Essential Role of Tumor Necrosis Factor Alpha in Alcohol-Induced Liver Injury in Mice

Details

• Personal Author:
  Bradford BU ; Gallucci RM ; Kono H ; Luster MI ; Thurman RG ; Wheeler MD ; Yin M
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Alcoholic Beverages Animals Digestive System Digestive System Diseases Laboratories Liver Mortality Neoplasms Occupational Health Safety
• Keywords:
  Alcoholism Animal-studies Laboratory-animals Liver-cancer Liver-disorders Liver-tumors Mortality-data Mortality-rates
• ISSN:
  0016-5085
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  North Carolina ; OSHA Region 3 ; OSHA Region 4 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  117
• Issue:
  4
• NIOSHTIC Number:
  nn:20025374
• Citation:
  Gastroenterology 1999 Oct; 117(4):942-952
• Contact Point Address:
  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
• Email:
  thurman@med.unc.edu
• Federal Fiscal Year:
  2000
• Peer Reviewed:
  True
• Source Full Name:
  Gastroenterology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:992ceddeb6371b4afde95c5713a2f605cb54ac20028bb986b32c59bb77e84698bd6112c5fe25399b5f732b1f58f8799a9d0e7d1dd201fd0c3e8591436f369cd4
• Download URL:
  https://stacks.cdc.gov/view/cdc/196773/cdc_196773_DS1.pdf
• File Type:
  [PDF - 530.52 KB ]