title: Cyclooxygenase-2-derived lipoxin A4 increases gastric resistance to aspirin-induced damage.
abstract: 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.
authors.affiliation: Clinica di Gastroenterologia ed Endoscopia Digestiva, Dipartimento di Medicina Clinica, Patologia e Farmacologia, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Octavio Menezes
authors.initials: OM
authors.lastname: de Lima
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Palazzetti
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Webb
authors.initials: W
authors.lastname: McKnight
authors.forename: Michael
authors.initials: M
authors.lastname: Dicay
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Mario
authors.initials: M
authors.lastname: Romano
authors.forename: Antonio
authors.initials: A
authors.lastname: Morelli
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
mesh_terms: 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
chemical_list: 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