ICAM-1 AND P-SELECTIN EXPRESSION IN A MODEL OF NSAID-INDUCED GASTROPATHY

A growing body of experimental evidence suggests that neutrophilic pol ymorphonuclear leukocyte (PMN)-endothelial cell interactions play a cr itical role in the pathophysiology of nonsteroidal anti-inflammatory d rug (NSAID)-induced gastropathy. The objective of this study was to di rectly determine whether the expression of endothelial cell adhesion m olecules is enhanced in a model of NSAID-induced gastropathy. Gastropa thy was induced in male Sprague-Dawley rats via oral administration of indomethacin (Indo, 20 mg/kg). Lesion scores, blood-to-lumen clearanc e of Cr-51-EDTA (mucosal permeability), and histological analysis (epi thelial necrosis) were used as indexes of gastric mucosal injury. Gast ric mucosal vascular expression of intercellular adhesion molecule 1 ( ICAM-1) or P-selectin were determined at 1 and 3 h after Indo administ ration using the dual radiolabeled monoclonal antibody (MAb) technique . For some experiments, a blocking MAb directed at either ICAM-1 (1A29 ) or P-selectin (RMP-1) or their isotype-matched controls was injected intravenously 10 min before Indo administration. We found that P-sele ctin expression was significantly increased at 1 h but not 3 h after I ndo administration, whereas ICAM-1 expression was significantly increa sed at both 1 and 3 h after Indo treatment. The blocking ICAM-1 and P- selectin MAbs both inhibited Indo-induced increases in lesion score, m ucosal permeability, and epithelial cell necrosis. However, the Indo-i nduced gastropathy was not associated with significant PMN infiltratio n into the gastric mucosal interstitium, nor did Indo reduce gastric m ucosal blood flow. We propose that NSAID-induced gastric mucosal injur y may be related to the expression of P-selectin and ICAM-1; however, this mucosal injury does not appear to be dependent on the extravasati on of inflammatory cells or mucosal ischemia.