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Inhibition of both COX-1 and COX-2 and resulting decrease in the level of prostaglandins E2 is responsible for
Ken-Ichiro Tanaka1, Shintaro Suemasu, Tomoaki Ishihara
1Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
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).
Insights
Non-steroidal anti-inflammatory drugs (NSAIDs) worsen inflammatory bowel disease by inhibiting both cyclooxygenase (COX)-1 and COX-2, leading to reduced prostaglandin E2 (PGE2) levels. Exogenous PGE2 administration reversed these effects, highlighting its protective role.
Area of Science:
- Gastroenterology
- Pharmacology
- Molecular Biology
Background:
- Clinical studies indicate non-steroidal anti-inflammatory drugs (NSAIDs) exacerbate inflammatory bowel disease (IBD).
- The precise molecular mechanisms underlying NSAID-induced IBD exacerbation remain incompletely understood.
- NSAIDs function by inhibiting cyclooxygenase (COX) enzymes, which exist as COX-1 and COX-2 isoforms.
Purpose of the Study:
- To investigate the impact of different NSAIDs on dextran sulfate sodium (DSS)-induced colitis, an animal model of IBD.
- To elucidate the role of COX-1 and COX-2 inhibition in NSAID-mediated exacerbation of colitis.
- To determine the involvement of prostaglandin E2 (PGE2) in NSAID-induced intestinal inflammation.
Main Methods:
- Utilized a dextran sulfate sodium (DSS)-induced colitis model in animals.
- Administered various NSAIDs, including non-selective, COX-1 selective, and COX-2 selective inhibitors, individually and in combination.
- Measured intestinal levels of PGE2, mucin protein expression, and intestinal mucosal cell growth in vivo and in vitro.
Main Results:
- Non-selective NSAIDs worsened DSS-induced colitis, while selective COX-1 or COX-2 inhibitors did not.
- A combination of COX-1 and COX-2 selective inhibitors exacerbated colitis, mirroring the effect of non-selective NSAIDs.
- NSAID administration significantly decreased intestinal PGE2 levels.
- Exogenous PGE2 administration suppressed NSAID-induced colitis exacerbation.
- NSAIDs reduced mucin protein expression and intestinal mucosal cell growth, effects reversed by PGE2.
Conclusions:
- Inhibition of both COX-1 and COX-2, leading to a substantial reduction in intestinal PGE2, is responsible for NSAID-dependent exacerbation of DSS-induced colitis.
- The observed exacerbation involves suppressed mucin protein expression and intestinal mucosal cell growth.
- Prostaglandin E2 (PGE2) plays a critical protective role against NSAID-induced intestinal damage in this model.
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