The superoxide dismutase mimetic MnTBAP prevents Fas-induced acute liver failure in the mouse
| Autor: | Yvon Calmus, Patrick Jaffray, Renaud Hammoud, Micheline Tulliez, Hélène Trebeden, Pierre Jacques Ferret, Benoît Malassagne, Sassia Bedda, Bernard Weill, Frédéric Batteux |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Metalloporphyrins
Apoptosis Mitochondria Liver Cell Separation Mitochondrion Fas ligand Superoxide dismutase chemistry.chemical_compound Mice In vivo Cardiolipin Animals fas Receptor chemistry.chemical_classification Reactive oxygen species Glutathione Peroxidase Mice Inbred BALB C Hepatology biology Superoxide Dismutase Cytochrome c Gastroenterology Antibodies Monoclonal Molecular biology chemistry Biochemistry Liver Acute Disease biology.protein Hepatocytes Female Reactive Oxygen Species Liver Failure |
| Zdroj: | Gastroenterology. 121(6) |
| ISSN: | 0016-5085 |
| Popis: | Background & Aims: Acute liver failure (ALF) of viral origin results from massive hepatocyte apoptosis induced by the interaction between Fas expressed on hepatocytes and Fas ligand on activated T lymphocytes. Because Fas-induced apoptosis of hepatocytes involves mitochondrial damages and potential reactive oxygen species (ROS) overproduction, we investigated whether manganese III tetrakis (5,10,15,20 benzoic acid) (MnTBAP), a nonpeptidyl mimic of superoxide dismutase (SOD), can inhibit Fas-induced ALF. Methods: An agonist anti-Fas monoclonal antibody was used to induce hepatocyte apoptosis in vitro and ALF in vivo. Results: Preventive and curative treatments by MnTBAP significantly increased survival rates and significantly reduced aspartate aminotransferase levels and parenchymal lesions. ROS generation was suggested by those beneficial effects and significant increases in SOD and Gpx activities after anti-Fas injection. Flow cytometry of isolated hepatocytes incubated with anti-Fas monoclonal antibody showed that ROS production was associated with the collapse of transmembrane potential and loss of cardiolipin content. After injection of anti-Fas monoclonal antibody, mitochondrial Bcl-2 was decreased, cytochrome c released, and caspase-3 activated. Mitochondrial alterations and their consequences were abrogated by MnTBAP. Conclusions: ROS are key executioners in Fas-induced hepatocyte apoptosis. This finding explains why a nonpeptidyl mimic of SOD can cure ALF in a model of viral hepatitis, pointing out the potential interest of this molecule in humans. GASTROENTEROLOGY 2001;121:1451-1459 |
| Databáze: | OpenAIRE |
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