Gastritis increases resistance to aspirin-induced mucosal injury via COX-2-mediated lipoxin synthesis.
Products of cyclooxygenase (COX)-2 contribute to mucosal defense. Acetylation of COX-2 by aspirin has been shown to result in the generation of 15(R)-epi-lipoxin A4, which exerts protective effects in the stomach. In gastritis, it is possible that lipoxin A4 makes a greater contribution to mucosal defense. We tested this hypothesis in the rat, by using the iodoacetamide-induced gastritis model. Iodoacetamide was added to the drinking water for 5 days. Rats were then given aspirin, and the extent of gastric damage was blindly assessed 3 h later. Gastric 15(R)-epi-lipoxin A4 and PGE2 levels were determined. The effects of pretreatment with a selective COX-2 inhibitor, rofecoxib, and of a lipoxin receptor antagonist were assessed. Effects of aspirin and the other test drugs on leukocyte adherence within mesenteric venules were assessed by intravital microscopy. Aspirin elicited greater lipoxin synthesis in the inflamed than in the normal stomach, and there was reduced gastric damage. Rofecoxib inhibited lipoxin synthesis and exacerbated aspirin-induced damage. The lipoxin antagonist also exacerbated aspirin-induced damage. In rats with gastritis, aspirin reduced leukocyte adherence (in contrast to an increase in normal rats), and this effect was reversed by rofecoxib or by the lipoxin antagonist. These results support the notion that aspirin-triggered lipoxin synthesis via COX-2 makes an important contribution to mucosal defense in both the normal and inflamed stomach.
Souza
Marcellus H L P
MH
Dept. of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.
de Lima
Octavio Menezes
OM
Zamuner
Stella R
SR
Fiorucci
Stefano
S
Wallace
John L
JL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004198:Disease Susceptibility; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D005756:Gastritis / Q000276:immunology / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D007962:Leukocytes / Q000276:immunology; D044045:Lipoxins; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D013450:Sulfones
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; D007783:Lactones; D044045:Lipoxins; D013450:Sulfones; C040527:lipoxin A4; C116926:rofecoxib; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001241:Aspirin