Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2

被引:333
|
作者
Cenac, N
Coelho, AM
Nguyen, C
Compton, S
Andrade-Gordon, P
MacNaughton, WK
Wallace, JL
Hollenberg, MD
Bunnett, NW
Garcia-Villar, R
Bueno, L
Vergnolle, N
机构
[1] Univ Calgary, Fac Med, Dept Pharm & Therapeut, Calgary, AB T2N 4N1, Canada
[2] Univ Calgary, Fac Med, Dept Physiol & Biophys, Calgary, AB T2N 4N1, Canada
[3] Inst Natl Rech Agron, Neurogastroenterol & Nutr Unit, Toulouse, France
[4] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA
[5] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA
[6] RW Johnson Pharmaceut Res Inst, Spring House, PA 19477 USA
来源
AMERICAN JOURNAL OF PATHOLOGY | 2002年 / 161卷 / 05期
关键词
D O I
10.1016/S0002-9440(10)64466-5
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Proteinase-activated receptor (PAR)-2, a G-protein-coupled receptor for trypsin and mast cell tryptase, is highly expressed in the intestine. Luminal trypsin and tryptase are elevated in the colon of inflammatory bowel disease patients. We hypothesized that luminal proteinases activate PAR-2 and induce colonic inflammation. Mice received intracolonically PAR-2 agonists; (trypsin, tryptase, and a selective PAR2-activating peptide) or control drugs (boiled enzymes, inactive peptide) and inflammatory parameters were followed at various times after this treatment. Colonic administration of PAR-2 agonists up-regulated PAR-2 expression and induced an inflammatory reaction characterized by granulocyte infiltration, increased wall thickness, tissue damage, and elevated T-helper cell type 1 cytokine. The inflammation was maximal between 4 and 6 hours and was resolved 48 hours after the intracolonic administration. PAR-2 activation also increased paracellular permeability of the colon and induced bacterial trans-location into peritoneal organs. These proinflammatory and pathophysiological changes observed in wild-type mice were not detected in PAR 2-deficient mice. Luminal proteinases activate PAR-2 in the mouse colon to induce inflammation and disrupt the integrity of the intestinal barrier. Because trypsin and tryptase are found at high levels in the colon lumen of patients with Crohn's disease or ulcerative colitis, our data may bear directly on the pathophysiology of human inflammatory bowel diseases.
引用
收藏
页码:1903 / 1915
页数:13
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