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

Abstract

Activated Kupffer cells provoke massive liver necrosis after endotoxin stimulation through microcirculatory disturbance caused by sinusoidal fibrin deposition in rats undergoing 70% hepatectomy. In these rats, serum activities of purine nucleoside phosphorylase (PNP) and alanine transaminase (ALT) were increased at 1 and 5 hours, respectively, following endotoxin administration. 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 perfusion, suggesting that activated Kupffer cells injured neither sinusoidal endothelial cells nor hepatocytes. The activity of tissue factor, an initiator of blood coagulation cascade, was much higher in Kupffer cells isolated from partially hepatectomized rats than in those from normal rats. In contrast, mRNA expressions of tissue factor pathway inhibitor (TFPI) as well as thrombomodulin were almost undetectable in normal and partially resected livers. When recombinant human TFPI was injected intravenously in 70% hepatectomized rats, TFPI was markedly stained on the surfaces of sinusoidal endothelial cells and microvilli of hepatocytes on immunohistochemistry. In these rats, endotoxin-induced liver injury was significantly attenuated compared with rats given no TFPI. Similar attenuation was also found in rats receiving recombinant human thrombomodulin. These results suggest that fibrin deposition developing in 70% hepatectomized rats after endotoxin administration may be caused by deranged blood coagulation in the hepatic sinusoids through increasing tissue factor activity in Massive liver necrosis develops after endotoxin administration in rats pretreated with heat-killed Propionibacterium acnes or those undergoing 70% liver resection as a result of microcirculatory disturbance caused by sinusoidal fibrin deposition. [1][2][3] In both models, Kupffer cells and hepatic macrophages are activated to provoke endothelial cell injury and fibrin deposition in the hepatic sinusoids. 2-6 However, an apparent difference exists in the stimulatory state of Kupffer cells and hepatic macrophages between both models, because activated Kupffer cells in the partial-hepatectomy model produced fewer cytotoxic mediators such as superoxide anions and tumor necrosis factor ␣ in response to endotoxin administration compared with activated hepatic macrophages in the P. acnes model, 6,7 although both cells can release a large amount of superoxide anions after stimulation with phorbol 12-myristate 13-acetate. 3,4 Northern blot analysis revealed that such difference resulted from expression of endotoxin receptors on the cells; P. acnes-treated rat liver showed increased mRNA expression of CD14, a receptor for lipopolysaccharide and its binding protein complex, compared with normal liver, while such expression was markedly reduced in partially hepatectomized rat liver. 7 In the P. acnes model, activated hepatic macrophages after endotoxin stimulatio...

Use of Proteomic Methods to Identify Serum Biomarkers Associated with Rat Liver Toxicity or Hypertrophy

“…Baseline and stimulated serum paraoxonase activities are decreased in chronic hepatitis and liver cirrhosis (10 ). In rats, PNP activity was demonstrated to increase 5 h after the administration of endotoxin (11 ).…”

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