CHRONIC ALCOHOL-INTOXICATION INDUCES HEPATIC-INJURY THROUGH ENHANCED MACROPHAGE INFLAMMATORY PROTEIN-2 PRODUCTION AND INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION IN THE LIVER

This study tested the hypothesis that prolonged consumption of alcohol directly or indirectly, through endotoxin influx in the circulation, stimulates the Kupffer cells to produce macrophage inflammatory protei n-2 (MIP(2)) and up-regulates the expression of adhesion molecules, i. e., CD18 on PMNs and its counter-receptor, intercellular adhesion mole cule-1 (ICAM-1), on hepatic cells, As a result, enhanced sequestration and cell-cell interaction among these cell types may occur in the liv er, which in turn could result in altered hepatic function and hepatot oxicity, This hypothesis was tested in alcohol-fed, specific pathogen- free, male Sprague-Dawley rats, After 16 weeks of feeding, endotoxin ( 0.2 +/- 0.043 EU/mL) and MIP(2) (625 +/- 100 pg/mL) were detected in t he sera of alcoholic rats but not in the pair-fed rats, Concomitantly, serum aspartate transaminase (AST) activity was significantly increas ed, Small lipid deposition and inflammatory-like changes in the liver were also observed, Isolated Kupffer cells from alcohol-fed rats relea sed large amount of MIP(2) (>600 pg/10(6) Kupffer cells/24 hr) in vitr o compared with Kupffer cells from pair-fed rats (<150 pg/10(6) Kupffe r cells/24 hr), At the same time, the expression of CD18 and ICAM-1 on polymorphonuclear neutrophils (PMNs) and hepatic cells was increased more than twofold, Monoclonal antibody 1F12, an anti-CD18 antibody, at tenuated hepatic injury in vivo and in PMN-hepatocyte coculture in vit ro in the alcohol-fed group, Another factor that could contribute to h epatic injury was MIP(2), which was cytotoxic to alcoholic hepatocytes in vitro, This was reversed by cycloheximide, thus suggesting the ind irect hepatotoxic effect of MIP(2), In addition, isolated PMNs and Kup ffer cells from alcohol-fed rats released large amounts of superoxide, which may also play a role in hepatic injury, These results demonstra te that MIP(2) and adhesion molecules may contribute, at least in part , in the initiation of hepatic injury during alcohol intoxication.