Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice.
Yin-M; Wheeler-MD; Kono-H; Bradford-BU; Gallucci-RM; Luster-MI; Thurman-RG
Gastroenterology 1999 Oct; 117(4):942-952
Tumor necrosis factor (TNF)-alpha is associated with increased mortality in alcoholics, but its role in early alcohol-induced liver injury is not fully understood. Recently, it was shown that injury induced by the enteral alcohol delivery model of Tsukamoto and French was reduced by antibodies to TNF-alpha. To obtain clear evidence for or against the hypothesis that TNF-alpha is involved, we studied TNF receptor 1 (TNF-R1, p55) or 2 (TNF-R2, p75) knockout mice. Long-term enteral alcohol delivery was modified for male gene-targeted mice lacking TNF-R1 and TNF-R2. Animals were given a high-fat liquid diet continuously with either ethanol or isocaloric maltose-dextrin as a control for 4 weeks. Ethanol elevated serum levels of alanine aminotransferase nearly 3-fold in wild-type and TNF-R2 knockout mice but not in TNF-R1 knockout mice. Likewise, ethanol caused severe liver injury in wild-type mice (pathology score, 5.5 +/- 0.6) and TNF-R2 knockout mice (pathology score, 5.0 +/- 0.4), but not in TNF-R1 knockout mice (pathology score, 0.8 +/- 0.4; P < 0.001). Long-term ethanol feeding caused liver injury in wild-type and TNF-R2 knockout mice but not in TNF-R1 knockout mice, providing solid evidence in support of the hypothesis that TNF-alpha plays an important role in the development of early alcohol-induced liver injury via the TNF-R1 pathway. Moreover, the long-term enteral ethanol feeding technique we described for the first time for knockout mice provides a useful new tool for alcohol research.
Alcoholism; Laboratory-animals; Animals; Animal-studies; Liver-tumors; Liver-disorders; Liver-cancer; Mortality-rates; Mortality-data
Ronald G. Thurman, Ph.D., Department of Pharmacology, Laboratory of Hepatobiology and Toxicology, CB 7365, Mary Ellen Jones Building, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365