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

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.