Chronic alcohol intoxication induces hepatic injury through enhanced macrophage inflammatory protein-2 production and...

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 protein-2 (MIP2) and up-regulates the expression of adhesion molecules, i.e., CD18 on PMNs and its counter-receptor, intercellular adhesion molecule-1 (ICAM-1), on hepatic cells. As a result, enhanced sequestration and cell-cell interaction among these cell types may occur in the liver, which in turn could result in altered hepatic function and hepatotoxicity. 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 MIP2 (625 +/- 100 pg/mL) were detected in the sera of alcoholic rats but not in the pair-fed rats. Concomitantly, serum aspartate transaminase (AST) activity was significantly increased. Small lipid deposition and inflammatory-like changes in the liver were also observed. Isolated Kupffer cells from alcohol-fed rats released large amount of MIP2 (> 600 pg/10(6) Kupffer cells/24 hr) in vitro compared with Kupffer cells from pair-fed rats (< 150 pg/10(6) Kupffer 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, attenuated hepatic injury in vivo, and in PMN-hepatocyte coculture in vitro in the alcohol-fed group. Another factor that could contribute to hepatic injury was MIP2, which was cytotoxic to alcoholic hepatocytes in vitro. This was reversed by cycloheximide, thus suggesting the indirect hepatotoxic effect of MIP2. In addition, isolated PMNs and Kupffer cells from alcohol-fed rats released large amounts of superoxide, which may also play a role in hepatic injury. These results demonstrate that MIP2 and adhesion molecules may contribute, at least in part, in the initiation of hepatic injury during alcohol intoxication.