Activated protein C prevents multiple organ injury following extensive hepatectomy in cirrhotic rats

Background/Aims: Extended hepatectomy for cirrhotic liver in patients with hepatocellular carcinoma often triggers posthepatectomy liver failure. It has been shown that the microcirculatory disturbance caused by microthrombus formation and sinusoidal endothelial cellular injury is one of the causes of posthepatectomy liver dysfunction. We therefore investigated the effect of activated protein C (APC), a potent antithrombotic serine protease with anti-in-flammatory effects, on posthepatectomy liver dysfunction and multiple organ injury in cirrhotic rats. Methods/Results: Dimethylnitrosamine-induced cirrhotic rats underwent 70% hepatectomy and received lipopolysaccharide (200 μg/kg) 48 h later to prepare a lethal posthepatectomy acute liver failure model. APC (1500 U/kg), given intravenously 15 min before and 1 h after endotoxin challenge, attenuated liver dysfunction and decreased serum tumor necrosis factor-α concentration. APC significantly improved the survival rate of rats at 12 h after endotoxin challenge. Histological examination revealed that APC treatment inhibited not only intrasinusoidal fibrin deposition and massive hepatocellular necrosis but also pulmonary injury and glomerular fibrin deposition. Immunohistochemically, expression of intercellular adhesion molecule-1 on sinusoidal cells and renal glomeruli was decreased in the APC-treated animals. Conclusions: APC administration prevented acute liver dysfunction and attenuated multiple organ injury following extended hepatectomy in cirrhotic rats, possibly via anticoagulant and anti-inflammatory effects.