Strictures in Crohn’s disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin

Gelbmann, Cornelia M.; Mestermann, S.; Groß, Volker; Köllinger, M; Schölmerich, J; Falk, Werner

doi:10.1136/gut.45.2.210

Cited by 147 publications

(103 citation statements)

References 30 publications

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“…Studies in mast cell-deficient mice suggest that tissue mast cells do not mediate the response of murine intestinal muscle to TNBS-induced inflammation (5). Although tissue mast cell numbers are decreased during the inflammatory response to TNBS and in Crohn's disease generally (19,22,27), an increase in mast cells in the submucosa and both circular and longitudinal smooth muscle layers is seen during the chronic, fibrotic response to TNBS and in the strictures of human Crohn's disease patients suggesting mast cells play a role in tissue fibrosis (6,23,31). During the course of chronic inflammation induced by TNBS in the mouse and in other models of colitis, a sequential pattern of immunological response is observed (1,3,4).…”

Section: Discussionmentioning

confidence: 98%

Endogenous IGF-I and α_vβ₃ integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

Hazelgrove

Flynn²,

Qiao³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hazelgrove KB, Flynn RS, Qiao LY, Grider JR, Kuemmerle JF. Endogenous IGF-I and ␣v␤3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol 296: G1230 -G1237, 2009. First published April 9, 2009 doi:10.1152/ajpgi.90508.2008.-Endogenous insulinlike growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented by the ␣v␤3 integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although ␣ v␤3 integrin expression was not altered by TNBSinduced colitis, vitronectin and fibronectin levels were increased by 80 Ϯ 10% and 90 Ϯ 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBStreated rats was increased by 86 Ϯ 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3␤ phosphorylation in muscle cells of TNBS-treated rats were also increased by 140 -180%. TNBS treatment increased basal muscle cell proliferation by 130 Ϯ 15% and decreased apoptosis by 20 Ϯ 2% compared with that in vehicletreated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an ␣v␤3 integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of ␣ v␤3 integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease.

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Section: Discussionmentioning

confidence: 98%

Endogenous IGF-I and α_vβ₃ integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

Hazelgrove

Flynn²,

Qiao³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…For example, we showed that experimental inflammatory arthritis was significantly attenuated in 6 − /7 − B6 mice and 6 − /7 + B6 mice relative to 6 + /7 − B6 mice (11,12). Increased numbers of hTryptase-β + MCs have been detected in intestinal specimens from patients with ulcerative colitis (UC) and Crohn disease (13). Colorectal biopsies from UC patients also constitutively released significantly more immunoreactive hTryptase-β into the conditioned medium than did colorectal biopsies from normal individuals (14).…”

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confidence: 94%

Essential role for mast cell tryptase in acute experimental colitis

Hamilton

Sinnamon

Lyng³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

102

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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.

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“…On this point, a recent paper has shown that, beside type 2 lymphocytes, mucosal mast cells are also a significant source of IL-5 in Crohn disease (26). This is particularly relevant when considering the mucosal infiltration with mast cells (27) as well as their activation even in quiescent Crohn disease (2,28). Such an impact of mast cells on mucosal eosinophil migration has already been suggested in asthma (29).…”

Section: Discussionmentioning

confidence: 99%

Increased Response of Blood Eosinophils to Various Chemotactic Agents in Quiescent Crohn Disease

Denis¹,

Louis²,

Malaise³

et al. 2001

Scandinavian Journal of Gastroenterology

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Background: The number of eosinophils is increased in the mucosae of the digestive and the respiratory tracts in Crohn disease, even clinically quiescent. The mechanisms underlying this panmucosal eosinophilia are unknown. Methods: The response of blood eosinophils to various chemotactic agents was assessed in 15 patients with clinically quiescent Crohn disease. The results were compared with 15 healthy controls. After purification, eosinophils were placed in Boyden microchambers and the chemotactic effect of PAF (10 -7 M), RANTES (50ng/ml), IL-5 (0-20ng/ml), IL-8 (0-50ng/ml), Eotaxin (0-50 ng/ml) was evaluated. The number of eosinophils in induced sputum of these Crohn disease patients and controls was also assessed and the correlation between chemotaxis and eosinophil count in induced sputum was studied.

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Strictures in Crohn’s disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin

Cited by 147 publications

References 30 publications

Endogenous IGF-I and α_vβ₃ integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

Endogenous IGF-I and α_vβ₃ integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

Essential role for mast cell tryptase in acute experimental colitis

Increased Response of Blood Eosinophils to Various Chemotactic Agents in Quiescent Crohn Disease

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Strictures in Crohn’s disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin

Cited by 147 publications

References 30 publications

Endogenous IGF-I and αvβ3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

Endogenous IGF-I and αvβ3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

Essential role for mast cell tryptase in acute experimental colitis

Increased Response of Blood Eosinophils to Various Chemotactic Agents in Quiescent Crohn Disease

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Product

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Endogenous IGF-I and α_vβ₃ integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

Endogenous IGF-I and α_vβ₃ integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis