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

Ken Ichiro Tanaka, Shintaro Suemasu, Tomoaki Ishihara, Yuichi Tasaka, Yasuhiro Arai, Tohru Mizushima

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 PGE2 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 PGE2.

Original languageEnglish
Pages (from-to)120-132
Number of pages13
JournalEuropean Journal of Pharmacology
Volume603
Issue number1-3
DOIs
Publication statusPublished - 2009 Jan 28
Externally publishedYes

Fingerprint

Cyclooxygenase 1
Cyclooxygenase 2
Colitis
Dinoprostone
Anti-Inflammatory Agents
Pharmaceutical Preparations
Dextran Sulfate
Cyclooxygenase 2 Inhibitors
Mucins
Inflammatory Bowel Diseases
Growth
Intestinal Mucosa
Prostaglandin-Endoperoxide Synthases
Proteins
Animal Models

Keywords

  • Colitis
  • Cyclooxygenase-1
  • Cyclooxygenase-2
  • NSAIDs
  • Prostaglandins E

ASJC Scopus subject areas

  • Pharmacology

Cite this

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. / Tanaka, Ken Ichiro; Suemasu, Shintaro; Ishihara, Tomoaki; Tasaka, Yuichi; Arai, Yasuhiro; Mizushima, Tohru.

In: European Journal of Pharmacology, Vol. 603, No. 1-3, 28.01.2009, p. 120-132.

Research output: Contribution to journalArticle

Tanaka, Ken Ichiro ; Suemasu, Shintaro ; Ishihara, Tomoaki ; Tasaka, Yuichi ; Arai, Yasuhiro ; Mizushima, Tohru. / 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. In: European Journal of Pharmacology. 2009 ; Vol. 603, No. 1-3. pp. 120-132.
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