Gastroenterology

Gastroenterology

Volume 123, Issue 5, November 2002, Pages 1598-1606
Gastroenterology

Basic–Alimentary Tract
Cyclooxygenase-2–derived lipoxin A4 increases gastric resistance to aspirin-induced damage*,**,*

https://doi.org/10.1053/gast.2002.36558Get rights and content

Abstract

Background & Aims: Cyclooxygenase-2 (COX-2) has been implicated as contributing to mucosal defense. Acetylation of COX-2 by aspirin can result in production of an antiinflammatory substance, 15(R)-epi-LXA4. We determined whether aspirin-triggered lipoxin (LX) production via COX-2 diminishes aspirin-induced damage in the rat stomach. Methods: Rats were treated with aspirin plus or minus celecoxib or rofecoxib. Gastric generation of LXA4 was measured. Effect of exogenous LXA4 or an LXA4 receptor antagonist on gastric resistance to aspirin-induced damage was examined. Aspirin-induced leukocyte adherence in mesenteric venules, and the effects of LXA4, were examined by intravital microscopy. Results: Celecoxib and rofecoxib significantly increased the severity of aspirin-induced gastric damage. Aspirin rapidly up-regulated COX-2 expression in the stomach and caused a significant increase in gastric 15(R)-epi-LXA4 production, which was abolished by celecoxib. LXA4 dose dependently (0.25–2.5 μg/kg, intraperitoneally) reduced the severity of aspirin-induced gastric damage and suppressed aspirin-induced leukocyte adherence, whereas an LXA4 antagonist had the opposite effects. Conclusions: Aspirin administration results in elevated production of 15(R)-epi-LXA4 via COX-2. LXA4 exerts very potent protective actions on the gastric mucosa. Co-administration of aspirin and a selective COX-2 inhibitor results in substantially more severe gastric injury than is produced with either agent alone.

GASTROENTEROLOGY 2002;123:1598-1606

Section snippets

Material and methods

Male Wistar rats weighing 200–300 g were obtained from Charles River (Montreal, Canada, or Monza, Italy). All experimental procedures described below were approved by our institutional animal research committees and were in accordance with nationally approved guidelines for the treatment of laboratory animals.

Suppression of COX-1 and COX-2 by aspirin

Preliminary dose-response studies indicated that doses of aspirin of >30 mg/kg produced significant gastric damage. We chose to use a dose of 50 mg/kg of aspirin for the studies described below. At this dosage, aspirin significantly suppressed COX-1 and COX-2. In the carrageenan-airpouch model, aspirin inhibited COX-2-derived PGE2 synthesis by 71% (reduced from 1.24 ± 0.21 ng/mL in the vehicle-treated group to 0.36 ± 0.23 ng/mL; P < 0.05) and suppressed COX-1 activity (whole-blood thromboxane

Discussion

Clinical trials suggest that selective COX-2 inhibitors produce severe gastrointestinal ulcer complications at about half the rate of conventional NSAIDs.22, 23 However, such a safety advantage may be significantly abrogated if the patient treated with a selective COX-2 inhibitor is also using low-dose aspirin, such as for cardioprotection.23 The results of the present study clearly show that selective inhibition of COX-2, with either celecoxib or rofecoxib, can lead to an exacerbation of the

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  • Cited by (0)

    *

    Address requests for reprints to: John L. Wallace, Ph.D., Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. e-mail: [email protected]; fax: (403) 270-3353.

    **

    Supported by a grant from the Canadian Institutes of Health Research.

    *

    Dr. Wallace is an Alberta Heritage Foundation for Medical Research Senior Scientist.

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