Inhibition of both COX-1 and COX-2 and resulting decrease in the level of prostaglandins E2 is responsible for non-steroidal anti-inflammatory drug (NSAID)-dependent exacerbation of colitis
Inhibition of both COX-1 and COX-2 and resulting decrease in the level of prostaglandins E2 is responsible for non-steroidal anti-inflammatory drug (NSAID)-dependent exacerbation of colitis
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DOI：
10.1016/j.ejphar.2008.11.058
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发表时间：
2009-01-28
影响因子：
5
通讯作者：
Mizushima, Tohru
中科院分区：
文献类型：
--
作者：
Tanaka, Ken-Ichiro;Suemasu, Shintaro;Mizushima, Tohru
许多临床研究表明，非类固醇抗炎药(NSAIDs)可加重炎症性肠病，但其发生的分子机制尚不清楚。非甾体抗炎药抑制环氧合酶(COX)，COX有COX-1和COX-2两种亚型。在这项研究中，我们研究了不同类型的非甾体抗炎药对葡聚糖硫酸钠(DSS)诱导的结肠炎的影响，这是一种炎症性肠病的动物模型。给予非选择性非甾体抗炎药可加重DSS诱导的结肠炎，但COX-1或COX-2选择性抑制剂不会加重DSS诱导的结肠炎。然而，COX-1和COX-2选择性抑制剂的联合应用加剧了结肠炎。给予COX-1和COX-2选择性抑制剂后，肠道PGE(2)水平显著降低，外源性PGE(2)可抑制NSAIDs加重结肠炎的作用。保护肠粘膜的粘蛋白的表达被非选择性NSAIDs抑制，而PGE2在体内和体外都恢复了这种表达。非选择性非甾体抗炎药抑制肠粘膜细胞生长，PGE2在体内和体外均可恢复肠粘膜细胞生长。这项研究提供的证据表明，抑制COX-1和COX-2以及由此导致的肠道PGE2水平的急剧下降是DSS诱导的结肠炎NSAID依赖加重的原因。此外，粘蛋白蛋白的表达和肠粘膜细胞的生长似乎与这种加重有关，并被PGE(2)抑制。(C)2008爱思唯尔B.V.保留所有权利。
A number of clinical studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) exacerbate inflammatory bowel disease; however the molecular mechanism whereby this occurs remains unclear. NSAIDs inhibit cyclooxygenase (COX), which has subtypes COX-1 and COX-2. In this study, we have examined the effect of various types of NSAIDs on the development of dextran sulfate sodium (DSS)-induced colitis, an animal model of inflammatory bowel disease. The DSS-induced colitis was worsened by administration of nonselective NSAIDs but not by COX-1 or COX-2 selective inhibitors. However, administration of a combination of both COX-1- and COX-2-selective inhibitors exacerbated the colitis. The intestinal level of PGE(2) dramatically decreased in response to administration of COX-1- and COX-2-selective inhibitors, and exogenously administered PGE2 suppressed the exacerbation of colitis by NSAIDs. The expression of mucin proteins, which protect the intestinal mucosa, was suppressed by non-selective NSAIDs and this expression was restored by PGE2, both in vivo and in vitro. Intestinal mucosal cell growth was inhibited by non-selective NSAIDs and this cell growth was restored by PGE2, both in vivo and in vitro. This study provides evidence that inhibition of both COX-1 and COX-2 and the resulting dramatic decrease in the intestinal level of PGE2 is responsible for NSAID-dependent exacerbation of DSS-induced colitis. Furthermore, expression of mucin proteins and intestinal mucosal cell growth seems to be involved in this exacerbation and its suppression by PGE(2). (C) 2008 Elsevier B.V. All rights reserved.