Deranged blood coagulation equilibrium as a factor of massive liver necrosis following endotoxin administration in partially hepatectomized rats

Activated Kupffer cells provoke massive liver necrosis after endotoxin stim ulation through microcirculatory disturbance caused by sinusoidal fibrin de position in rats undergoing 70% hepatectomy. In these rats, serum activitie s of purine nucleoside phosphorylase (PNP) and alanine transaminase (ALT) w ere increased at 1 and 5 hours, respectively, following endotoxin administr ation, When 70% resected liver was perfused with Dulbecco's modified Eagle medium (DMEM) containing heat-inactivated fetal calf serum, the increase in both enzyme activities was not affected by addition of endotoxin during pe rfusion, suggesting that activated Kupffer cells injured neither sinusoidal endothelial cells nor hepatocytes. The activity of tissue factor, an initi ator of blood coagulation cascade, was much higher in Kupffer cells isolate d from partially hepatectomized rats than in those from normal rats. In con trast, mRNA expressions of tissue factor pathway inhibitor (TFPI) as well a s thrombomodulin were almost undetectable in normal and partially resected livers. When recombinant human TFPI was injected intravenously in 70% hepat ectomized rats, TFPI was markedly stained on the surfaces of sinusoidal end othelial cells and microvilli of hepatocytes on immunohistochemistry. In th ese rats, endotoxin-induced liver injury was significantly attenuated compa red with rats given no TFPI. Similar attenuation was also found in rats rec eiving recombinant human thrombomodulin. These results suggest that fibrin deposition developing in 70% hepatectomized rats after endotoxin administra tion may be caused by deranged blood coagulation in the hepatic sinusoids t hrough increasing tissue factor activity in Kupffer cells and minimal TFPI and thrombomodulin in endothelial cells, The destruction of sinusoidal endo thelial cells as well as hepatocytes may occur as a result of microcirculat ory disturbance caused by such sinusoidal fibrin deposition.