Treatment of resistant A/J mice with methylprednisolone (MP) results in loss of resistance to murine hepatitis strain 3 (MHV-3) and induction of macrophage procoagulant activity (PCA).
BALB/cJ mice die of fulminant hepatitis within 7 days of exposure to murine hepatitis virus strain 3 (MHV-3) whereas A/J mice are fully resistant to the lethal effects of MHV-3 infection. Previous studies have implicated macrophage activation with production of a unique macrophage prothrombinase (PCA) and lymphocyte cytokine secretion in the pathogenesis of MHV-3 susceptibility and have demonstrated that immunosuppression induces susceptibility in resistant mice. This study was undertaken to determine whether macrophages, derived from resistant A/J mice and treated in vitro with methylprednisolone sodium succinate (MP), elaborated PCA following MHV-3 exposure and whether therapy with MP altered resistance of A/J mice to MHV-3 infection in vivo. Macrophages, incubated with MP in vitro, expressed dose dependent increases in PCA following infection with MHV-3. No induction of PCA occurred in macrophages treated with MHV-3 or MP alone. Analysis of mRNA transcripts for mouse fibrinogen like protein (musfiblp), the MHV-3 specific prothrombinase, in macrophages which were incubated with MP prior to exposure to MHV-3 demonstrated significantly increased mRNA levels as compared to macrophages not incubated with MP prior to MHV-3 exposure. In vivo, A/J mice treated for 3 days with 500 mg/kg/day of MP prior to infection with MHV-3 demonstrated extensive hepatocyte necrosis and fibrin deposition in hepatic sinusoids on histological examination of liver tissue, elevated serum transaminases and 100% mortality within 10 days of infection. These results therefore provide further support for the role of increased PCA in the pathogenesis of MHV-3 related liver necrosis.
Fingerote
R J
RJ
Department of Medicine, Toronto Hospital, University of Toronto, Ontario, Canada.
Leibowitz
J L
JL
Rao
Y S
YS
Levy
G A
GA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D002478:Cells, Cultured; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007700:Kinetics; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology*; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D008805:Mice, Inbred A; D006517:Murine hepatitis virus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D013997:Time Factors; D014774:Virulence; D014779:Virus Replication / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001779:Blood Coagulation Factors; C045072:macrophage procoagulant activity; D008775:Methylprednisolone