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Alcohol-induced free radicals in mice: direct toxicants or signaling molecules?
1Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Abstract:
Tumor necrosis factor alpha (TNF-alpha) and free radicals are produced in early alcohol-induced liver injury. Recently, pathology caused by alcohol was blocked nearly completely in tumor necrosis factor alpha receptor 1 (TNF-R1) knockout mice. With this model, it is now possible to evaluate whether free radicals are directly toxic or act as redox regulators of TNF-alpha production. Specifically, if free radicals were directly toxic, a parallel decrease in free radicals and pathology in TNF-R1 knockout mice would be predicted. If they only affect TNF-alpha production, radicals would be expected to remain high while pathology is diminished. Accordingly, free radical production in TNF-R1 knockout mice was studied here. The enteral alcohol delivery model used mice lacking TNF-R1 (p55) and wild-type control C57Bl/6J mice. Animals received a liquid diet continuously with either ethanol or isocaloric maltose-dextrin as control for 4 weeks. Urine ethanol levels fluctuated from 10 to 500 mg/dL in a cyclic pattern in mice receiving ethanol. Ethanol elevated liver:body weight ratios, serum alanine transaminase (ALT) levels, and pathology scores in wild-type mice. These parameters were blunted nearly completely in TNF-R1 knockout mice. Ethanol treatment increased free radical production in wild-type mice compared with animals fed a high-fat control diet. There were no differences in intensity of free radical signals regardless of the presence or absence of TNF-R1; however, pathology differed markedly between these groups. These findings are consistent with the hypothesis that free radicals act as redox signals for TNF-alpha production and do not directly damage cells in early alcohol-induced hepatic injury.
Insights
Free radicals act as redox signals, not direct toxins, in early alcohol-induced liver injury. Blocking tumor necrosis factor alpha receptor 1 (TNF-R1) reduced liver damage without decreasing free radical levels.
Area of Science:
- Hepatology
- Toxicology
- Immunology
Background:
- Alcohol-induced liver injury involves tumor necrosis factor alpha (TNF-alpha) and free radicals.
- Pathology was significantly reduced in mice lacking TNF-R1, suggesting its critical role.
Purpose of the Study:
- To investigate the role of free radicals in early alcohol-induced liver injury.
- To determine if free radicals are directly toxic or act as redox regulators of TNF-alpha production.
Main Methods:
- Utilized a mouse model with and without TNF-R1 (p55) knockout.
- Administered ethanol or a control diet for 4 weeks via enteral delivery.
- Measured liver:body weight ratios, serum ALT levels, pathology scores, and free radical production.
Main Results:
- Ethanol increased liver damage markers in wild-type mice, which were blunted in TNF-R1 knockout mice.
- Ethanol increased free radical production in wild-type mice.
- Free radical levels were similar in both knockout and wild-type mice, despite significant differences in pathology.
Conclusions:
- Free radicals likely act as redox signals that promote TNF-alpha production in alcohol-induced liver injury.
- Free radicals do not appear to directly cause cellular damage in this early stage of injury.