Combination gene therapy of HGF and truncated type II TGF-β receptor for rat liver cirrhosis after partial hepatectomy

Background. In a cirrhotic liver, the regenerative abilily and specific junctions are impaired; a hepatic resection increases the possibility of postoperative liver failure. Hepatocyte growth factor (HGF) stimulates liver regeneration, accelerates restoration of hepatic function, and improves fibrosis. A truncated type H transforming growth factor-beta receptor (T beta TR), which specifically inhibits TGF-beta signaling as a dominant-negative receptor, appears to prevent. the progression of liver fibrosis. We demonstrated the therapeutic efficacy of adenovirus-mediated HGF and T beta TR gene transduction after partial hepatectomy for liver cirrhosis. Methods. Rats were treated with dimethylnitrosamine for 3 weeks, and they all had severe cirrhosis. After partial hepatectomy (10%), we injected adenovirus expressing bacterial beta-galactosidase (AdLacZ), adenovirus expressing a truncated type II TGF-beta receptor (AdT beta TR), adenovirus expressing hepatocyte growth factor (AdHGF), or AdT beta TR + AdHGF into the portal vein, which was followed by an additional 2-week dimethylnitrosamine treatment. Results. On histologic examination, fibrotic tissue had decreased. in the livers of the AdT beta TR + AdHGF-treated. rats compared with rats that were treated by AdLacZ, AdT beta TR alone, and AdHGF alone. Liver function, which included serum levels of alanine aminotransferase, improved significantly in AdT beta TR + AdHGF-treated rats compared with all. other groups. The number of hepatocytes that were positive for proliferating-cell nuclear antigen was greater (P < .05) in AdHGF alone and AdT beta TR + AdHGF-treated rat livers than in AdLacZ and AdT beta TR-treated rats. All AdT beta TR + AdHGF-treated rats survived > 60 days, and AdT beta TR + AdHGF treatment markedly improved the survival rate after a partial hepatectomy. Conclusion. Our results suggest that the combination of HGF and T beta TR gene therapy may increase the possibility of hepatectomy in a cirrhotic liver by improving fibrosis, hepatic function, and hepatocyte regeneration.