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

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Background : In a cirrhotic liver, the regenerative ability and specific functions are impaires ; a hepatic resection increases the possibility of postoperative liver failure. Hepatocyte growth factor (HGF) stimulates liver regeneration, accelates restoration of hepatic function, and improves fibrosis. A truncated type II transforming growth factor-β receptor (TβTR), which specifically inhibits TGF-β signaling as a dominant-negative receptor, appears to prevent the progression of liver fibrosis. We demonstrated the therapeutic efficacy of adenovirus-mediated HGF and TβTR gene transducation after partial hepatectomy for liver cirrhosis.Methods/Results : Rats were treated with dimethylnitrosamine for 3 weeks, and they all had severe cirrhosis. First, to examine the toxicity and the transduction efficiency of adenoviral (Ad) vector in this model, AdLacZ that ranged from 1.0×10^8 to 2.0×10^9 pfu was administered through the portal vein to the rats, and determined that the optimal dose of A … More d vector in cirrhotic rat was range from 5.0×10^8 to 1.0×10^9 pfu. Second, after the 10% partial hepatectomy in rats of this model, we injected AdLacZ (5.0×10^8 pfu), Ad TβTR, AdHGF, or Ad TβTR + AdHGF (1:1 total 1.0×10^9 pfu) into the portal vein, which was followed by an additionl 2-week dimethylnitrosamine treatment. On histologic examination, fibrotic tissue had decreased in the livers of the Ad TβTR + AdHGF-treated rats compared with rats that were treated by AdLacZ, Ad TβTR alone, and AdHGF alone. Liver function, which included serum levels of alanine aminotransferase, improved significantly in Ad TβTR + 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 Ad TβTR + AdHGF -treated rat livers than in Ad LacZ-and TβTR-treated rats. All Ad TβTR + AdHGF -treated rats survived >60 days, and Ad TβTR + AdHGF treatment markedly improved the survival rate after a partial hepatectomy.Conclusion : Our results suggest that the combination of HGF and TβTR gene therapy may increase the possibility of hepatectomy in a cirrhotic liver by improving fibrosis, hepatic function, and hepatocyte regeneration. Less