Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2
Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2
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DOI：
10.1016/s0002-9440(10)64466-5
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发表时间：
2002-11-01
影响因子：
6
通讯作者：
Vergnolle, N
中科院分区：
文献类型：
--
作者：
Cenac, N;Coelho, AM;Vergnolle, N
蛋白水解酶激活受体(PAR)-2是一种G蛋白偶联的胰酶和肥大细胞类胰蛋白酶受体，在肠道中高度表达。炎症性肠病患者结肠中管腔胰酶和胰蛋白酶升高。我们假设腔蛋白水解酶激活PAR-2并诱导结肠炎。小鼠接受结肠内PAR-2激动剂(胰酶、胰蛋白酶和选择性PAR2激活肽)或对照药物(煮沸的酶、失活肽)，并在治疗后的不同时间跟踪炎症参数。结肠给予PAR-2激动剂上调了PAR-2的表达，并诱导了以粒细胞浸润、壁厚增加、组织损伤和T辅助细胞1型细胞因子升高为特征的炎症反应。炎症反应在4-6小时达到最大，48小时后消退。PAR-2的激活也增加了结肠的细胞旁通透性，并诱导细菌移位到腹膜器官。在野生型小鼠中观察到的这些促炎和病理生理变化在PAR 2缺陷小鼠中没有检测到。腔蛋白水解酶激活小鼠结肠中的PAR-2以诱导炎症并破坏肠道屏障的完整性。由于在克罗恩病或溃疡性结肠炎患者的结肠腔中发现高水平的胰酶和胰蛋白酶，我们的数据可能直接与人类炎症性肠病的病理生理学有关。
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.