Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage

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-LXA(4). 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 LXA(4) was measured. Effect of exogenous LXA(4) or an LXA(4) receptor antagonist on gastric resistance to aspirin-induced damage was examined. Aspirin-induced leukocyte adherence in mesenteric venules, and the effects of LXA(4), 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-LXA(4) production, which was abolished by celecoxib. LXA(4) dose dependently (0.25-2.5 mug/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-LXA(4) via COX-2. LXA(4) 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.