Activated protein C prevents multiple organ injury following extensive hepatectomy in cirrhotic rats.
OBJECTIVE
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 post-hepatectomy liver dysfunction. We therefore investigated the effect of activated protein C (APC), a potent antithrombotic serine protease with anti-inflammatory effects, on posthepatectomy liver dysfunction and multiple organ injury in cirrhotic rats.


RESULTS
Dimethylnitrosamine-induced cirrhotic rats underwent 70% hepatectomy and received lipopolysaccharide (200 microg/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-alpha 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.
Yoshikawa
A
A
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Japan.
Kaido
T
T
Seto
S
S
Katsuura
Y
Y
Imamura
M
M
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D006498:Hepatectomy; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000097:blood / Q000601:surgery*; D008168:Lung / Q000473:pathology; D008297:Male; D008833:Microcirculation; D009102:Multiple Organ Failure / Q000517:prevention & control*; D011183:Postoperative Complications / Q000517:prevention & control*; D011184:Postoperative Period; D011486:Protein C / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D012079:Renal Circulation; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D011486:Protein C; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1