Hepatocyte growth factor promotes liver regeneration with prompt improvement of hyperbilirubinemia in hepatectomized cholestatic rats.
BACKGROUND
In hepatectomy for patients with liver cirrhosis or cholestasis, prolonged postoperative hyperbilirubinemia is a troublesome complication and, if uncontrolled, often leads to life-threatening hepatic failure. Hepatocyte growth factor (HGF), first identified as the most potent mitogen for primary hepatocytes, has been shown to have multiple biological properties on liver, including mitogenic, antifibrotic, and cytoprotective activities. This study investigated the beneficial effects of a perioperative HGF supply to jaundiced liver after hepatectomy in rats.


METHODS
As a model of jaundiced liver, we used an alpha-naphtylisocyocyanate (ANIT)-induced intrahepatic cholestasis model. Forty-eight hours after intraperitoneal injection of ANIT (75 mg/kg), when the total serum bilirubin level was moderately increased, a 70 % hepatectomy was performed. Human recombinant HGF (250 microgram/kg) (n = 15) or vehicle alone (n = 15) was intermittently administered to the rats 12 h before surgery and every 12 h after that until sacrifice.


RESULTS
Perioperative HGF treatment effectively accelerated hepatocellular DNA synthesis of cholestatic liver followed by increase in the regenerated liver weight. Moreover, HGF supply promptly improved hyperbilirubinemia within 24 h after surgery. Histological examination revealed that HGF administration attenuated periportal inflammation and formation of bile duct obstructions. Postoperative serum concentrations of tumor necrosis factor-alpha, a representative inflammatory cytokine, were not altered by HGF treatment.


CONCLUSIONS
Perioperative HGF supply not only promotes liver regeneration but also ameliorates hyperbilirubinemia in hepatectomized cholestatic rats. This mode of HGF treatment may be clinically useful for hepatectomy in patients with cholestasis.
Yoshikawa
A
A
Department of Surgery and Surgical Basic Science, Kyoto University School of Medicine, Kyoto, 606-8507, Japan.
Kaido
T
T
Seto
S
S
Yamaoka
S
S
Sato
M
M
Ishii
T
T
Imamura
M
M
D000818:Animals; D002779:Cholestasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000096:biosynthesis; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006932:Hyperbilirubinemia / Q000188:drug therapy* / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D004247:DNA