Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice.
Gastroenterology
; 117(4): 942-52, 1999 Oct.
Article
en En
| MEDLINE
| ID: mdl-10500078
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factor de Necrosis Tumoral alfa
/
Hepatopatías Alcohólicas
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Gastroenterology
Año:
1999
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos