RRC ID 37793
Author Tanaka K, Suemasu S, Ishihara T, Tasaka Y, Arai Y, Mizushima T.
Title 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.
Journal Eur. J. Pharmacol.
Abstract 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 non-selective 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 PGE(2) 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 PGE(2), both in vivo and in vitro. Intestinal mucosal cell growth was inhibited by non-selective NSAIDs and this cell growth was restored by PGE(2), 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 PGE(2) 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).
Volume 603(1-3)
Pages 120-32
Published 2009-1-28
DOI 10.1016/j.ejphar.2008.11.058
PII S0014-2999(08)01212-0
PMID 19101538
MeSH Animals Anti-Inflammatory Agents, Non-Steroidal / adverse effects* Apoptosis / drug effects Cell Line Cell Proliferation / drug effects Colitis / chemically induced* Colitis / enzymology Colitis / metabolism* Colitis / pathology Cyclooxygenase 1 / metabolism* Cyclooxygenase 2 / metabolism* Cyclooxygenase Inhibitors / pharmacology* Cytokines / metabolism Dextran Sulfate / toxicity Dinoprostone / metabolism* Dinoprostone / pharmacology Epithelial Cells / drug effects Epithelial Cells / metabolism Epithelial Cells / pathology Gene Expression Regulation / drug effects Intestinal Mucosa / drug effects Intestinal Mucosa / pathology Mucins / metabolism Reactive Oxygen Species / metabolism
IF 3.04
Times Cited 28
Human and Animal Cells