% confidence interval (CI) 3.639–5.126; p < 0.0001). Only in DICA 2 patients was therapy effective for prevention of AD occurrence/recurrence with a hazard ratio (95% CI) of 0.598 (0.391–0.914) (p = 0.006, log rank test). Mesalazine-based therapies reduced the risk of AD occurrence/recurrence and needs of surgery with a hazard ratio (95% CI) of 0.2103 (0.122–0.364) and 0.459 (0.258–0.818), respectively. Conclusions DICA classification is a valid parameter to predict the risk of diverticulitis occurrence/recurrence in patients suffering from diverticular disease of the colon. PMID:27536372

  10. 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.

  11. [Acute abdomen caused by colo-colic invagination: a case of invagination of a colonic lipoma].

    PubMed

    Rassu, P C; Bronzino, P; Cassinelli, G; La Spisa, C; Cuneo, A; Partipilo, F; Rusca, I; Boccardo, F; Zoppi, S; Casaccia, M

    2003-03-01

    The Authors report a case of intestinal occlusion due to a colo-colonic intussusception arising from a lipoma of trasverse colon and, by a review of the cases in the Literature, they discuss diagnostic and therapeutic procedures in emergency.

  12. 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.

  13. 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.

  14. Chemopreventive effects of silymarin against 1,2-dimethylhydrazine plus dextran sodium sulfate-induced inflammation-associated carcinogenicity and genotoxicity in the colon of gpt delta rats.

    PubMed

    Toyoda-Hokaiwado, Naomi; Yasui, Yumiko; Muramatsu, Mina; Masumura, Kenichi; Takamune, Makiko; Yamada, Masami; Ohta, Toshihiro; Tanaka, Takuji; Nohmi, Takehiko

    2011-10-01

    Silymarin, a natural flavonoid from the seeds of milk thistle, is used for chemoprevention against various cancers in clinical settings and in experimental models. To examine the chemopreventive mechanisms of silymarin against colon cancer, we investigated suppressive effects of silymarin against carcinogenicity and genotoxicity induced by 1,2-dimethylhydrazine (DMH) plus dextran sodium sulfate (DSS) in the colon of F344 gpt delta transgenic rats. Male gpt delta rats were given a single subcutaneous injection of 40 mg/kg DMH and followed by 1.5% DSS in drinking water for a week. They were fed diets containing silymarin for 4 weeks, starting 1 week before DMH injection and samples were collected at 4, 20 and 32 weeks after the DMH treatment. Silymarin at doses of 100 and 500 p.p.m. suppressed the tumor formation in a dose-dependent manner and the reduction was statistically significant. In the mutation assays, DMH plus DSS enhanced the gpt mutant frequency (MF) in the colon, and the silymarin treatments reduced the MFs by 20%. Silymarin also reduced the genotoxicity of DMH in a dose-dependent manner in bacterial mutation assay with Salmonella typhimurium YG7108, a sensitive strain to alkylating agents, and the maximum reduction was >80%. These results suggest that silymarin is chemopreventive against DMH/DSS-induced inflammation-associated colon carcinogenesis and silymarin might act as an antigenotoxic agent, in part.

  15. 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

  16. Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia.

    PubMed

    Jost, Tanja Rezzonico; Borga, Chiara; Radaelli, Enrico; Romagnani, Andrea; Perruzza, Lisa; Omodho, Lorna; Cazzaniga, Giovanni; Biondi, Andrea; Indraccolo, Stefano; Thelen, Marcus; Te Kronnie, Geertruy; Grassi, Fabio

    2016-06-01

    Infiltration of the central nervous system is a severe trait of T cell acute lymphoblastic leukemia. Inhibition of CXC chemokine receptor 4 significantly ameliorates T cell acute lymphoblastic leukemia in murine models of the disease; however, signaling by CXC chemokine receptor 4 is important in limiting the divagation of peripheral blood mononuclear cells out of the perivascular space into the central nervous system parenchyma. Therefore, Inhibition of CXC chemokine receptor 4 potentially may untangle T cell acute lymphoblastic leukemia cells from retention outside the brain. Here, we show that leukemic lymphoblasts massively infiltrate cranial bone marrow, with diffusion to the meninges without invasion of the brain parenchyma, in mice that underwent xenotransplantation with human T cell acute lymphoblastic leukemia cells or that developed leukemia from transformed hematopoietic progenitors. We tested the hypothesis that T cell acute lymphoblastic leukemia neuropathology results from meningeal infiltration through CXC chemokine receptor 4-mediated bone marrow colonization. Inhibition of leukemia engraftment in the bone marrow by pharmacologic CXC chemokine receptor 4 antagonism significantly ameliorated neuropathologic aspects of the disease. Genetic deletion of CXCR4 in murine hematopoietic progenitors abrogated leukemogenesis induced by constitutively active Notch1, whereas lack of CCR6 and CCR7, which have been shown to be involved in T cell and leukemia extravasation into the central nervous system, respectively, did not influence T cell acute lymphoblastic leukemia development. We hypothesize that lymphoblastic meningeal infiltration as a result of bone marrow colonization is responsible for the degenerative alterations of the neuroparenchyma as well as the alteration of cerebrospinal fluid drainage in T cell acute lymphoblastic leukemia xenografts. Therefore, CXC chemokine receptor 4 may constitute a pharmacologic target for T cell acute lymphoblastic

  17. Unique characteristics of adolescent and young adult acute lymphoblastic leukemia, breast cancer, and colon cancer.

    PubMed

    Tricoli, James V; Seibel, Nita L; Blair, Donald G; Albritton, Karen; Hayes-Lattin, Brandon

    2011-04-20

    Each year in the United States, nearly 70 000 individuals between the ages of 15 and 40 years are diagnosed with cancer. Although overall cancer survival rates among pediatric and older adult patients have increased in recent decades, there has been little improvement in survival of adolescent and young adult (AYA) cancer patients since 1975 when collected data became adequate to evaluate this issue. In 2006, the AYA Oncology Progress Review Group made recommendations for addressing the needs of this population that were later implemented by the LIVESTRONG Young Adult Alliance. One of their overriding questions was whether the cancers seen in AYA patients were biologically different than the same cancers in adult and/or pediatric patients. On June 9-10, 2009, the National Cancer Institute (NCI) and the Lance Armstrong Foundation (LAF) convened a workshop in Bethesda, MD, entitled "Unique Characteristics of AYA Cancers: Focus on Acute Lymphocytic Leukemia (ALL), Breast Cancer and Colon Cancer" that aimed to examine the current state of basic and translational research on these cancers and to discuss the next steps to improve their prognosis and treatment.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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

  7. In vitro evaluation of the cytotoxicity and modulation of mechanisms associated with inflammation induced by perfluorooctanesulfonate and perfluorooctanoic acid in human colon myofibroblasts CCD-18Co.

    PubMed

    Giménez-Bastida, Juan Antonio; Surma, Magdalena; Zieliński, Henryk

    2015-10-01

    Perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the most notable members of an emerging class of persistent organic pollutants (POPs), poly- and perfluoroalkyl acids (PFASs). In this study, the CCD-18Co myofibroblasts were selected as a cell model to investigate the cytotoxic effects of PFOS and PFOA. The aim was to perform an in vitro evaluation of the ability of these compounds to induce cytotoxicity and modulate mechanisms associated with inflammation as measured by (i) colon fibroblasts viability, (ii) colon fibroblasts proliferation, and (iii) IL-6 production. The data provided in this study suggest that PFOS and PFOA can have cytotoxic potential and modulate processes associated with intestinal inflammation such as myofibroblasts proliferation and IL-6 production at concentrations similar to those detected in vivo. Our results also highlight the influence of culture serum concentration in cytotoxic in vitro studies, which should be considered in future toxicity studies involving PFOS and PFOA. The results contribute to a better knowledge of the effects of PFOS and PFOA in human cells, a phenomenon still not fully examined.

  8. 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

  9. Effects in the use of a genetically engineered strain of Lactococcus lactis delivering in situ IL-10 as a therapy to treat low-grade colon inflammation.

    PubMed

    Martín, Rebeca; Chain, Florian; Miquel, Sylvie; Natividad, Jane M; Sokol, Harry; Verdu, Elena F; Langella, Philippe; Bermúdez-Humarán, Luis G

    2014-01-01

    Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain, discomfort, and bloating. Interestingly, there is now evidence of the presence of a low-grade inflammatory status in many IBS patients, including histopathological and mucosal cytokine levels in the colon, as well as the presence of IBS-like symptoms in quiescent inflammatory bowel disease (IBD). The use of a genetically engineered food-grade bacterium, such as Lactococcus lactis, secreting the anti-inflammatory cytokine IL-10 has been proven by many pre-clinical studies to be a successful therapy to treat colon inflammation. In this study, we first reproduced the recovery-recurrence periods observed in IBS-patients in a new chronic model characterized by 2 episodes of DiNitro-BenzeneSulfonic-acid (DNBS)-challenge and we tested the effects of a recombinant strain of L. lactis secreting IL-10 under a Stress-Inducible Controlled Expression (SICE) system. In vivo gut permeability, colonic serotonin levels, cytokine profiles, and spleen cell populations were then measured as readouts of a low-grade inflammation. In addition, since there is increasing evidence that gut microbiota tightly regulates gut barrier function, tight junction proteins were also measured by qRT-PCR after administration of recombinant L. lactis in DNBS-treated mice. Strikingly, oral administration of L. lactis secreting active IL-10 in mice resulted in significant protective effects in terms of permeability, immune activation, and gut-function parameters. Although genetically engineered bacteria are, for now, used only as a "proof-of-concept," our study validates the interest in the use of the novel SICE system in L. lactis to express therapeutic molecules, such as IL-10, locally at mucosal surfaces.

  10. 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

  11. 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.

  12. Focal bowel wall changes detected with colour Doppler ultrasound: diagnostic value in acute non-diverticular diseases of the colon.

    PubMed

    Danse, E M; Jamart, J; Hoang, P; Laterre, P F; Kartheuser, A; Van Beers, B E

    2004-11-01

    We performed a study to determine if colour Doppler findings may help to identify the cause of wall thickening in acute non-diverticular diseases of the colon. The study group included 66 patients admitted to the emergency department with a final diagnosis of infectious colitis (n=23), inflammatory colitis (n=10), ischaemic colitis (n=23) and malignant tumours (n=10). The following ultrasound features were assessed: maximal wall thickness, wall stratification, arterial flow in the colonic wall and arteriolar resistive index. Higher values of wall thickness were observed in malignant tumour (18.2+/-6.2 mm, p<0.001). Moderately thickened wall (6.6+/-1.3 mm, p< or =0.06), preserved stratification (90% versus 46% in the remainder of the study population) and lower resistive index (0.51+/-0.10, p< or =0.05) were significantly related to inflammatory colitis. Absence of arterial flow was more frequently observed in ischaemia (43% versus 12% in the remainder of the study population). In conclusion, despite some overlap, both ultrasound and colour Doppler features are helpful in the differential diagnosis of colonic thickening related to non-diverticular colonic lesions.

  13. 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

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. Beneficial Effects of Anti-Interleukin-6 Antibodies on Impaired Gastrointestinal Motility, Inflammation and Increased Colonic Permeability in a Murine Model of Sepsis Are Most Pronounced When Administered in a Preventive Setup

    PubMed Central

    Nullens, Sara; Staessens, Michael; Peleman, Cédric; Plaeke, Philip; Malhotra-Kumar, Surbhi; Francque, Sven; De Man, Joris G.; De Winter, Benedicte Y.

    2016-01-01

    Background and Objectives During sepsis, gastrointestinal ileus, mucosal barrier dysfunction and bacterial translocation are accepted to be important triggers that can maintain or exacerbate the septic state. In the caecal ligation and puncture animal model of sepsis, we demonstrated that systemic and colonic interleukin-6 levels are significantly increased coinciding with an impaired colonic barrier function. We therefore aimed to study the effect of therapeutic or curative administration of anti-IL6 antibodies on overall GI motility, colonic permeability and translocation of intestinal bacteria in blood and mesenteric lymph nodes in the mouse caecal ligation and puncture model. Methods OF-1 mice were randomized to either the preventive or curative protocol, in which they received 1 mg/kg of antibodies to interleukin-6, or its IgG isotype control solution. They subsequently underwent either the caecal ligation and puncture procedure, or sham-surgery. GI motility was assessed 48h following the procedure, as well as colonic permeability, serum and colon cytokines, colonic tight junction proteins at the mRNA level; cultures of blood and mesenteric lymph nodes were performed. Results Preventive administration of anti-interleukin-6 antibodies successfully counteracted the gastrointestinal motility disturbances and impaired colonic barrier function that could be observed in vehicle-treated septic animals. Serum and colonic levels of proinflammatory cytokines were significantly lower when animals were preventively treated with anti-interleukin-6 antibodies. A repetitive injection 24h later resulted in the most pronounced effects. Curative treatment significantly lowered systemic and colonic inflammation markers while the effects on transit and permeability were unfortunately no longer significant. Conclusions Caecal ligation and puncture resulted in septic ileus with an increased colonic permeability. Antibodies to interleukin-6 were able to ameliorate gastro

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon

    PubMed Central

    Rivollier, Aymeric; He, Jianping; Kole, Abhisake; Valatas, Vassilis

    2012-01-01

    Dendritic cells (DCs) and macrophages (MPs) are important for immunological homeostasis in the colon. We found that F4/80hiCX3CR1hi (CD11b+CD103−) cells account for 80% of mouse colonic lamina propria MHC-IIhi cells. Both CD11c+ and CD11c− cells within this population were identified as MPs based on multiple criteria, including an MP transcriptome revealed by microarray analysis. These MPs constitutively released high levels of IL-10 at least partially in response to the microbiota via an MyD88-independent mechanism. In contrast, cells expressing low to intermediate levels of F4/80 and CX3CR1 were identified as DCs based on phenotypic and functional analysis and comprise three separate CD11chi cell populations: CD103+CX3CR1−CD11b− DCs, CD103+CX3CR1−CD11b+ DCs, and CD103−CX3CR1intCD11b+ DCs. In noninflammatory conditions, Ly6Chi monocytes (MOs) differentiated primarily into CD11c+ but not CD11c− MPs. In contrast, during colitis, Ly6Chi MOs massively invaded the colon and differentiated into proinflammatory CD103−CX3CR1intCD11b+ DCs, which produced high levels of IL-12, IL-23, iNOS, and TNF. These findings demonstrate the dual capacity of Ly6Chi blood MOs to differentiate into either regulatory MPs or inflammatory DCs in the colon and that the balance of these immunologically antagonistic cell types is dictated by microenvironmental conditions. PMID:22231304

  8. 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

  9. 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.

  10. A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.

    PubMed

    Bu, Pengcheng; Wang, Lihua; Chen, Kai-Yuan; Srinivasan, Tara; Murthy, Preetish Kadur Lakshminarasimha; Tung, Kuei-Ling; Varanko, Anastasia Kristine; Chen, Huanhuan Joyce; Ai, Yiwei; King, Sarah; Lipkin, Steven M; Shen, Xiling

    2016-02-04

    Emerging evidence suggests that microRNAs can initiate asymmetric division, but whether microRNA and protein cell fate determinants coordinate with each other remains unclear. Here, we show that miR-34a directly suppresses Numb in early-stage colon cancer stem cells (CCSCs), forming an incoherent feedforward loop (IFFL) targeting Notch to separate stem and non-stem cell fates robustly. Perturbation of the IFFL leads to a new intermediate cell population with plastic and ambiguous identity. Lgr5+ mouse intestinal/colon stem cells (ISCs) predominantly undergo symmetric division but turn on asymmetric division to curb the number of ISCs when proinflammatory response causes excessive proliferation. Deletion of miR-34a inhibits asymmetric division and exacerbates Lgr5+ ISC proliferation under such stress. Collectively, our data indicate that microRNA and protein cell fate determinants coordinate to enhance robustness of cell fate decision, and they provide a safeguard mechanism against stem cell proliferation induced by inflammation or oncogenic mutation.

  11. Monitoring of Tumor Promotion and Progression in a Mouse Model of Inflammation-Induced Colon Cancer with Magnetic Resonance Colonography1

    PubMed Central

    Young, Matthew R; Ileva, Lilia V; Bernardo, Marcelino; Riffle, Lisa A; Jones, Yava L; Kim, Young S; Colburn, Nancy H; Choyke, Peter L

    2009-01-01

    Early detection of precancerous tissue has significantly improved survival of most cancers including colorectal cancer (CRC). Animal models designed to study the early stages of cancer are valuable for identifying molecular events and response indicators that correlate with the onset of disease. The goal of this work was to investigate magnetic resonance (MR) colonography in a mouse model of CRC on a clinical MR imager. Mice treated with azoxymethane and dextran sulfate sodium were imaged by serial MR colonography (MRC) from initiation to euthanasia. Magnetic resonance colonography was obtained with both T1- and T2-weighted images after administration of a Fluorinert enema to remove residual luminal signal and intravenous contrast to enhance the colon wall. Individual tumor volumes were calculated and validated ex vivo. The Fluorinert enema provided a clear differentiation of the lumen of the colon from the mucosal lining. Inflammation was detected 3 days after dextran sulfate sodium exposure and subsided during the next week. Tumors as small as 1.2 mm3 were detected and as early as 29 days after initiation. Individual tumor growths were followed over time, and tumor volumes were measured by MR imaging correlated with volumes measured ex vivo. The use of a Fluorinert enema during MRC in mice is critical for differentiating mural processes from intraluminal debris. Magnetic resonance colonography with Fluorinert enema and intravenous contrast enhancement will be useful in the study of the initial stages of colon cancer and will reduce the number of animals needed for preclinical trials of prevention or intervention. PMID:19242605

  12. 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

  13. Acute large bowel obstruction secondary to stage 4 colonic carcinoma in an elderly man with severe aortic stenosis: a therapeutic challenge

    PubMed Central

    Prabhu, Raghunath; Kumar, Neha; Sadhu, Sakshi; Natarajan, Arjun

    2014-01-01

    Colonic adenocarcinoma is a common gastrointestinal malignancy affecting the elderly, and has a multifactorial aetiology. Depending on the individual circumstances, surgical resection is the treatment of choice for colon cancer even for oligometastasis. Metastatic evidence as well as presence of comorbidities, particularly in the elderly, make surgical management difficult and often present a clinical challenge for clinicians. This is a case report exploring the treatment options for an 80-year-old male patient presenting with acute large bowel obstruction secondary to colonic adenocarcinoma with disseminated metastases and severe aortic stenosis. PMID:24557473

  14. Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling

    PubMed Central

    Yang, Yong Ryoul; Kim, Dae Hyun; Seo, Young-Kyo; Park, Dohyun; Jang, Hyun-Jun; Choi, Soo Youn; Lee, Yong Hwa; Lee, Gyun Hui; Nakajima, Kazuki; Taniguchi, Naoyuki; Kim, Jung-Min; Choi, Eun-Jeong; Moon, Hyo Youl; Kim, Il Shin; Choi, Jang Hyun; Lee, Ho; Ryu, Sung Ho; Cocco, Lucio; Suh, Pann-Ghill

    2015-01-01

    O-GlcNAcylation is a reversible post-translational modification. O-GlcNAc addition and removal is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. More recent evidence indicates that regulation of O-GlcNAcylation is important for inflammatory diseases and tumorigenesis. In this study, we revealed that O-GlcNAcylation was increased in the colonic tissues of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) animal models. Moreover, the O-GlcNAcylation level was elevated in human CAC tissues compared with matched normal counterparts. To investigate the functional role of O-GlcNAcylation in colitis, we used OGA heterozygote mice, which have an increased level of O-GlcNAcylation. OGA+/− mice have higher susceptibility to DSS-induced colitis than OGA+/+ mice. OGA+/− mice exhibited a higher incidence of colon tumors than OGA+/+ mice. In molecular studies, elevated O-GlcNAc levels were shown to enhance the activation of NF-κB signaling through increasing the binding of RelA/p65 to its target promoters. We also found that Thr-322 and Thr352 in the p65-O-GlcNAcylation sites are critical for p65 promoter binding. These results suggest that the elevated O-GlcNAcylation level in colonic tissues contributes to the development of colitis and CAC by disrupting regulation of NF-κB-dependent transcriptional activity. PMID:25915426

  15. Interleukin-17A Contributes to the Control of Streptococcus pyogenes Colonization and Inflammation of the Female Genital Tract

    PubMed Central

    Carey, Alison J.; Weinberg, Jason B.; Dawid, Suzanne R.; Venturini, Carola; Lam, Alfred K.; Nizet, Victor; Caparon, Michael G.; Walker, Mark J.; Watson, Michael E.; Ulett, Glen C.

    2016-01-01

    Postpartum women are at increased risk of developing puerperal sepsis caused by group A Streptococcus (GAS). Specific GAS serotypes, including M1 and M28, are more commonly associated with puerperal sepsis. However, the mechanisms of GAS genital tract infection are not well understood. We utilized a murine genital tract carriage model to demonstrate that M1 and M28 GAS colonization triggers TNF-α, IL-1β, and IL-17A production in the female genital tract. GAS-induced IL-17A significantly influences streptococcal carriage and alters local inflammatory responses in two genetically distinct inbred strains of mice. An absence of IL-17A or the IL-1 receptor was associated with reduced neutrophil recruitment to the site of infection; and clearance of GAS was significantly attenuated in IL-17A−/− mice and Rag1−/− mice (that lack mature lymphocytes) but not in mice deficient for the IL-1 receptor. Together, these findings support a role for IL-17A in contributing to the control of streptococcal mucosal colonization and provide new insight into the inflammatory mediators regulating host-pathogen interactions in the female genital tract. PMID:27241677

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. Scintigraphic demonstration of acute gastrointestinal bleeding caused by gallbladder carcinoma eroding the colon

    SciTech Connect

    Czerniak, A.; Zwas, S.T.; Rabau, M.Y.; Avigad, I.; Borag, B.; Wolfstein, I.

    1985-08-01

    Massive lower gastrointestinal (GI) bleeding caused by gallbladder carcinoma eroding into the colonic wall was demonstrated accurately by Tc-99m RBCs. In addition, retrograde bleeding into the gallbladder was also identified while arteriography did not show contrast extravasation. This case supports the use of Tc-99m RBCs over Tc-99m sulfur colloid for more accurate localization of lower GI bleeding.

  5. Use of a high-throughput screen to identify Leptospira mutants unable to colonize the carrier host or cause disease in the acute model of infection.

    PubMed

    Marcsisin, Renee A; Bartpho, Thanatchaporn; Bulach, Dieter M; Srikram, Amporn; Sermswan, Rasana W; Adler, Ben; Murray, Gerald L

    2013-10-01

    The molecular basis for leptospirosis infection and colonization remains poorly understood, with no efficient methods available for screening libraries of mutants for attenuation. We analysed the attenuation of leptospiral transposon mutants in vivo using a high-throughput method by infecting animals with pooled sets of transposon mutants. A total of 95 mutants was analysed by this method in the hamster model of acute infection, and one mutant was identified as attenuated (M1233, lb058 mutant). All virulence factors identified in Leptospira to date have been characterized in the acute model of infection, neglecting the carrier host. To address this, a BALB/c mouse colonization model was established. The lb058 mutant and two mutants defective in LPS synthesis were colonization deficient in the mouse model. By applying the high-throughput screening method, a further five colonization-deficient mutants were identified for the mouse model; these included two mutants in genes encoding proteins with a predicted role in iron uptake (LB191/HbpA and LB194). Two attenuated mutants had transposon insertions in either la0589 or la2786 (encoding proteins of unknown function). The final attenuated mutant had an unexpected deletion of genes la0969-la0975 at the point of transposon insertion. This is the first description of defined, colonization-deficient mutants in a carrier host for Leptospira. These mutants were either not attenuated or only weakly attenuated in the hamster model of acute leptospirosis, thus illustrating that different factors that may be required in the carrier and acute models of leptospiral infection. High-throughput screening can reduce the number of animals used in virulence studies and increase the capacity to screen mutants for attenuation, thereby enhancing the likelihood of detecting unique virulence factors. A comparison of virulence factors required in the carrier and acute models of infection will help to unravel colonization and dissemination

  6. Helicobacter hepaticus urease is not required for intestinal colonization but promotes hepatic inflammation in male A/JCr mice.

    PubMed

    Ge, Zhongming; Lee, Amy; Whary, Mark T; Rogers, Arlin B; Maurer, Kirk J; Taylor, Nancy S; Schauer, David B; Fox, James G

    2008-07-01

    Urease activity contributes to bacterial survival in the acidic environment of the stomach and is essential for persistent infection by known gastric helicobacters such as the human pathogen Helicobacter pylori. Several enterohepatic Helicobacter species (EHS) that primarily infect the less acidic intestine also have very active urease enzymes. The importance of urease and its contribution to pathogenesis for these EHS are poorly understood. In this study, we generated a urease-deficient, isogenic mutant (HhureNT9) of Helicobacter hepaticus 3B1 (Hh 3B1), an EHS that possesses a urease gene cluster similar to that of H. pylori. Lack of urease activity did not affect the level of cecal colonization by HhureNT9 compared to Hh 3B1 in male A/JCr mice (P=0.48) at 4 months post-inoculation (MPI). In contrast, there was no HhureNT9 detected in the livers of any infected mice, whereas all livers from the Hh 3B1-infected mice were PCR-positive for Hh 3B1. The mice infected with HhureNT9 developed significantly less severe hepatitis (P=0.017) and also produced significantly lower hepatic mRNA levels of proinflammatory cytokines IFN-gamma (P=0.0007) and TNF-alpha (P<0.0001) compared to the Hh 3B1-infected mice. The Hh 3B1-infected mice developed significantly higher total IgG, Th1-associated IgG2a and Th2-associated IgG1 responses to infection. These results indicate that H. hepaticus urease activity plays a crucial role in hepatic disease but is not required for cecal colonization by H. hepaticus.

  7. 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

  8. 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.

  9. Acute Colonic Pseudo-Obstruction with Feeding Intolerance in Critically Ill Patients: A Study according to Gut Wall Analysis

    PubMed Central

    Zhao, Chenyan; Xie, Tingbin; Li, Jun; Cheng, Minhua; Shi, Jialiang; Gao, Tao; Xi, Fengchan; Shen, Juanhong; Cao, Chun

    2017-01-01

    Objective. To compare the differences between acute colonic pseudo-obstruction (ACPO) with and without acute gut wall thickening. Methods. ACPO patients with feeding tolerance were divided into ACPO with no obvious gut wall thickening (ACPO-NT) group and ACPO with obvious acute gut wall thickening (ACPO-T) group according to computed tomography and abdominal radiographs. Patients' condition, responses to supportive measures, pharmacologic therapy, endoscopic decompression, and surgeries and outcomes were compared. Results. Patients in ACPO-T group had a significantly higher APACHE II (11.82 versus 8.25, p = 0.008) and SOFA scores (6.47 versus 3.54, p < 0.001) and a significantly higher 28-day mortality (17.78% versus 4.16%, p = 0.032) and longer intensive care unit stage (4 versus 16 d, p < 0.001). Patients in ACPO-NT group were more likely to be responsive to supportive treatment (62.50% versus 24.44%, p < 0.001), neostigmine (77.78% versus 17.64%, p < 0.001), and colonoscopic decompression (75% versus 42.86%, p = 0.318) than those in ACPO-T group. Of the patients who underwent ileostomy, 81.25% gained benefits. Conclusions. ACPO patients with gut wall thickening are more severe and are less likely to be responsive to nonsurgical treatment. Ileostomy may be a good option for ACPO patients with gut wall thickening who are irresponsive to nonsurgical treatment. PMID:28386273

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. Marie Ménard apples with high polyphenol content and a low-fat diet reduce 1,2-dimethylhydrazine-induced colon carcinogenesis in rats: effects on inflammation and apoptosis.

    PubMed

    Femia, Angelo Pietro; Luceri, Cristina; Bianchini, Francesca; Salvadori, Maddalena; Salvianti, Francesca; Pinzani, Pamela; Dolara, Piero; Calorini, Lido; Caderni, Giovanna

    2012-08-01

    Inflammation may increase cancer risk, therefore, we studied whether polyphenol-rich Marie Ménard (MM) apples with reported anti-inflammatory activity prevent 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats and, likewise whether high-fat (HF) diet promoting carcinogenesis, may affect inflammation. DMH-induced rats were fed for 15 weeks with: an HF diet (23% corn oil w/w); an HF diet containing 7.6% w/w lyophilized MM (apple diet (AD)); a low-fat (LF) diet and an HF diet containing piroxicam (PXC) (0.01% w/w) as control. Mucin depleted foci (MDF), precancerous lesions in the colon, were dramatically reduced in the AD, LF, and PXC groups compared with the HF. Peritoneal macrophage activation, an index of systemic inflammation, was significantly decreased in the AD, LF, and PXC groups. TNF-α, iNOS, IL-1β, IL-6 m-RNA expression in the colon, as well as CD68 cells and plasmatic PGE2 were lower in the AD, but not in the LF group. Apoptosis in the MDF of both the AD and LF-fed rats was significantly higher than in HF rats. In conclusion, AD has a strong chemopreventive effect, reducing inflammation, and increasing apoptosis, while the chemopreventive effect of the LF diet seems mediated mainly by increased apoptosis in MDF.

  16. Acute left-sided colonic diverticulitis: clinical expressions, therapeutic insights, and role of computed tomography

    PubMed Central

    Ambrosetti, Patrick

    2016-01-01

    The diagnostic approach of patients with suspected acute diverticulitis remains debated. On the one hand, a scoring system with the best predictive value in diagnosing acute diverticulitis has been developed in order to reduce the use of computed tomography (CT) scan, while, on the other hand, patients with a high probability of acute diverticulitis should benefit from CT scan from a clinical viewpoint, ensuring that they will receive the most appropriate treatment. The place and classification of CT scan for acute diverticulitis need to be reassessed. If the management of uncomplicated acute diverticulitis, abscess, and fecal peritonitis is now well codified, urgent surgical or medical treatment of hemodynamically stable patients presenting with intraperitoneal air or fluid without uncontrolled sepsis is still under discussion. Furthermore, the indications for laparoscopic lavage are not yet well established. It is known for years that episode(s) of acute uncomplicated diverticulitis may induce painful recurrent bowel symptoms, known as symptomatic uncomplicated diverticular disease and irritable bowel syndrome-like diverticular disease. These two clinical expressions of diverticular disease, that may darken quality of life, are treated medically aimed at symptom relief. The possible place of surgery should be discussed. Clinical and CT scan classifications should be separated entities. PMID:27574459

  17. Red wine polyphenolics reduce the expression of inflammation markers in human colon-derived CCD-18Co myofibroblast cells: potential role of microRNA-126.

    PubMed

    Angel-Morales, Gabriela; Noratto, Giuliana; Mertens-Talcott, Susanne

    2012-07-01

    Chronic intestinal inflammation is an established risk factor for colon cancer. Polyphenolic compounds from fruit and vegetables have been shown to have anti-inflammatory properties in several cell lines and tissues. However, their anti-inflammatory mechanisms, involving microRNAs in the regulation of inflammation, have not been extensively investigated. The goal of this research was to assess the chemopreventive potential of polyphenolics extracted from red wine made with Lenoir grapes (Vitis aestivalis hybrid) in human colon-derived CCD-18Co myofibroblasts cells, and to assess the potential involvement of microRNA-126 (miR-126) in the underlying mechanisms. The results show that the polyphenolic red wine extract (WE) decreased mRNA expression of lipopolysaccharide (LPS)-induced inflammatory mediators NF-kB, ICAM-1, VCAM-1, and PECAM-1 by 1.95-, 1.98-, 1.52-, and 1.84-fold respectively, in a dose dependent manner (0-100 μg of gallic acid equivalent (GAE) mL(-1)) down to 0.80-, 0.79-, 0.66-, and 0.68-fold in DMSO-treated control cells not challenged with LPS, respectively. Correspondingly, miR-126, which has a target region within the 3'-UTR of VCAM-1 mRNA, was increased 2.79-fold by the WE at 100 μg GAE mL(-1). The potential role of miR-126 was confirmed by transfecting cells with a specific miR-126-antagomir, as-miR-126. Transfection with as-miR-126 down-regulated miR-126 to 0.71-fold in the control cells and up-regulated mRNA levels of NF-kB, ICAM-1, VCAM-1, and PECAM-1 to 1.80-, 1.49-, 2.30-, and 1.95-fold of controls, respectively. WE at 100 μg GAE mL(-1) partially reversed the effects of the as-miR-126 to 1.02-, 1.01-, 1.04-, and 1.05-fold, for mRNA levels of NF-kB, ICAM-1, VCAM-1, and PECAM-1 respectively. This indicates the potential role of miR-126 in the anti-inflammatory properties of polyphenolics from red wine in CCD-18Co myofibroblasts cells.

  18. Primary anastomosis in the treatment of acute disease of the unprepared left colon.

    PubMed

    Trillo, C; Paris, M F; Brennan, J T

    1998-09-01

    Between June 1, 1990 and December 31, 1996, 58 consecutive patients with unprepared colons were urgently explored for nontraumatic disease with intent to proceed with primary left-sided colonic anastomosis. Unprotected anastomoses were not attempted in 15 patients. The causes of exclusion included preoperative and intraoperative shock in three patients, and three patients were on long-term high-dose steroids, four had gross fecal contamination of the peritoneal cavity, four had large pelvic abscesses, and one had ischemic colitis. All 43 patients undergoing anastomosis without protective colostomy had stapled anastomoses. Indications included complicated diverticular disease in 32 cases. There were nine cases of obstruction from colorectal carcinoma and one obstruction due to sigmoid volvulus. There was one case of perforation from pseudomembranous enterocolitis. The most common complications were: atelectasis in nine cases, wound infection in two cases, and prolonged ileus in two cases. Pelvic abscess occurred in one case. There was one wound dehiscence. There was one anastomotic dehiscence, and there was no mortality. Operative time averaged 85 minutes and hospital length of stay 9.7 days. Primary anastomosis of the unprepared left colon is safe in most urgent and emergent situations, thus avoiding the significant morbidity and cost of colostomy closure.

  19. 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

  20. 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

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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

  7. Risk factors of admission for acute colonic diverticulitis in a population-based cohort study: The North Trondelag Health Study, Norway

    PubMed Central

    Jamal Talabani, Aras; Lydersen, Stian; Ness-Jensen, Eivind; Endreseth, Birger Henning; Edna, Tom-Harald

    2016-01-01

    AIM To assess risk factors of hospital admission for acute colonic diverticulitis. METHODS The study was conducted as part of the second wave of the population-based North Trondelag Health Study (HUNT2), performed in North Trondelag County, Norway, 1995 to 1997. The study consisted of 42570 participants (65.1% from HUNT2) who were followed up from 1998 to 2012. Of these, 22436 (52.7%) were females. The cases were defined as those 358 participants admitted with acute colonic diverticulitis during follow-up. The remaining participants were used as controls. Univariable and multivariable Cox regression analyses was used for each sex separately after multiple imputation to calculate HR. RESULTS Multivariable Cox regression analyses showed that increasing age increased the risk of admission for acute colonic diverticulitis: Comparing with ages < 50 years, females with age 50-70 years had HR = 3.42, P < 0.001 and age > 70 years, HR = 6.19, P < 0.001. In males the corresponding values were HR = 1.85, P = 0.004 and 2.56, P < 0.001. In patients with obesity (body mass index ≥ 30) the HR = 2.06, P < 0.001 in females and HR = 2.58, P < 0.001 in males. In females, present (HR = 2.11, P < 0.001) or previous (HR = 1.65, P = 0.007) cigarette smoking increased the risk of admission. In males, breathlessness (HR = 2.57, P < 0.001) and living in rural areas (HR = 1.74, P = 0.007) increased the risk. Level of education, physical activity, constipation and type of bread eaten showed no association with admission for acute colonic diverticulitis. CONCLUSION The risk of hospital admission for acute colonic diverticulitis increased with increasing age, in obese individuals, in ever cigarette smoking females and in males living in rural areas. PMID:28082819

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  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. 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.

  15. 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.

  16. 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

  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. 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

  20. 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

  1. 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.

  2. 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.

  3. Carvacrol exhibits anti-oxidant and anti-inflammatory effects against 1, 2-dimethyl hydrazine plus dextran sodium sulfate induced inflammation associated carcinogenicity in the colon of Fischer 344 rats.

    PubMed

    Arigesavan, Kaninathan; Sudhandiran, Ganapasam

    2015-05-29

    Chronic inflammation is one of the remarkable etiologic factors for various human ailments including cancer. The well known hypothesis is that persistent inflammation in colon can increase the risk of colorectal cancer (CRC). In this study, a pharmacological evaluation of carvacrol, a phenolic monoterpene constituent of essential oils produced from aromatic plant Oreganum vulgarea sp. on colitis associated colon cancer (CACC) induced by 1,2 Dimethylhydrazine (DMH) and dextran sodium sulfate (DSS) in male Fischer 344 rat model was studied. F344 rats were given three subcutaneous injections of DMH (40 mg/kg body wt) in the first week and were given free access to drinking water containing 1% DSS for the next one week followed by 7-14 days of water as three cycles. Carvacrol was administrated before and after tumor induction at a concentration of 50 mg/kg body weight (o.p). Carvacrol treated groups promotes the endogenous antioxidant system and suppress the inflammation in DMH/DSS induced animals. An increased antioxidant status and restoration of histological lesions in the inflamed colonic mucosa was observed in carvacrol treated rats. This effect was confirmed biochemically by reducing free-radical accumulation and suppressing expression of pro-inflammatory mediators. In this study, Carvacrol significantly increased the anti-oxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) glutathione (GSH) levels and reduced lipid peroxides (LPO), myeloperoxidase (MPO) and nitric oxide (NO) as compared to DMH/DSS induced rats. These dramatic changes facilitate the suppression of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), and interleukin-1 beta (IL-1β) in CACC induced rats. Taken together, these findings suggest that Carvacrol may play a beneficial role in DMH/DSS induced experimental rat model and serve as an excellent dietary antioxidant as well as anti-inflammatory agent. It may represent novel therapeutic interventions

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. Colon-derived uremic biomarkers induced by the acute toxicity of Kansui radix: A metabolomics study of rat plasma and intestinal contents by UPLC-QTOF-MS(E).

    PubMed

    Yang, Zhou; Hou, Jin-Jun; Qi, Peng; Yang, Min; Yan, Bing-Peng; Bi, Qi-Rui; Feng, Rui-Hong; Yang, Wen-Zhi; Wu, Wan-Ying; Guo, De-An

    2016-07-15

    Kansui radix (KR) is a poisonous Chinese herbal medicine recorded in the Chinese Pharmacopoeia, and the acute toxicity obstructs its clinical applications. To explore its acute toxicity mechanism to enhance clinical safety, a metabolomics study based on UPLC-ESI-QTOF-MS(E) was performed. Wistar rats were exposed for 4h to the aqueous and ethyl acetate extracts prepared from KR at a high dose (25g/kg). The contents of six different sections of rat intestine, including the duodenum, jejunum, ileum, cecum, colon, and rectum were collected as samples for the first time, as well as the rat plasma. The interesting results showed that only those rats exposed to the ethyl acetate extract showed a watery diarrhea, similar to the observed acute human toxicity. The identified biomarkers found in the plasma, such as phenol sulfate, indoxyl sulfate, and p-cresol sulfate were significantly perturbed in the rats. These biomarkers are known as colon-derived uremic compounds, which were first reported with respect to KR. The three essential amino acids which produced these biomarkers were only found in the contents of colon and rectum. A hypothesis was proposed that only the colon-derived uremic compounds induced by KR might be responsible for the acute toxicity. Three traditional process methods to reduce the toxicity of KR were compared based on these biomarkers, and different levels of toxicity modulation were observed. These results may be helpful to further understand the mechanism of acute toxicity, and the relevance of the traditional process methods to ameliorate the adverse effects of KR.

  12. 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.

  13. 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

  14. 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.

  15. 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)

  16. 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.

  17. Wheat germ agglutinin anchored chitosan microspheres of reduced brominated derivative of noscapine ameliorated acute inflammation in experimental colitis.

    PubMed

    Kaur, Kamalpreet; Sodhi, Rupinder Kaur; Katyal, Anju; Aneja, Ritu; Jain, Upendra Kumar; Katare, Om Prakash; Madan, Jitender

    2015-08-01

    Reduced brominated derivative of noscapine (Red-Br-Nos, EM012), has potent anti-inflammatory property. However, physicochemical limitations of Red-Br-Nos like low aqueous solubility (0.43×10(-3) g/mL), high lipophilicity (logP∼2.94) and ionization at acidic pH greatly encumber the scale-up of oral drug delivery systems for the management of colitis. Therefore, in present investigation, chitosan microspheres bearing Red-Br-Nos (CTS-MS-Red-Br-Nos) were prepared by emulsion polymerization method and later coated with wheat germ agglutinin (WGA-CTS-MS-Red-Br-Nos) to boost the bioadhesive property. The mean particle size and zeta-potential of CTS-MS-Red-Br-Nos were measured to be 10.5±5.4 μm and 8.1±2.2 mV, significantly (P<0.05) lesser than, 30.2±3.2 μm and 19.2±2.3 mV of WGA-CTS-MS-Red-Br-Nos. Furthermore, various spectral techniques like SEM, FT-IR, DSC and PXRD substantiated that Red-Br-Nos was molecularly dispersed in tailored microspheres in amorphous state. Surface bioadhesive property of WGA-CTS-MS-Red-Br-Nos promoted the affinity toward colon mucin cells in simulated colonic fluid (SCF, pH∼7.2). In vitro release studies carried out on WGA-CTS-MS-Red-Br-Nos and CTS-MS-Red-Br-Nos indicated that SCF with colitis milieu (pH∼4.7) favored the controlled release of Red-Br-Nos, owing to solubilization at acidic pH. Consistently, in vivo investigation also demonstrated the utility of WGA-CTS-MS-Red-Br-Nos, which remarkably attenuated the DSS encouraged neutrophil infiltration, myeloperoxidase activity, and pro-inflammatory cytokine production in C57BL6J mice, as compared to CTS-MS-Red-Br-Nos and Red-Br-Nos suspension. The noteworthy anti-inflammatory activity of WGA-CTS-MS-Red-Br-Nos against acute colitis may be attributed to enhanced drug delivery, affinity and utmost drug exposure at inflamed mucosal layers of colon. In conclusion, WGA-CTS-MS-Red-Br-Nos warrants further in-depth in vitro and in vivo investigations to scale-up the technology for clinical

  18. Regulated Inflammation and Lipid Metabolism in Colon mRNA Expressions of Obese Germfree Mice Responding to Enterobacter cloacae B29 Combined with the High Fat Diet.

    PubMed

    Yan, Huiying; Fei, Na; Wu, Guojun; Zhang, Chenhong; Zhao, Liping; Zhang, Menghui

    2016-01-01

    Increased evidences have demonstrated that gut microbiota targeted diet intervention can alleviate obesity and related metabolic disorders. The underlying mechanism of interactions among diet, microbiota, and host still remains unclear. Enterobacter cloacae B29, an endotoxin-producing strain dominated in the gut of a morbidly obese volunteer (weight 174.8 kg, BMI 58.8 kg m(-2)) was isolated and transplanted to germfree mice (inoculated 10(10) cells of B29 per day for 1 week). Using deep mRNA sequencing technology, we compared different gene expression profiles in the colon samples of the germfree mice treated with/without B29 and/or high fat diet (HFD) for 16 weeks and identified 279 differential expressed genes in total, including up-regulated genes Apoa4 (fold change, 2.77), Ido1 (2.66), Cyp4a10 (7.01), and down-regulated genes Cyp2e1 (0.11), Cyp26b1 (0.34), Akr1b7 (0.42), Adipoq (0.36), Cyp1a1 (0.11), Apoa1 (0.44), Npc1l1 (0.37), Tff2 (0.13), Apoc1 (0.30), Ctla2a (0.34), Mttp (0.49), Lpl (0.48). Fifty-nine GO biological processes and five KEGG pathways, particularly the peroxisome proliferator-activated receptors signaling pathway, were significantly enriched in response to HFD+B29, which were mainly relevant to inflammation and the metabolism of lipid, lipoprotein, and sterols. These functional changes were consistent with the developed obesity, insulin-resistance, and aggravated inflammatory conditions of the HFD+B29 mice. This work provides insight into the gene expression changes in response to HFD+B29, helping to understand the mechanism of the interactions among HFD, B29 and the germfree mice.

  19. Regulated Inflammation and Lipid Metabolism in Colon mRNA Expressions of Obese Germfree Mice Responding to Enterobacter cloacae B29 Combined with the High Fat Diet

    PubMed Central

    Yan, Huiying; Fei, Na; Wu, Guojun; Zhang, Chenhong; Zhao, Liping; Zhang, Menghui

    2016-01-01

    Increased evidences have demonstrated that gut microbiota targeted diet intervention can alleviate obesity and related metabolic disorders. The underlying mechanism of interactions among diet, microbiota, and host still remains unclear. Enterobacter cloacae B29, an endotoxin-producing strain dominated in the gut of a morbidly obese volunteer (weight 174.8 kg, BMI 58.8 kg m-2) was isolated and transplanted to germfree mice (inoculated 1010 cells of B29 per day for 1 week). Using deep mRNA sequencing technology, we compared different gene expression profiles in the colon samples of the germfree mice treated with/without B29 and/or high fat diet (HFD) for 16 weeks and identified 279 differential expressed genes in total, including up-regulated genes Apoa4 (fold change, 2.77), Ido1 (2.66), Cyp4a10 (7.01), and down-regulated genes Cyp2e1 (0.11), Cyp26b1 (0.34), Akr1b7 (0.42), Adipoq (0.36), Cyp1a1 (0.11), Apoa1 (0.44), Npc1l1 (0.37), Tff2 (0.13), Apoc1 (0.30), Ctla2a (0.34), Mttp (0.49), Lpl (0.48). Fifty-nine GO biological processes and five KEGG pathways, particularly the peroxisome proliferator-activated receptors signaling pathway, were significantly enriched in response to HFD+B29, which were mainly relevant to inflammation and the metabolism of lipid, lipoprotein, and sterols. These functional changes were consistent with the developed obesity, insulin-resistance, and aggravated inflammatory conditions of the HFD+B29 mice. This work provides insight into the gene expression changes in response to HFD+B29, helping to understand the mechanism of the interactions among HFD, B29 and the germfree mice. PMID:27877172

  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. 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.

  2. 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.

  3. 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

  4. 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

  5. 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

  6. [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.

  7. 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.

  8. CT findings of colonic complications associated with colon cancer.

    PubMed

    Kim, Sang Won; Shin, Hyeong Cheol; Kim, Il Young; Kim, Young Tong; Kim, Chang-Jin

    2010-01-01

    A broad spectrum of colonic complications can occur in patients with colon cancer. Clinically, some of these complications can obscure the presence of underlying malignancies in the colon and these complications may require emergency surgical management. The complications of the colon that can be associated with colon cancer include obstruction, perforation, abscess formation, acute appendicitis, ischemic colitis and intussusception. Although the majority of these complications only rarely occur, familiarity with the various manifestations of colon cancer complications will facilitate making an accurate diagnosis and administering prompt management in these situations. The purpose of this pictorial essay is to review the CT appearance of the colonic complications associated with colon cancer.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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.

  2. Jussara (Euterpe edulis Mart.) Supplementation during Pregnancy and Lactation Modulates the Gene and Protein Expression of Inflammation Biomarkers Induced by trans-Fatty Acids in the Colon of Offspring

    PubMed Central

    Almeida Morais, Carina; Oyama, Lila Missae; de Oliveira, Juliana Lopez; Carvalho Garcia, Márcia; de Rosso, Veridiana Vera; Sousa Mendes Amigo, Laís; do Nascimento, Claudia Maria Oller; Pisani, Luciana Pellegrini

    2014-01-01

    Maternal intake of trans-fatty acids (TFAs) in the perinatal period triggers a proinflammatory state in offspring. Anthocyanins contained in fruit are promising modulators of inflammation. This study investigated the effect of Jussara supplementation in the maternal diet on the proinflammatory state of the colon in offspring exposed to perinatal TFAs. On the first day of pregnancy rats were divided into four groups: control diet (C), control diet with 0.5% Jussara supplementation (CJ), diet enriched with hydrogenated vegetable fat, rich in TFAs (T), or T diet supplemented with 0.5% Jussara (TJ) during pregnancy and lactation. We showed that Jussara supplementation in maternal diet (CJ and TJ groups) reduced carcass lipid/protein ratios, serum lipids, glucose, IL-6, TNF-α, gene expression of IL-6R, TNF-αR (P < 0.05), TLR-4 (P < 0.01), and increase Lactobacillus spp. (P < 0.05) in the colon of offspring compared to the T group. The IL-10 (P = 0.035) and IL-10/TNF-α ratio (P < 0.01) was higher in the CJ group than in the T group. The 0.5% Jussara supplementation reverses the adverse effects of perinatal TFAs, improving lipid profiles, glucose levels, body composition, and gut microbiota and reducing low-grade inflammation in the colon of 21-day-old offspring, and could contribute to reducing chronic disease development. PMID:25276060

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. Pro-oncogenic role of alternative p38 mitogen-activated protein kinases p38γ and p38δ, linking inflammation and cancer in colitis-associated colon cancer.

    PubMed

    Del Reino, Paloma; Alsina-Beauchamp, Dayanira; Escós, Alejandra; Cerezo-Guisado, Ma Isabel; Risco, Ana; Aparicio, Noelia; Zur, Rafal; Fernandez-Estévez, Marian; Collantes, Elena; Montans, Jose; Cuenda, Ana

    2014-11-01

    p38 MAPK signaling has been implicated in the regulation of processes leading to cancer development and progression. Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association remains largely unknown. The related p38αMAPK (MAPK14) proteins p38γ (MAPK12) and p38δ (MAPK13) were recently shown to modulate the immune response, although their role in tumorigenesis remains controversial and their function in inflammation-associated cancer has not been studied. We analyzed the role of p38γ and p38δ in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model in wild-type (WT), p38γ-, p38δ-, and p38γ/δ-deficient (p38γ/δ(-/-)) mice. We found that p38γ/δ deficiency significantly decreased tumor formation, in parallel with a decrease in proinflammatory cytokine and chemokine production. Analysis of leukocyte populations in p38γ/δ(-/-) mouse colon showed less macrophage and neutrophil recruitment than in WT mice. Furthermore, WT chimeric mice with transplanted p38γ/δ(-/-) bone marrow had less tumors than WT mice transplanted with WT bone marrow, whereas tumor number was significantly increased in p38γ/δ(-/-) chimeric mice with WT bone marrow compared with p38γ/δ(-/-) mice transplanted with p38γ/δ(-/-) bone marrow. Together, our results establish that p38γ and p38δ are central to colitis-associated colon cancer formation through regulation of hematopoietic cell response to injury, and validate p38γ and p38δ as potential targets for cancer therapy.

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. Salmonella Typhimurium exploits inflammation to its own advantage in piglets

    PubMed Central

    Chirullo, Barbara; Pesciaroli, Michele; Drumo, Rosanna; Ruggeri, Jessica; Razzuoli, Elisabetta; Pistoia, Claudia; Petrucci, Paola; Martinelli, Nicola; Cucco, Lucilla; Moscati, Livia; Amadori, Massimo; Magistrali, Chiara F.; Alborali, Giovanni L.; Pasquali, Paolo

    2015-01-01

    Salmonella Typhimurium (S. Typhimurium) is responsible for foodborne zoonotic infections that, in humans, induce self-limiting gastroenteritis. The aim of this study was to evaluate whether the wild-type strain S. Typhimurium (STM14028) is able to exploit inflammation fostering an active infection. Due to the similarity between human and porcine diseases induced by S. Typhimurium, we used piglets as a model for salmonellosis and gastrointestinal research. This study showed that STM14028 is able to efficiently colonize in vitro porcine mono-macrophages and intestinal columnar epithelial (IPEC-J2) cells, and that the colonization significantly increases with LPS pre-treatment. This increase was then reversed by inhibiting the LPS stimulation through LPS antagonist, confirming an active role of LPS stimulation in STM14028-intracellular colonization. Moreover, LPS in vivo treatment increased cytokines blood level and body temperature at 4 h post infection, which is consistent with an acute inflammatory stimulus, capable to influence the colonization of STM14028 in different organs and tissues. The present study proves for the first time that in acute enteric salmonellosis, S. Typhimurium exploits inflammation for its benefit in piglets. PMID:26441914

  17. 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

  18. 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

  19. 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

  20. Inflammation-associated alterations to the intestinal microbiota reduce colonization resistance against non-typhoidal Salmonella during concurrent malaria parasite infection.

    PubMed

    Mooney, Jason P; Lokken, Kristen L; Byndloss, Mariana X; George, Michael D; Velazquez, Eric M; Faber, Franziska; Butler, Brian P; Walker, Gregory T; Ali, Mohamed M; Potts, Rashaun; Tiffany, Caitlin; Ahmer, Brian M M; Luckhart, Shirley; Tsolis, Renée M

    2015-10-05

    Childhood malaria is a risk factor for disseminated infections with non-typhoidal Salmonella (NTS) in sub-Saharan Africa. While hemolytic anemia and an altered cytokine environment have been implicated in increased susceptibility to NTS, it is not known whether malaria affects resistance to intestinal colonization with NTS. To address this question, we utilized a murine model of co-infection. Infection of mice with Plasmodium yoelii elicited infiltration of inflammatory macrophages and T cells into the intestinal mucosa and increased expression of inflammatory cytokines. These mucosal responses were also observed in germ-free mice, showing that they are independent of the resident microbiota. Remarkably, P. yoelii infection reduced colonization resistance of mice against S. enterica serotype Typhimurium. Further, 16S rRNA sequence analysis of the intestinal microbiota revealed marked changes in the community structure. Shifts in the microbiota increased susceptibility to intestinal colonization by S. Typhimurium, as demonstrated by microbiota reconstitution of germ-free mice. These results show that P. yoelii infection, via alterations to the microbial community in the intestine, decreases resistance to intestinal colonization with NTS. Further they raise the possibility that decreased colonization resistance may synergize with effects of malaria on systemic immunity to increase susceptibility to disseminated NTS infections.

  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. Colonic insult impairs lymph flow, increases cellular content of the lymph, alters local lymphatic micro-environment and leads to sustained inflammation in the rat ileum

    PubMed Central

    Cromer, Walter; Wang, Wei; Zawieja, Scott D.; von der Weid, Pierre-Yves; Newell Rogers, M. Karen; Zawieja, David C.

    2015-01-01

    Background Lymphatic dysfunction has been linked to inflammation since the 1930’s. Lymphatic function in the gut and mesentery is grossly underexplored in models of IBD despite the use of lymphatic occlusion in early models of IBD. Activation of the innate and adaptive immune system is a hallmark of TNBS-induced inflammation and is linked to disruption of the intrinsic lymph pump. Recent identification of crosstalk between lymphatic vessel resident immune cells and regulation of lymphatic vessel contractility underscore the importance of the timing of lymphatic dysfunction during tissue inflammation in response to TNBS. Methods To evaluate lymphatic function in TNBS induced inflammation, lymph was collected and flow measured from mesenteric lymphatics. Cellularity and cytokine profile of the lymph was also measured. Histopathology was performed to determine severity of injury and immunofluorescent staining of the mesentery was done to evaluate changes in the population of immune cells that reside near and on gastro-intestinal collecting lymphatics. Results Lymph transport fell 24hrs after TNBS administration and began recovering at 72hrs. Significant reduction of lymph flow preceded significant increase in histopathological score and occurred simultaneously with increased MPO activity. These changes were preceded by increased MHCII+ cells surrounding mesenteric lymphatics leading to an altered lymphatic environment that would favor dysfunction. Conclusions Alterations in environmental factors that effect lymphatic function occur before the development of gross GI inflammation. Reduced lymphatic function in TNBS-mediated inflammation is likely an early factor in the development of injury and that recovery of function is associated with resolution of inflammation. PMID:25939039

  3. 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.

  4. Reducing Length of Hospital Stay Does Not Increase Readmission Rates in Early-Stage Gastric, Colon, and Lung Cancer Surgical Cases in Japanese Acute Care Hospitals

    PubMed Central

    Kunisawa, Susumu; Fushimi, Kiyohide; Imanaka, Yuichi

    2016-01-01

    Background The Japanese government has worked to reduce the length of hospital stay by introducing a per-diem hospital payment system that financially incentivizes the timely discharge of patients. However, there are concerns that excessively reducing length of stay may reduce healthcare quality, such as increasing readmission rates. The objective of this study was to investigate the temporal changes in length of stay and readmission rates as quality indicators in Japanese acute care hospitals. Methods We used an administrative claims database under the Diagnosis Procedure Combination Per-Diem Payment System for Japanese hospitals. Using this database, we selected hospitals that provided data continuously from July 2010 to March 2014 to enable analyses of temporal changes in length of stay and readmission rates. We selected stage I (T1N0M0) gastric, colon, and lung cancer surgical patients who had been discharged alive from the index hospitalization. The outcome measures were length of stay during the index hospitalization and unplanned emergency readmissions within 30 days after discharge. Results From among 804 hospitals, we analyzed 42,585, 15,467, and 40,156 surgical patients for gastric, colon, and lung cancer, respectively. Length of stay was reduced by approximately 0.5 days per year. In contrast, readmission rates were generally stable at approximately 2% or had decreased slightly over the 4-year period. Conclusions In early-stage gastric, colon, and lung cancer surgical patients in Japan, reductions in length of stay did not result in increased readmission rates. PMID:27832182

  5. 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.

  6. Colonic inflammation and enhanced-beta-catenin signaling accompany an increase of the Lachnospiraceae/Streptococcaceae in the hind gut of high-fat diet-fed mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Consumption of an obesigenic / high-fat (HF) diet is associated with a high colon cancer risk, and may alter the gut microbiota. To test the hypothesis that a HF feeding accelerates inflammatory process and changes gut microbiome composition, C57BL/6 mice were fed a HF (45% energy) or low-fat (LF) (...

  7. [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.

  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. 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

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Histamine H2 Receptor-Mediated Suppression of Intestinal Inflammation by Probiotic Lactobacillus reuteri

    PubMed Central

    Gao, Chunxu; Major, Angela; Rendon, David; Lugo, Monica; Jackson, Vanessa; Shi, Zhongcheng; Mori-Akiyama, Yuko

    2015-01-01

    ABSTRACT Probiotics and commensal intestinal microbes suppress mammalian cytokine production and intestinal inflammation in various experimental model systems. Limited information exists regarding potential mechanisms of probiotic-mediated immunomodulation in vivo. In this report, we demonstrate that specific probiotic strains of Lactobacillus reuteri suppress intestinal inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model. Only strains that possess the hdc gene cluster, including the histidine decarboxylase and histidine-histamine antiporter genes, can suppress colitis and mucosal cytokine (interleukin-6 [IL-6] and IL-1β in the colon) gene expression. Suppression of acute colitis in mice was documented by diminished weight loss, colonic injury, serum amyloid A (SAA) protein concentrations, and reduced uptake of [18F]fluorodeoxyglucose ([18F]FDG) in the colon by positron emission tomography (PET). The ability of probiotic L. reuteri to suppress colitis depends on the presence of a bacterial histidine decarboxylase gene(s) in the intestinal microbiome, consumption of a histidine-containing diet, and signaling via the histamine H2 receptor (H2R). Collectively, luminal conversion of l-histidine to histamine by hdc+ L. reuteri activates H2R, and H2R signaling results in suppression of acute inflammation within the mouse colon. PMID:26670383

  18. 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

  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. 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.

  1. A transgenic probiotic secreting a parasite immunomodulator for site-directed treatment of gut inflammation.

    PubMed

    Whelan, Rose A; Rausch, Sebastian; Ebner, Friederike; Günzel, Dorothee; Richter, Jan F; Hering, Nina A; Schulzke, Jörg-Dieter; Kühl, Anja A; Keles, Ahmed; Janczyk, Pawel; Nöckler, Karsten; Wieler, Lothar H; Hartmann, Susanne

    2014-10-01

    New treatment strategies for inflammatory bowel disease are needed and parasitic nematode infections or application of helminth components improve clinical and experimental gut inflammation. We genetically modified the probiotic bacterium Escherichia coli Nissle 1917 to secrete the powerful nematode immunomodulator cystatin in the gut. This treatment was tested in a murine colitis model and on post-weaning intestinal inflammation in pigs, an outbred model with a gastrointestinal system similar to humans. Application of the transgenic probiotic significantly decreased intestinal inflammation in murine acute colitis, associated with increased frequencies of Foxp3(+) Tregs, suppressed local interleukin (IL)-6 and IL-17A production, decreased macrophage inflammatory protein-1α/β, monocyte chemoattractant protein -1/3, and regulated upon activation, normal T-cell expressed, and secreted expression and fewer inflammatory macrophages in the colon. High dosages of the transgenic probiotic were well tolerated by post-weaning piglets. Despite being recognized by T cells, secreted cystatin did not lead to changes in cytokine expression or macrophage activation in the colon. However, colon transepithelial resistance and barrier function were significantly improved in pigs receiving the transgenic probotic and post-weaning colon inflammation was reduced. Thus, the anti-inflammatory efficiency of a probiotic can be improved by a nematode-derived immunoregulatory transgene. This treatment regimen should be further investigated as a potential therapeutic option for inflammatory bowel disease.

  2. A Transgenic Probiotic Secreting a Parasite Immunomodulator for Site-Directed Treatment of Gut Inflammation

    PubMed Central

    Whelan, Rose A; Rausch, Sebastian; Ebner, Friederike; Günzel, Dorothee; Richter, Jan F; Hering, Nina A; Schulzke, Jörg-Dieter; Kühl, Anja A; Keles, Ahmed; Janczyk, Pawel; Nöckler, Karsten; Wieler, Lothar H; Hartmann, Susanne

    2014-01-01

    New treatment strategies for inflammatory bowel disease are needed and parasitic nematode infections or application of helminth components improve clinical and experimental gut inflammation. We genetically modified the probiotic bacterium Escherichia coli Nissle 1917 to secrete the powerful nematode immunomodulator cystatin in the gut. This treatment was tested in a murine colitis model and on post-weaning intestinal inflammation in pigs, an outbred model with a gastrointestinal system similar to humans. Application of the transgenic probiotic significantly decreased intestinal inflammation in murine acute colitis, associated with increased frequencies of Foxp3+ Tregs, suppressed local interleukin (IL)-6 and IL-17A production, decreased macrophage inflammatory protein-1α/β, monocyte chemoattractant protein -1/3, and regulated upon activation, normal T-cell expressed, and secreted expression and fewer inflammatory macrophages in the colon. High dosages of the transgenic probiotic were well tolerated by post-weaning piglets. Despite being recognized by T cells, secreted cystatin did not lead to changes in cytokine expression or macrophage activation in the colon. However, colon transepithelial resistance and barrier function were significantly improved in pigs receiving the transgenic probotic and post-weaning colon inflammation was reduced. Thus, the anti-inflammatory efficiency of a probiotic can be improved by a nematode-derived immunoregulatory transgene. This treatment regimen should be further investigated as a potential therapeutic option for inflammatory bowel disease. PMID:24985163

  3. 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

  4. 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

  5. Laparoscopic colostomy for acute left colon obstruction caused by diverticular disease in high risk patient: A case report

    PubMed Central

    Palladino, Elisa; Cappiello, Antonio; Guarino, Vincenzo; Perrotta, Nicola; Loffredo, Domenico

    2015-01-01

    Introduction The colostomy is often necessary in complicated divertcular disease. The laparoscopic colostomy is not widely used for the treatment of complicated diverticular disease. Its use in patients with high operative risk is still on debate. The aim of this case report was to present the benefits of laparoscopic colostomy in patients with high peri-and postoperative risk factors. Presentation of case We present a case of 76-year-old female admitted to emergency unit for left colonic obstruction. The patient had a past history of liver cirrhosis HCV-related with a severe malnutrition, hypertrophic cardiomyopathy, diverticular disease, hiatal ernia, previous appendectomy. Patient was classified according to their preoperative risk ASA 3 (classification of the American society of Anestesia-ASA score). Contrast-enhanced abdominal CT revealed a marked thickening in the sigmoid colon and a marked circumferential stenosis in the sigmoid colon in absence of neoplasm, and/or abscess. The laparoscopic procedure is proposed as first intention. Discussion The operation time was 50 min, and the hospital stay was 4 days. Post operative complications grade I according to the Clavien Dindo Classification. Conclusions Laparoscopic colostomy is safe and feasible procedure in experienced hands. It is associated with low morbidity and short stay in hospital and should be considered a good alternative to a laparotomy. PMID:26036456

  6. [Purulent pericarditis and colonic infiltrating to Salmonella enteritidis complicated by acute intussusception in a case of IL-12Rβ1 deficiency].

    PubMed

    Ailal, F; Tazi, A; Bustamante, J; Picard, C; Najib, J; Casanova, J-L; Bousfiha, A A

    2014-12-01

    IL-12 receptor β1 deficiency (IL-12Rβ1) predisposes patients to mycobacteria and Salmonella infections. We report a case of IL-12Rβ1 deficiency with a fatal multi-resistant Salmonella enteritidis infection. This boy was born after from a consanguineous marriage, and diagnosed as having a IL-12Rβ1 deficiency since the age of 3 months. He presented with recurrent Salmonella enteritidis essentially digestive localization, complicated by purulent pericarditis at the same germ at the age of two and a half years. At the age of 3, a colonic infiltration due to a Salmonella enteritidis resistant to antibiotics, was complicated by acute intussusception, and the child died. The IL-12Rβ1 deficiency is considered as having a good prognosis, in contrast to what happened in our patient. We review therapeutic issues in these patients.

  7. Dipotassium Glycyrrhizate Inhibits HMGB1-Dependent Inflammation and Ameliorates Colitis in Mice

    PubMed Central

    Vitali, Roberta; Palone, Francesca; Cucchiara, Salvatore; Negroni, Anna; Cavone, Leonardo; Costanzo, Manuela; Aloi, Marina; Dilillo, Anna; Stronati, Laura

    2013-01-01

    Background High mobility group box-1 (HMGB1) is a DNA-binding protein that is released from injured cells during inflammation. Advances in targeting HMGB1 represent a major challenge to improve the treatment of acute/chronic inflammation. Aim This study is aimed at verifying whether the inhibition of HMGB1 through dipotassium glycyrrhizate (DPG) is a good strategy to reduce intestinal inflammation. Methods Human colon adenocarcinoma cell line, HT29, human epithelial colorectal adenocarcinoma, Caco2, and murine macrophage cell line, RAW 264.7, were cultured to investigate the effect of DPG on the secretion of HMGB1. Acute colitis was induced in C57BL/6 mice through administration of 3% dextran sodium sulphate (DSS); a combined treatment with DSS and 3 or 8 mg/kg/day DPG was used to investigate the effects of DPG on intestinal inflammation. Animals were euthanized at seventh day and colonic samples underwent molecular and histological analyses. Results DPG significantly reduces in vitro the release of HMGB1 in the extracellular matrix as well as expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, by inhibiting HMGB1. Moreover, DPG significantly decreases the severity of DSS-induced colitis in mice. Murine colonic samples show decreased mRNA levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, RAGE and TLR4. Finally, HMGB1, abundantly present in the feces of mice with DSS-induced colitis, is strongly reduced by DPG. Conclusions HMGB1 is an early pro-inflammatory cytokine and an active protagonist of mucosal gut inflammation. DPG exerts inhibitory effects against HMGB1 activity, significantly reducing intestinal inflammation. Thus, we reason that DPG could represent an innovative tool for the management of human intestinal inflammation. PMID:23840500

  8. 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.

  9. Activation of mucosal mast cells promotes inflammation-related colon cancer development through recruiting and modulating inflammatory CD11b(+)Gr1(+) cells.

    PubMed

    Xu, Lingzhi; Yi, Hong-Gan; Wu, Zhiyuan; Han, Wenxiao; Chen, Kun; Zang, Mengya; Wang, Dongmei; Zhao, Xinhua; Wang, Hongying; Qu, Chunfeng

    2015-08-10

    Mast cells (MCs) have been reported to be one of the important immunoregulatory cells in promoting the development of colitis-related colon cancer (CRC). It is not clear which MC subtypes play critical roles in CRC progression from colitis to cancer because mucosal mast cells (MMCs) are distinct from connective tissue mast cells (CTMCs) in maintaining intestinal barrier function under homeostatic and inflammatory conditions. In the current study, we found that MMC numbers and the gene expressions of MMC-specific proteases increased significantly in an induced CRC murine model. The production of mast cell protease-1 (mMCP-1) after MMC activation not only resulted in the accumulation of CD11b(+)Gr1(+) inflammatory cells in the colon tissues but also modulated the activities of CD11b(+)Gr1(+) cells to support tumor cell growth and to inhibit T cell activation. Blocking the MMC activity in mice that had developed colitis-related epithelium dysplasia, CD11b(+)Gr1(+) infiltration was reduced and CRC development was inhibited. Our results suggest that MMC activation recruited and modulated the CD11b(+)Gr1(+) cells to promote CRC and that MMCs can be potential therapeutic targets for the prevention of CRC development.

  10. 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

  11. 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

  12. 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.

  13. Anti-inflammatory effects of eugenol on lipopolysaccharide-induced inflammatory reaction in acute lung injury via regulating inflammation and redox status.

    PubMed

    Huang, Xianfeng; Liu, Yuanyuan; Lu, Yingxun; Ma, Chunhua

    2015-05-01

    Acute lung injury (ALI) represents a clinical syndrome that results from complex responses of the lung to a multitude of direct and indirect insults. This study aims to evaluate the possible mechanisms responsible for the anti-inflammatory effects of eugenol (EUL) on lipopolysaccharide (LPS)-induced inflammatory reaction in ALI. ALI was induced in mice by intratracheal instillation of LPS (0.5 mg/kg), and EUL (5, and 10 mg/kg) was injected intraperitoneally 1h prior to LPS administration. After 6h, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings suggest that the protective mechanism of EUL may be attributed partly to decreased production of proinflammatory cytokines through the regulating inflammation and redox status. The results support that use of EUL is beneficial in the treatment of ALI.

  14. 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.

  15. Colon cancer

    MedlinePlus

    Colorectal cancer; Cancer - colon; Rectal cancer; Cancer - rectum; Adenocarcinoma - colon; Colon - adenocarcinoma ... In the United States, colorectal cancer is one of the leading causes of deaths due to cancer. Early diagnosis can often lead to a complete cure. Almost ...

  16. Homeostatic responses of colonic LGR5+ stem cells following acute in vivo exposure to a genotoxic carcinogen.