The superoxide dismutase mimetic MnTBAP prevents Fas-induced acute liver failure in the mouse.
OBJECTIVE
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.
Malassagne
B
B
Laboratoire d'Immunologie, Faculté Cochin, Université Paris V, 75679 Paris Cedex 14, France.
Ferret
P J
PJ
Hammoud
R
R
Tulliez
M
M
Bedda
S
S
Trébéden
H
H
Jaffray
P
P
Calmus
Y
Y
Weill
B
B
Batteux
F
F
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D002469:Cell Separation; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D017093:Liver Failure / Q000139:chemically induced* / Q000517:prevention & control*; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; D019014:fas Receptor; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase