Factor VIII expression in azoxymethane-induced murine fulminant hepatic failure.
Fulminant hepatic failure (FHF) in humans produces a bleeding diathesis due in large part to a reduction in the biosynthesis of liver-derived coagulation factors. Remarkably, factor VIII procoagulant activity is elevated in most of these patients despite widespread liver cell death. FHF can be modeled in mice by administration of azoxymethane, the active ingredient found in cycad palm nuts. We compared the expression of factor VIII to other hepatic hemostatic factors in azoxymethane-induced murine FHF. Mice displayed dose-dependent decreases in all coagulation factor activities measured, including factors V, VII, VIII, and IX. At the highest dose of azoxymethane (50 microg/g body weight), factor VIII activity in plasma decreased by 98% within 36 hours after treatment, which was associated with an 80% reduction in hepatic factor VIII messenger RNA (mRNA). In contrast, factor VIII mRNA levels in spleen, kidney, and lung tissue of azoxymethane-treated mice were unchanged. Cellular damage in these mice appeared to be limited to hepatocytes as evident by histologic examination. This finding is supported by 2 observations. First, hepatic mRNA levels of von Willebrand factor, which is synthesized by liver sinusoidal endothelial cells but not hepatocytes, were unchanged. Second, von Willebrand factor was detected antigenically in liver sections of azoxymethane-treated mice by immunofluorescence. These results indicate that the contribution of the liver to factor VIII biosynthesis is not replaced or significantly supplemented by other tissues in this model of FHF.
Doering
Christopher B
CB
Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
Josephson
Cassandra D
CD
Craddock
Heather N
HN
Lollar
Pete
P
D000818:Animals; D001391:Azo Compounds / Q000008:administration & dosage / Q000494:pharmacology; D001779:Blood Coagulation Factors / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005169:Factor VIII / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D017093:Liver Failure / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D014018:Tissue Distribution; D014841:von Willebrand Factor / Q000378:metabolism
D001391:Azo Compounds; D001779:Blood Coagulation Factors; D012333:RNA, Messenger; D014841:von Willebrand Factor; C001825:azomethane; D005169:Factor VIII