CYTOPROTECTIVE EFFECTS OF CI-959 IN THE RAT GASTRIC-MUCOSA - MODULATION OF LEUKOCYTE ADHESION

Background & Aims: CI-959 is an anti-inflammatory agent that inhibits neutrophil adhesion, respiratory burst, and mast cell histamine releas e in vitro. In view of the emerging role of neutrophils in gastric ero sive damage, the goals of this study were to assess the gastric cytopr otective effects of CI-959 and identify the mechanism responsible for this action. Methods: Cytoprotective effects in the rat nonsteroidal a nti-inflammatory drug and ethanol erosion models were assessed using i mage analysis. The in vivo effects of CI-959 on gastric acid secretion , arachidonic acid metabolism, and intracellular sulfhydryl and leukoc yte adhesion were also examined. Results: CI-959 protected prophylacti cally against the erosive damage induced by aspirin, indomethacin, and ethanol with 50% effective doses (ED(50)s) of 0.05, 1.0, and 0.07 mg/ kg administered orally, respectively. When administered after indometh acin or ethanol, CI-959 had no effect on the healing of erosive damage . CI-959 did not alter gastric acid secretion, arachidonic acid metabo lism, or intracellular sulfhydryl levels. In vivo, CI-959 blocked leuk ocyte adhesion in intravital microscopy studies using indomethacin (ED (50), <5 mg/kg orally) or platelet-activating factor (50% inhibiting c oncentration, similar to 10 mu mol/L) as the adhesion stimulus. Conclu sions: The most likely mechanism responsible for the cytoprotective ef fects of CI-595 is its inhibitory effects on leukocyte trafficking and /or adhesion.