Relative contribution of acetylated cyclo-oxygenase (COX)-2 and 5-lipooxygenase (LOX) in regulating gastric mucosal integrity and adaptation to aspirin

FASEB J. 2003 Jun;17(9):1171-3. doi: 10.1096/fj.02-0777fje. Epub 2003 Apr 22.

Abstract

In addition to inhibiting formation of prothrombotic eicosanoids, aspirin causes the acetylation of cyclooxygenase (COX)-2. The acetylated COX-2 remains active, and upon cell activation, initiates the generation of 15R-HETE, a lipid substrate for 5-lipoxygenase (LOX) leading to the formation of 15-epi-LXA4 (also termed "aspirin-triggered lipoxin," or ATL). Because ATL potently inhibits polymorphonuclear cell (PMN) function, we assessed the relative contribution of this lipid mediator in conjunction with another 5-LOX product, the leukotriene (LT)B4, to the pathogenesis of acute damage and gastric adaptation to aspirin. Data presented herein indicate that acute injury and gastric adaptation to aspirin is associated with ATL generation. Administration of COX inhibitors (celecoxib, indomethacin, ketoprofen) to aspirin-treated rats exacerbated acute injury and abolished adaptation to aspirin. Moreover, it inhibited ATL formation and caused a four- to fivefold increase in LTB4 synthesis. In contrast, licofelone, a COX/5-LOX inhibitor, did not exacerbate acute gastric injury nor did it interfere with gastric adaptation to aspirin. Although licofelone blocked ATL and LTB4 formation in aspirin-treated rats, it attenuated aspirin-induced gastric PMN margination. These findings indicate that the balance between the production of LTB4 and ATL modulates PMN recruitment/function and gastric mucosal responses to aspirin.

MeSH terms

  • Acetates / toxicity
  • Acetylation
  • Adaptation, Physiological
  • Animals
  • Arachidonate 5-Lipoxygenase / chemistry
  • Arachidonate 5-Lipoxygenase / physiology*
  • Aspirin / toxicity*
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / toxicity*
  • Gastric Mucosa / drug effects*
  • Gastric Mucosa / enzymology
  • Gastric Mucosa / pathology
  • Gastric Mucosa / physiology
  • Hydroxyeicosatetraenoic Acids / biosynthesis
  • Isoenzymes / chemistry
  • Isoenzymes / physiology*
  • Leukotriene B4 / biosynthesis
  • Lipoxins*
  • Lipoxygenase Inhibitors / toxicity
  • Models, Biological
  • Prostaglandin-Endoperoxide Synthases / chemistry
  • Prostaglandin-Endoperoxide Synthases / physiology*
  • Pyrroles / toxicity
  • Rats

Substances

  • Acetates
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • Isoenzymes
  • Lipoxins
  • Lipoxygenase Inhibitors
  • Pyrroles
  • lipoxin A4
  • Leukotriene B4
  • Arachidonate 5-Lipoxygenase
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • licofelone
  • Aspirin