Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage.
OBJECTIVE
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 microg/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.
Fiorucci
Stefano
S
Clinica di Gastroenterologia ed Endoscopia Digestiva, Dipartimento di Medicina Clinica, Patologia e Farmacologia, Università degli Studi di Perugia, Perugia, Italy.
de Lima
Octavio Menezes
OM
Mencarelli
Andrea
A
Palazzetti
Barbara
B
Distrutti
Eleonora
E
McKnight
Webb
W
Dicay
Michael
M
Ma
Li
L
Romano
Mario
M
Morelli
Antonio
A
Wallace
John L
JL
D000818:Animals; D001241:Aspirin / Q000009:adverse effects* / Q000494:pharmacology; D000068579:Celecoxib; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D004351:Drug Resistance / Q000502:physiology; D005753:Gastric Mucosa / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D044045:Lipoxins; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; D007783:Lactones; D044045:Lipoxins; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C040527:lipoxin A4; C116926:rofecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D000068579:Celecoxib; D001241:Aspirin