Pathogenesis of herpes simplex hepatitis in macrophage-depleted mice: possible involvement of tumor necrosis factor-alpha and inducible nitric oxide synthase in massive apoptosis.
Massive liver cell death provoked in silica-treated mice subsequently infected with herpes simplex virus (HSV)-1 is very similar pathohistologically to the cell death observed in human fulminant hepatitis. Previously, we have shown this liver cell death to be extensive apoptosis. In the present study, we examined various factors related to liver damage patho- and immunologically, as well as by reverse transcription-polymerase chain reaction. Tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), interferon (IFN)-alpha, and interleukin-6 mRNAs were detected to a much greater extent in silica-treated mice compared with control mice after HSV-1 infection, and excessive expression of iNOS mRNA and cytokine mRNAs in the liver may be closely related to massive liver cell apoptosis. The apoptosis was less related to the fas ligand than to TNF-alpha. Silica blockage of macrophages makes the liver cell extremely vulnerable to HSV-1 infection, and it induced expression of E-selectin and neutrophil margination in the liver. Subsequent HSV-1 infection induced excessive production of iNOS and cytokines, particularly TNF-alpha, but administration of anti-TNF-alpha antibody or NG-monomethyl-L-arginine was not completely efficacious for the survival of the mice. Overproduction of free radicals in combination with cytokines, such as TNF-alpha, IL-6 and IFN-alpha, may result in hepatic cell apoptosis.
Irie
Hiroshi
H
Teikyo University School of Medicine, Department of Anatomy, Tokyo, Japan. iriehiro@med.teikyo-u.ac.jp
Shiga
Junji
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017931:DNA Primers; D019040:E-Selectin / Q000378:metabolism; D006524:Hepatitis, Viral, Animal / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D016898:Interferon-alpha / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012822:Silicon Dioxide / Q000633:toxicity; D018139:Simplexvirus; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D017931:DNA Primers; D019040:E-Selectin; D016898:Interferon-alpha; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide; D052247:Nitric Oxide Synthase Type II