scholarly journals Essential role for mast cell tryptase in acute experimental colitis

2010 ◽  
Vol 108 (1) ◽  
pp. 290-295 ◽  
Author(s):  
Matthew J. Hamilton ◽  
Mark J. Sinnamon ◽  
Gregory D. Lyng ◽  
Jonathan N. Glickman ◽  
Xueli Wang ◽  
...  
Keyword(s):  
Weight Loss ◽  
Mast Cell ◽  
Experimental Colitis ◽  
Distal Colon ◽  
Trinitrobenzene Sulfonic Acid ◽  
Chemically Induced ◽  
Inflammatory Bowel ◽  
Proinflammatory Role ◽  
Mouse Mast Cell ◽  
Microarray Analyses

Patients with inflammatory bowel disease (IBD) have increased numbers of human tryptase-β (hTryptase-β)-positive mast cells (MCs) in the gastrointestinal tract. The amino acid sequence of mouse mast cell protease (mMCP)-6 is most similar to that of hTryptase-β. We therefore hypothesized that this mMCP, or the related tryptase mMCP-7, might have a prominent proinflammatory role in experimental colitis. The dextran sodium sulfate (DSS) and trinitrobenzene sulfonic acid (TNBS) colitis models were used to evaluate the differences between C57BL/6 (B6) mouse lines that differ in their expression of mMCP-6 and mMCP-7 with regard to weight loss, colon histopathology, and endoscopy scores. Microarray analyses were performed, and confirmatory real-time PCR, ELISA, and/or immunohistochemical analyses were carried out on a number of differentially expressed cytokines, chemokines, and matrix metalloproteinases (MMPs). The mMCP-6–null mice that had been exposed to DSS had significantly less weight loss as well as significantly lower pathology and endoscopy scores than similarly treated mMCP-6–expressing mice. This difference in colitis severity was confirmed endoscopically in the TNBS-treated mice. Evaluation of the distal colon segments revealed that numerous proinflammatory cytokines, chemokines that preferentially attract neutrophils, and MMPs that participate in the remodeling of the ECM were all markedly increased in the colons of DSS-treated WT mice relative to untreated WT mice and DSS-treated mMCP-6–null mice. Collectively, our data show that mMCP-6 (but not mMCP-7) is an essential MC-restricted mediator in chemically induced colitis and that this tryptase acts upstream of many of the factors implicated in IBD.

scholarly journals Corticotropin-Releasing Hormone Deficiency Is Associated with Reduced Local Inflammation in a Mouse Model of Experimental Colitis

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3403-3409 ◽  
Author(s):  
Jérôme Gay ◽  
Efi Kokkotou ◽  
Michael O’Brien ◽  
Charalabos Pothoulakis ◽  
Katia P. Karalis
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Experimental Colitis ◽  
Neutrophil Infiltration ◽  
Hormone Deficiency ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Bowel ◽  
Proinflammatory Role ◽  
Deficient Mice

CRH, the hypothalamic component of the hypothalamic-pituitary adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. CRH is expressed in the intestine and up-regulated in patients with ulcerative colitis. However, its pathophysiological significance in intestinal inflammatory diseases has just started to emerge. In a mouse model of acute, trinitrobenzene sulfonic acid-induced experimental colitis, we demonstrate that, despite low glucocorticoid levels, CRH-deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis and possibly in inflammatory bowel disease in humans. Moreover, the results suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism.

scholarly journals Loss of Nckx3 Exacerbates Experimental DSS-Induced Colitis in Mice through p53/NF-κB Pathway

2021 ◽  
Vol 22 (5) ◽  
pp. 2645
Author(s):  
Dinh Nam Tran ◽  
Seon Myeong Go ◽  
Seon-Mi Park ◽  
Eui-Man Jung ◽  
Eui-Bae Jeung
Keyword(s):  
Immune Response ◽  
Cellular Proliferation ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Experimental Colitis ◽  
Innate Immune ◽  
Inflammatory Conditions ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Microarray Analyses

Inflammatory bowel diseases (IBDs) comprises a range of chronic inflammatory conditions of the intestinal tract. The incidence and prevalence of IBDs are increasing worldwide, but the precise etiology of these diseases is not completely understood. Calcium signaling plays a regulatory role in cellular proliferation. Nckx3, a potassium-dependent Na+/Ca2+ exchanger, is not only expressed in the brain but also in the aortic, uterine, and intestinal tissues, which contain abundant smooth muscle cells. This study investigated the role of Nckx3 in intestinal inflammation. Microarray analyses revealed the upregulation of the innate immune response-associated genes in the duodenum of Nckx3 knockout (KO) mice. The Nckx3 KO mice also showed an increase in IBD- and tumorigenesis-related genes. Using dextran sodium sulfate (DSS)-induced experimental colitis mice models, the Nckx3 KO mice showed severe colitis. Furthermore, the pathways involving p53 and NF-κB signaling were significantly upregulated by the absence of Nckx3. Overall, Nckx3 plays a critical role in the innate immune and immune response and may be central to the pathogenesis of IBD.

Proinflammatory role of vasopressin through V1b receptors in hapten-induced experimental colitis in rodents: implication in IBD

2010 ◽  
Vol 299 (6) ◽  
pp. G1298-G1307 ◽  
Author(s):  
Laurent Ferrier ◽  
Claudine Serradeil-Le Gal ◽  
Anke M. Schulte ◽  
Valentina Vasina ◽  
Eric Gaultier ◽  
...  
Keyword(s):  
Mast Cell ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Paracellular Permeability ◽  
Mast Cell Activation ◽  
Receptor Interaction ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Status ◽  
V1b Receptor

Vasopressin and its receptors modulate several gut functions, but their role in intestinal inflammation is unknown. Our aims were to determine 1) the localization of V1b receptors in human and rodent colon, 2) the role of vasopressin and V1b receptors in experimental colitis using two approaches: V1b−/− mice and a selective V1b receptor antagonist, SSR149415, and 3) the mechanisms involved. V1b receptors were localized in normal and inflamed colon from humans and rats. Experimental colitis was induced in rats and mice and some groups were treated before or after colitis induction with oral SSR149415 (3–30 mg/kg). Other groups of mice were submitted to dehydration to increase vasopressin plasma levels, prior to colitis induction. Body weight, damage scores, MPO, and TNF-α tissue levels were determined. Finally, colonic segments of wild-type (WT) and V1b−/− mice were mounted in Ussing chambers and paracellular permeability in response to vasopressin was studied. V1b receptors were expressed in enterocytes and ganglia cells of the enteric nervous system of human and rat intestine. Expression levels were independent from inflammatory status. Colitis was less severe in rodents treated by either preventive or curative SSR149415 and in V1b−/− mice. 2,4,6-Trinitrobenzene sulfonic acid induced a strong mortality in dehydrated animals that was reversed by preventive SSR149415 or mast cell stabilizer. Vasopressin significantly increased paracellular permeability in WT, but not in V1b−/− mice. Preincubation of colon tissues with SSR149415 abolished the vasopressin effect. Similarly, vasopressin had no effect in colonic preparations from WT mice pretreated with mast cell stabilizers. Vasopressin, through V1b receptor interaction, has proinflammatory properties linked to mast cell activation and downstream alterations of the colonic epithelial barrier. These findings underline the potential interest of V1b receptor blockers in gut inflammatory diseases.

Thiadiazolidinone-8 Ameliorates Inflammation Associated with Experimental Colitis in Mice

Pharmacology ◽  
2017 ◽  
Vol 101 (1-2) ◽  
pp. 35-42 ◽  
Author(s):  
Vanessa Mateus ◽  
João Rocha ◽  
Paula Alves ◽  
Hélder Mota-Filipe ◽  
Bruno Sepodes ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Experimental Colitis ◽  
Trinitrobenzene Sulfonic Acid ◽  
Protective Actions ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
Gsk 3Β ◽  
Necrosis Factor

Thiadiazolidinone-8 (TDZD-8) is an effective thiadiazolidinone derivate that is able to suppress the expression of inflammatory cytokines; it also presents tissue protective actions by glycogen synthase kinase (GSK)-3β inhibition, promoting thus an anti-inflammatory effect. Since inflammatory bowel disease is a chronic disease with reduced quality of life, where currently available therapies are only able to induce or maintain the patient in remission, it is crucial to investigate new pharmacological approaches. The main objective of this study was to evaluate the effect of TDZD-8 in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Male CD-1 mice with TNBS-induced colitis were treated with a daily dose of TDZD-8 5 mg/kg/day IP during 4 days. The anti-inflammatory properties of TDZD-8 in the TNBS-induced colitis were confirmed by suppression of pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and myeloperoxidase, as well as by the significant increase of the anti-inflammatory cytokine, IL-10. These treated mice also presented a reduction in fecal hemoglobin and alkaline phosphatase, suggesting a beneficial effect of TDZD-8. Furthermore, renal and hepatic biomarkers remained stabilized after treatment. In conclusion, TDZD-8 reduces the inflammatory response associated with TNBS-induced colitis in mice, and modulation of GSK-3β seems to be an interesting pharmacological target in colitis.

scholarly journals Hyaluronan Synthase 3 Null Mice Exhibit Decreased Intestinal Inflammation and Tissue Damage in the DSS-Induced Colitis Model

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Sean P. Kessler ◽  
Dana R. Obery ◽  
Carol de la Motte
Keyword(s):  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Experimental Colitis ◽  
Hyaluronan Synthase ◽  
Wild Type ◽  
Colon Tissue ◽  
Dss Colitis ◽  
Chemically Induced ◽  
Inflammatory Bowel ◽  
Colitis Model

Hyaluronan (HA) overproduction is a hallmark of multiple inflammatory diseases, including inflammatory bowel disease (IBD). Hyaluronan can act as a leukocyte recruitment molecule and in the most common mouse model of intestinal inflammation, the chemically induced dextran sodium sulfate (DSS) experimental colitis model, we previously determined that changes in colon distribution of HA occur before inflammation. Therefore, we hypothesized that, during a pathologic challenge, HA promotes inflammation. In this study, we tested the progression of inflammation in mice null for the hyaluronan synthase genes (HAS1, HAS3, or both HAS1 and HAS3) in the DSS-colitis model. Our data demonstrate that both the HAS1/HAS3 double and the HAS3 null mice are protected from colitis, compared to wild-type and HAS1 null mice, as determined by measurement of weight loss, disease activity, serum IL-6 levels, histologic scoring, and immunohistochemistry. Most notable is the dramatic increase in submucosal microvasculature, hyaluronan deposition, and leukocyte infiltration in the inflamed colon tissue of wild-type and HAS1 null mice. Our data suggest, HAS3 plays a crucial role in driving gut inflammation. Developing a temporary targeted therapeutic intervention of HAS3 expression or function in the microcirculation may emerge as a desirable strategy toward tempering colitis in patients undergoing flares of IBD.

scholarly journals Protective Effect of Anthocyanins Extract from Blueberry on TNBS-Induced IBD Model of Mice

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Lin-Hua Wu ◽  
Zeng-Lai Xu ◽  
Di Dong ◽  
Shan-An He ◽  
Hong Yu
Keyword(s):  
Body Weight ◽  
Protective Effect ◽  
Sulfonic Acid ◽  
Experimental Colitis ◽  
Trinitrobenzene Sulfonic Acid ◽  
Protective Effects ◽  
Histological Score ◽  
Inflammatory Bowel ◽  
Necrosis Factor ◽  
Different Doses

This study was carried out to evaluate the protective effect of anthocyanins extract of blueberry on trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel disease (IBD) model of mice. The study employed female C57BL/6 mice (n= 50), and colitis was induced by intracolonic injection of 0.5 mg of TNBS dissolved in 50% ethanol–phosphate buffered solution. The mice were divided into five groups (n= 10): vehicle, TNBS control and anthocyanins groups that received different doses of anthocyanins extract (10, 20 and 40 mg kg-1) daily for 6 days. Both increase in body weight and diarrhea symptoms were monitored each day. After 6 days, the animals were killed, and the following parameters were assessed: colon length, morphological score, histological score and biochemical assay (NO, myeloperoxidase (MPO), interleukin (IL)-12, IL-10, tumor necrosis factor (TNF)-αand interferon (IFN)-γ). The results showed that the anthocyanins extract of blueberry rendered strong protection against TNBS-induced colonic damage at a dosage of 40 mg kg-1. When compared with the control, anthocyanins extract significantly prevented loss of body weight and ameliorated the scores of diarrhea, morphology and histology. Treatment with anthocyanins extract restored IL-10 excretion, as well as caused reduction in the levels of NO, MPO, IL-12, TNF-αand IFN-γ. Our research revealed the protective effect of anthocyanins extract from blueberry on TNBS-induced experimental colitis in mice, as well as examined whether high levels of dietary blueberries would lower the risk or have protective effects on human IBD, which may require further investigation.

scholarly journals Anti-Inflammatory Mechanisms of Enteric Heligmosomoides polygyrus Infection against Trinitrobenzene Sulfonic Acid-Induced Colitis in a Murine Model

2008 ◽  
Vol 76 (10) ◽  
pp. 4772-4782 ◽  
Author(s):  
Thomas L. Sutton ◽  
Aiping Zhao ◽  
Kathleen B. Madden ◽  
Justin E. Elfrey ◽  
Blaine A. Tuft ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mast Cell ◽  
Sulfonic Acid ◽  
Helminth Infection ◽  
Cytokine Expression ◽  
Trinitrobenzene Sulfonic Acid ◽  
Heligmosomoides Polygyrus ◽  
Th2 Cytokine ◽  
Inflammatory Bowel ◽  
Th1 Cytokines

ABSTRACT Recent studies showed that enteric helminth infection improved symptoms in patients with inflammatory bowel disease as well as in experimental models of colitis. The aim of this study was to determine the mechanism of the protective effect of helminth infection on colitis-induced changes in immune and epithelial cell function. BALB/c mice received an oral infection of Heligmosomoides polygyrus third-stage larvae, were given intrarectal saline or trinitrobenzene sulfonic acid (TNBS) on day 10 postinfection, and were studied 4 days later. Separate groups of mice received intrarectal saline or TNBS on day 10 and were studied on day 14. Muscle-free colonic mucosae were mounted in Ussing chambers to measure mucosal permeability and secretion. Expression of cytokines was assessed by quantitative real-time PCR, and mast cells were visualized by immunohistochemistry. TNBS-induced colitis induced mucosal damage, upregulated Th1 cytokines, and depressed secretory responses. Heligmosomoides polygyrus elevated Th2 cytokine expression, increased mast cell infiltration and mucosal resistance, and also reduced some secretory responses. Prior H. polygyrus infection prevented TNBS-induced upregulation of Th1 cytokines and normalized secretory responses to specific agonists. TNBS-induced colitis did not alter H. polygyrus-induced mast cell infiltration or upregulation of Th2 cytokine expression. The results indicate that the protective mechanism of enteric nematode infection against TNBS-induced colitis involves prevention of Th1 cytokine expression and improved colonic function by a mechanism that may involve mast cell-mediated protection of neural control of secretory function. Similar response patterns could account for the clinical improvement seen in inflammatory bowel disease with helminthic therapy.

scholarly journals The Chymase Mouse Mast Cell Protease-4 Regulates Intestinal Cytokine Expression in Mature Adult Mice Infected with Giardia intestinalis

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 925 ◽  
Author(s):  
Zhiqiang Li ◽  
Dimitra Peirasmaki ◽  
Staffan Svärd ◽  
Magnus Åbrink
Keyword(s):  
Weight Loss ◽  
Mast Cell ◽  
Giardia Intestinalis ◽  
Secretory Proteins ◽  
Myeloperoxidase Activity ◽  
Rapid Weight Loss ◽  
Mature Adult ◽  
Mast Cell Protease ◽  
Adult Mice ◽  
Mouse Mast Cell

Mast cells have been shown to affect the control of infections with the protozoan parasite Giardia intestinalis. Recently, we demonstrated that Giardia excretory-secretory proteins inhibited the activity of the connective tissue mast cell-specific protease chymase. To study the potential role of the chymase mouse mast cell protease (mMCP)-4 during infections with Giardia, mMCP-4+/+ and mMCP-4−/− littermate mice were gavage-infected with G. intestinalis trophozoites of the human assemblage B isolate GS. No significant changes in weight gain was observed in infected young (≈10 weeks old) mMCP-4−/− and mMCP-4+/+ littermate mice. In contrast, infections of mature adult mice (>18 weeks old) caused significant weight loss as compared to uninfected control mice. We detected a more rapid weight loss in mMCP-4−/− mice as compared to littermate mMCP-4+/+ mice. Submucosal mast cell and granulocyte counts in jejunum increased in the infected adult mMCP-4−/− and mMCP-4+/+ mice. This increase was correlated with an augmented intestinal trypsin-like and chymotrypsin-like activity, but the myeloperoxidase activity was constant. Infected mice showed a significantly lower intestinal neutrophil elastase (NE) activity, and in vitro, soluble Giardia proteins inhibited human recombinant NE. Serum levels of IL-6 were significantly increased eight and 13 days post infection (dpi), while intestinal IL-6 levels showed a trend to significant increase 8 dpi. Strikingly, the lack of mMCP-4 resulted in significantly less intestinal transcriptional upregulation of IL-6, TNF-α, IL-25, CXCL2, IL-2, IL-4, IL-5, and IL-10 in the Giardia-infected mature adult mice, suggesting that chymase may play a regulatory role in intestinal cytokine responses.

Cyclooxygenase-2-derived prostaglandin D2 is an early anti-inflammatory signal in experimental colitis

2000 ◽  
Vol 279 (1) ◽  
pp. G238-G244 ◽  
Author(s):  
Maureen N. Ajuebor ◽  
Anita Singh ◽  
John L. Wallace
Keyword(s):  
Activity Index ◽  
Experimental Colitis ◽  
Cyclooxygenase 2 ◽  
Trinitrobenzene Sulfonic Acid ◽  
Prostaglandin D2 ◽  
Myeloperoxidase Activity ◽  
Granulocyte Infiltration ◽  
Inflammatory Bowel ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

The ability of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors to exacerbate inflammatory bowel disease suggests that prostaglandins are important anti-inflammatory mediators in this context. Prostaglandin D2 has been suggested to exert anti-inflammatory effects. We investigated the possibility that prostaglandin D2 derived from cyclooxygenase-2 plays an important role in downregulating colonic inflammation in rats. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid. At various times thereafter (from 1 h to 7 days), colonic prostaglandin synthesis and myeloperoxidase activity (index of granulocyte infiltration) were measured. Prostaglandin D2synthesis was elevated >4-fold above controls within 1–3 h of induction of colitis, preceding significant granulocyte infiltration. Treatment with a selective cyclooxygenase-2 inhibitor abolished the increase in prostaglandin D2 synthesis and caused a doubling of granulocyte infiltration. Colonic granulocyte infiltration was significantly reduced by administration of prostaglandin D2 or a DP receptor agonist (BW-245C). These results demonstrate that induction of colitis results in a rapid increase in prostaglandin D2 synthesis via cyclooxygenase-2. Prostaglandin D2 downregulates granulocyte infiltration into the colonic mucosa, probably through the DP receptor.

scholarly journals Ketotifen Treatment of Active Colitis in Patients with 5-Aminosalicylate Intolerance

1998 ◽  
Vol 12 (4) ◽  
pp. 273-275 ◽  
Author(s):  
John K Marshall ◽  
E Jan Irvine
Keyword(s):  
Ulcerative Colitis ◽  
Mast Cell ◽  
Collagenous Colitis ◽  
Experimental Colitis ◽  
Aminosalicylic Acid ◽  
Mucosal Mast Cells ◽  
Active Colitis ◽  
Inflammatory Bowel ◽  
Allergic Disorders

Mast cell stabilizers are commonly used in the treatment of asthma and allergic disorders. Although the role of mucosal mast cells in the pathogenesis of inflammatory bowel disease remains uncertain, mast cell stabilizers have been shown in animal models to attenuate the severity of experimental colitis. The authors' experience with ketotifen in three patients - one each with Crohn's disease, ulcerative colitis and collagenous colitis - who had demonstrated allergy to, or intolerance of, 5-aminosalicylic acid is reported.

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