Effect of chronic ethanol feeding on endotoxin-induced hepatic injury: role of adhesion molecules on leukocytes and hepatic sinusoid.

Endotoxin is postulated to be an important aggravating factor for alcoholic liver disease. We have previously reported that rats fed ethanol are more vulnerable to endotoxin-induced liver damage, and hepatic microcirculatory disturbance plays an important role for this liver damage by observation with an intravital microscopy. In this study, we have investigated the role of adhesion molecules in endotoxin-induced microcirculatory disturbance in chronic ethanol-fed rats. Male Wistar rats were pair-fed with ethanol liquid diet (ethanol group) or an isocaloric control diet (control group) for 6 weeks. Leukocyte adherence to the hepatic sinusoid by stimulation with lipopolysaccharides (1 mg/kg of body weight) was observed by an inverted fluorescence microscopy equipped with a silicon-intensified target camera and was found to be enhanced in ethanol-fed rats. Tumor necrosis factor-alpha and GRO/CINC-1 (rat counterpart of interleukin-8) was increased in the blood in these animals. Subsequent expression of adhesion molecules, LFA-1 beta-chain on leukocytes were demonstrated by flow cytometry, which suggests a possible involvement of leukocyte adherence to the hepatic damage in ethanol-fed animals. Preadministration of anti-rat LFA-1 beta-chain monoclonal antibody effectively suppressed leukocyte adherence to the hepatic sinusoid. These results suggest that the enhanced sequestration of neutrophils to the liver with these adhesion molecules may play a significant role in the pathogenesis of alcoholic liver disease.