ROLE OF XANTHINE OXIDASE-DERIVED OXIDANTS AND LEUKOCYTES IN ETHANOL-INDUCED JEJUNAL MUCOSAL INJURY

Previous reports indicate that intestinal intraluminal ethanol increas es mucosal permeability (an index of mucosal injury) and histamine rel ease by mast cells, and that the released histamine plays a role in me diating the increased permeability. In the present study, we investiga ted whether reactive oxygen metabolites and their major sources (xanth ine oxidase and leukocytes) were involved in these ethanol effects. In rabbits, segments of the jejunum were perfused with a control solutio n or with 6% ethanol. In these segments, mucosal permeability was asse ssed by determining jejunal clearance of i.v. administered Cr-51-ethyl enediaminetetraacetate (Cr-51-EDTA) and I-125-bovine serum albumin (I- 125-BSA), and mast cell histamine release was estimated from the hista mine concentration of the gut effluent. Ethanol increased Cr-51-EDTA c learance, I-125-BSA clearance, and histamine release. These ethanol ef fects decreased when the animals were given superoxide dismutase plus catalase (scavenger of O2- and H2O2, respectively), allopurinol; or ox ypurinol (xanthine oxidase inhibitors). Administration of a monoclonal antibody (R15.7) against leukocyte adhesion molecule, CD18, inhibited completely the ethanol-induced increased Cr-51-EDTA and I-125-BSA cle arances and histamine release. These and supplementary data suggest th at (a) ethanol-induced mucosal injury and mast cell histamine release are mediated primarily by leukocytes, and (b) oxy radicals, especially those generated by xanthine oxidase, mediate these ethanol effects ma inly by promoting leukocyte infiltration.