ICAM-1 is involved in the mechanism of alcohol-induced liver injury: studies with knockout mice

To test the hypothesis that leukocyte infiltration mediated by intercellula r adhesion molecule (ICAM)-1 is involved in early alcohol-induced liver inj ury, male wild-type or ICAM-1 knockout mice were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin for 4 wk. There were no differences in mean urine alcohol concentrations between the groups fed eth anol. Alcohol administration significantly increased liver size and serum a lanine aminotransferase levels in wild-type mice over high-fat controls, ef fects that were blunted significantly in ICAM-1 knockout mice. Dietary etha nol caused severe steatosis, mild inflammation, and focal necrosis in liver s from wild-type mice. Furthermore, livers from wild-type mice fed ethanol showed significant increases in the number of infiltrating leukocytes, whic h were predominantly lymphocytes. These pathological changes were blunted s ignificantly in ICAM-1 knockout mice. Tumor necrosis factor (TNF)-alpha mRN A expression was increased in wild-type mice fed ethanol but not in ICAM-1 knockout mice. These data demonstrate that ICAM-1 and infiltrating leukocyt es play important roles in early alcohol-induced liver injury, most likely by mechanisms involving TNF-alpha.