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 intercellular adhesion molecule (ICAM)-1 is involved in early alcohol-induced liver injury, 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 ethanol. Alcohol administration significantly increased liver size and serum alanine aminotransferase levels in wild-type mice over high-fat controls, effects that were blunted significantly in ICAM-1 knockout mice. Dietary ethanol caused severe steatosis, mild inflammation, and focal necrosis in livers from wild-type mice. Furthermore, livers from wild-type mice fed ethanol showed significant increases in the number of infiltrating leukocytes, which were predominantly lymphocytes. These pathological changes were blunted significantly in ICAM-1 knockout mice. Tumor necrosis factor (TNF)-alpha mRNA expression was increased in wild-type mice fed ethanol but not in ICAM-1 knockout mice. These data demonstrate that ICAM-1 and infiltrating leukocytes play important roles in early alcohol-induced liver injury, most likely by mechanisms involving TNF-alpha.
Kono
H
H
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
Uesugi
T
T
Froh
M
M
Rusyn
I
I
Bradford
B U
BU
Thurman
R G
RG
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000431:Ethanol / Q000652:urine; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D009504:Neutrophils / Q000473:pathology; D009929:Organ Size; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015430:Weight Gain
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000431:Ethanol; D009195:Peroxidase; D000410:Alanine Transaminase