Inactivation of Kupffer cells prevents early alcohol-induced liver injury.
It is well recognized that consumption of alcohol leads to liver disease in a dose-dependent manner; however, the exact mechanisms remain unclear. Hypoxia subsequent to a hypermetabolic state may be involved; therefore, when it was observed recently that inactivation of Kupffer cells prevented stimulation of hepatic oxygen uptake by alcohol, the idea that Kupffer cells participate in early events that ultimately lead to alcohol-induced liver disease became a real possibility. The purpose of this study was to test that hypothesis. Male Wistar rats were exposed to ethanol continuously by means of intragastric feeding for up to 4 weeks using the model developed by Tsukamoto and French. In this model, ethanol causes fatty liver, necrosis and inflammation--changes characteristic of alcohol-induced liver disease in human beings. Kupffer cells were inactivated by twice weekly treatment with gadolinium chloride (GdCl3), a selective Kupffer cell toxicant. AST levels were elevated to 192 +/- 13 and 244 +/- 56 IU/L in rats exposed to ethanol for 2 and 4 wk, respectively (control value, 88 +/- 7). This injury was prevented almost completely by GdCl3 treatment. Fatty changes, inflammation and necrosis were also all reduced dramatically by GdCl3 treatment. The average hepatic pathological score of rats treated with ethanol for 4 wk was 4.3 +/- 0.6, which was reduced significantly in ethanol- and GdCl3-treated rats to 1.8 +/- 0.5 (p < 0.05). Rates of ethanol elimination were elevated 2- to 3-fold in rats exposed to ethanol for 2 to 4 wk. This elevation was blocked by GdCl3 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Adachi
Y
Y
Department of Pharmacology, University of North Carolina at Chapel Hill 27599-7365.
Bradford
B U
BU
Gao
W
W
Bojes
H K
HK
Thurman
R G
RG
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D000431:Ethanol / Q000633:toxicity*; D005682:Gadolinium / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000431:Ethanol; D005682:Gadolinium; D001219:Aspartate Aminotransferases; C038958:gadolinium chloride