Hyun E, Andrade-Gordon P, Steinhoff M, Vergnolle N
Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Canada.
Gut. 2008 Sep;57(9):1222-9. doi: 10.1136/gut.2008.150722. Epub 2008 May 6.
The role of protease-activated receptor-2 (PAR(2)) during intestinal inflammation is still unclear due to the fact that PAR(2)-activating peptide has both pro- and anti-inflammatory properties. The aim of this study was to investigate the effects of PAR(2) deficiency (using PAR(2)-deficient mice, PAR(2)(-/-)) in models of colitis, in order to elucidate the role of endogenous PAR(2) in the process of inflammation in the gut.
Colonic inflammation in wild-type and PAR(2)(-/-) mice was induced by dextran sodium sulfate, trinitrobenzene sulfonic acid (TNBS), a T helper-1 predominant model, or oxazolone, a T helper-2 predominant model. Leukocyte recruitment, assessed by intravital microscopy, and inflammatory parameters (myeloperoxidase (MPO), macroscopic and microscopic damage) were assessed during the development of colitis. Lastly, the protein levels of cyclooxygenases (COXs) and adhesion molecules (ICAM-1, VCAM-1, alpha-M, alpha-4) were assessed by using western blot analysis.
In all three models of colitis, MPO activity, macroscopic damage score and bowel thickness were significantly lower in PAR(2)(-/-) mice. Changes in vessel leukocyte recruitment parameters (rolling and adhesion) were also significantly reduced in PAR(2)(-/-) mice compared to wild-type mice after the induction of colitis. The protein expression of ICAM-1, VCAM-1 and alpha-4 was significantly attenuated, whereas the expression of COX-1 was significantly increased in PAR(2)(-/-) mice challenged with TNBS-induced colitis.
The role of endogenous PAR(2) in the gut is pro-inflammatory and independent of the T helper-1 or -2 cytokine profile. Endogenous PAR(2) activation controls leukocyte recruitment in the colon and thus appears as a new potential therapeutic target for the treatment of inflammatory bowel disease.
由于蛋白酶激活受体-2（PAR(2)）激活肽具有促炎和抗炎双重特性，其在肠道炎症中的作用仍不明确。本研究旨在通过结肠炎模型研究PAR(2)缺陷（使用PAR(2)基因敲除小鼠，PAR(2)(-/-)）的影响，以阐明内源性PAR(2)在肠道炎症过程中的作用。
通过右旋糖酐硫酸钠、三硝基苯磺酸（TNBS，一种以辅助性T细胞1为主导的模型）或恶唑酮（一种以辅助性T细胞2为主导的模型）诱导野生型和PAR(2)(-/-)小鼠发生结肠炎症。在结肠炎发展过程中，通过活体显微镜评估白细胞募集情况，并评估炎症参数（髓过氧化物酶（MPO）、大体和显微镜下损伤）。最后，采用蛋白质印迹分析评估环氧化酶（COXs）和黏附分子（ICAM-1、VCAM-1、α-M、α-4）的蛋白质水平。
在所有三种结肠炎模型中，PAR(2)(-/-)小鼠的MPO活性、大体损伤评分和肠壁厚度均显著降低。与野生型小鼠相比，PAR(2)(-/-)小鼠在诱导结肠炎后血管白细胞募集参数（滚动和黏附）的变化也显著减少。在用TNBS诱导结肠炎的PAR(2)(-/-)小鼠中，ICAM-1、VCAM-1和α-4的蛋白质表达显著减弱，而COX-1的表达显著增加。
内源性PAR(2)在肠道中的作用是促炎的，且独立于辅助性T细胞1或辅助性T细胞2细胞因子谱。内源性PAR(2)激活控制结肠中的白细胞募集，因此似乎是治疗炎症性肠病的一个新的潜在治疗靶点。
