Caspase-dependent apoptosis in fulminant hepatic failure induced by herpes simplex virus in mice.
OBJECTIVE
Herpes simplex virus (HSV) is known to induce fulminant hepatic failure. The aim of this study is to clarify the molecular basis of liver injury in HSV-induced hepatitis.


METHODS
Immunocompetent mice were inoculated with HSV or ultraviolet-inactivated HSV (UV-HSV) intravenously. Extent of liver injury was evaluated by changes of serum enzymes and histopathology. Apoptosis was assessed by DNA fragmentation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Immunohistochemistry for caspase-3 and Fas ligand was performed. Reverse transcriptase-polymerase chain reaction for Fas ligand was also performed.


RESULTS
All mice died of rapid and massive liver cell death after HSV infection, whereas no change was observed in mice after UV-HSV inoculation. The extent of viral replication and DNA fragmentation correlated well with the severity of liver injury. Caspase-3 was activated in the liver after HSV infection, but not UV-HSV. Positive reaction for TUNEL was observed not only in HSV-antigen positive cells but also in HSV-antigen negative cells. Fas ligand was induced in the liver infected with HSV, but not with UV-HSV.


CONCLUSIONS
Caspase-dependent apoptosis is involved in HSV-associated liver injury. Not only viral replication but also non-viral factor such as Fas ligand may facilitate rapid development of this disease.
Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
Koji
K
Hashimoto
Hiroko
H
Minagawa
Yusuke
Y
Yanagi
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D053938:DNA Fragmentation; D018450:Disease Progression; D053222:Fas Ligand Protein; D006561:Herpes Simplex / Q000150:complications*; D007150:Immunohistochemistry; D017093:Liver Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000821:virology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D013997:Time Factors; D014779:Virus Replication
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases