PREVENTIVE AND THERAPEUTIC EFFECTS IN RATS OF HEPATOCYTE GROWTH-FACTOR INFUSION ON LIVER FIBROSIS CIRRHOSIS/

Liver fibrosis/cirrhosis is characterized by hyper-accumulation of fib rous tissue components and is commonly observed in later or terminal s tates of chronic hepatic diseases, In ongoing work, we found that the administration of human recombinant hepatocyte growth factor (hrHGF) s uppressed the onset of liver fibrosis/cirrhosis in several distinct mo dels and accelerated the recovery from liver fibrosis/cirrhosis in rat s, Repeated administration of porcine serum for 10 weeks to rats induc ed liver fibrosis without any accompanying hepatocellular injuries; in addition, the intravenous (i.v.) administration of hepatocyte growth factor (HGF) to these rats suppressed increases in fibrous components and hydroxyproline contents in the liver, thus preventing the onset of liver fibrosis, Repeated administration of dimethylnitrosamine (DMN) for four weeks induced liver cirrhosis, as characterized by the hypera ccumulation of fibrous components, infiltration of mononuclear leukocy tes, and hepatic dysfunction. When HGF was injected daily for four wee ks along with DMN-treatment, the onset of DMN-induced hepatic fibrosis /cirrhosis was suppressed; the numbers of infiltrating mononuclear cel ls, fibrous tissue components, and hydroxyproline content in the liver were decreased. When HGF was injected for two weeks following four we eks of DMN-treatment, HGF accelerated the recovery from liver cirrhosi s and prevented death due to hepatic dysfunction. Likewise, HGF-inject ion suppressed the onset of liver fibrosis, when liver fibrosis had be en induced by long-term treatment with carbon tetrachloride (CCl4). Th us, the administration of HGF holds great promise for treating subject s with liver fibrosis/cirrhosis as a result of chronic hepatic injury.