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Tumor necrosis factor-induced lethal hepatitis: pharmacological intervention with verapamil, tannic acid, picotamide
W Van Molle1, J Vanden Berghe, P Brouckaert
1Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, University of Gent, K.L. Ledeganckstraat 35, B-9000, Gent, Belgium.
Abstract:
Tumor necrosis factor (TNF) induces hepatitis when injected in human beings or in rodents. The molecular mechanism by which TNF induces hepatic distress remains largely unknown, although induction of apoptosis of hepatocytes appears to be an essential step. In order to increase the therapeutic value of TNF, we have studied the protective activity of several molecules and found that four chemically totally different substances confer significant protection in the model of TNF-induced lethal hepatitis in mice sensitized with D-(+)-galactosamine (GalN), but not in mice sensitized with actinomycin-D (ActD) or against anti-Fas-induced lethal hepatitis. Verapamil, a calcium-channel blocker, tannic acid, picotamide, a thromboxane A(2) receptor antagonist, and K76COOH, an inhibitor, amongst others, of complement, protected significantly against induction of lethality, release of the liver-specific enzyme alanine aminotransferase (ALT) and induction of apoptosis in the liver after TNF/GalN, except for K76COOH, which paradoxically increased ALT values after challenge, and which also protected against TNF/GalN in complement-deficient mice. The data suggest that activation of platelets and neutrophils, as well as induction of inflammation occur in the TNF/GalN model, but not in the TNF/ActD or anti-Fas models, in which direct induction of apoptosis of hepatocytes may be more relevant. The protective activity of the drugs may lead to an increase in therapeutic value of TNF.
Insights
Tumor necrosis factor (TNF) can cause hepatitis. Researchers found verapamil, tannic acid, and picotamide protect against TNF-induced liver injury in mice, suggesting new therapeutic strategies for liver diseases.
Area of Science:
- Hepatology
- Immunology
- Pharmacology
Background:
- Tumor necrosis factor (TNF) is known to induce hepatitis in humans and rodents.
- The precise molecular mechanisms underlying TNF-induced liver injury are not fully understood, but hepatocyte apoptosis is implicated.
- Enhancing the therapeutic potential of TNF requires understanding and mitigating its adverse hepatic effects.
Purpose of the Study:
- To investigate protective agents against TNF-induced hepatitis.
- To elucidate the mechanisms of TNF-induced liver injury using different sensitization models.
- To identify compounds that can increase the therapeutic utility of TNF.
Main Methods:
- Utilized a mouse model of TNF-induced lethal hepatitis sensitized with D-(+)-galactosamine (GalN).
- Compared protection against TNF/GalN with models using actinomycin-D (ActD) or anti-Fas antibody.
- Assessed lethality, alanine aminotransferase (ALT) release, and hepatocyte apoptosis as outcome measures.
Main Results:
- Verapamil, tannic acid, and picotamide demonstrated significant protection against TNF/GalN-induced lethality, ALT release, and apoptosis.
- K76COOH showed paradoxical ALT increase and protected in complement-deficient mice, suggesting a role for complement.
- The TNF/GalN model involves platelet/neutrophil activation and inflammation, unlike TNF/ActD or anti-Fas models.
Conclusions:
- Specific compounds can protect against TNF-induced hepatitis, particularly in the GalN-sensitized model.
- The protective mechanisms differ between sensitization models, highlighting distinct pathways of liver injury.
- Findings suggest potential strategies to improve TNF-based therapies by mitigating liver toxicity.