Beneficial effect of deletion variant of hepatocyte growth factor for impaired hepatic regeneration in the ischemically damaged liver.

Abstract

This study was conducted to determine the influence of hepatic ischemia and reperfusion (HIR) injury on liver regeneration and the effect of the deletion variant of hepatocyte growth factor (dHGF) under these conditions. Male Sprague-Dawley rats were subjected to 60 minutes of total hepatic ischemia, and two-thirds hepatectomy was performed just before reperfusion. Animals received intravenous administration of either vehicle buffer (vehicle control group) or dHGF (1 mg/kg) (HGF group) at the end of the period of hepatic ischemia and again 6 hours after reperfusion. At 8 hours after hepatectomy, plasma HGF levels in the vehicle control group were significantly lower than those in the nonischemic controls. Plasma aspartate transaminase levels in the vehicle control group reached 3,462 +/- 1,039 IU/L, but levels in the HGF group were significantly inhibited to 1,849 +/- 605 IU/L. The relative liver weight in the vehicle control group was significantly greater than in the HGF group, a finding that was implicated in focal liver necrosis with sinusoidal congestion. Less histological damage was observed in the HGF group. Twenty-four hours after hepatectomy, an increase in the relative liver weight in nonischemic controls and in the HGF group was higher than that in vehicle control group, and the 5-bromo-2?deoxyuridine (BrdU) labeling index in the HGF group was 23% versus 18% in the nonischemic controls. Administration of dHGF significantly improved the 7-day survival to 82% versus 40% in the vehicle control group. dHGF has potential benefit as a pharmacological agent to ameliorate impairment of the hepatic microcirculation and to potentiate a regeneration response in the ischemically damaged liver after hepatectomy and/or liver transplantation.