RRC ID 2278
Author Ozawa S, Uchiyama K, Nakamori M, Ueda K, Iwahashi M, Ueno H, Muragaki Y, Ooshima A, Yamaue H.
Title Combination gene therapy of HGF and truncated type II TGF-beta receptor for rat liver cirrhosis after partial hepatectomy.
Journal Surgery
Abstract BACKGROUND:In a cirrhotic liver, the regenerative ability and specific functions 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 II transforming growth factor-beta receptor (TbetaTR), 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 TbetaTR 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 (AdTbetaTR), adenovirus expressing hepatocyte growth factor (AdHGF), or AdTbetaTR + 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 AdTbetaTR + AdHGF-treated rats compared with rats that were treated by AdLacZ, AdTbetaTR alone, and AdHGF alone. Liver function, which included serum levels of alanine aminotransferase, improved significantly in AdTbetaTR + 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 AdTbetaTR + AdHGF-treated rat livers than in AdLacZ- and AdTbetaTR-treated rats. All AdTbetaTR + AdHGF-treated rats survived >60 days, and AdTbetaTR + AdHGF treatment markedly improved the survival rate after a partial hepatectomy.
CONCLUSION:Our results suggest that the combination of HGF and TbetaTR gene therapy may increase the possibility of hepatectomy in a cirrhotic liver by improving fibrosis, hepatic function, and hepatocyte regeneration.
Volume 139(4)
Pages 563-73
Published 2006-4-1
DOI 10.1016/j.surg.2005.10.003
PII S0039-6060(05)00647-1
PMID 16627068
MeSH Adenoviridae / genetics Animals Combined Modality Therapy Dimethylnitrosamine Disease Models, Animal Genetic Therapy / methods* Genetic Vectors Hepatectomy Hepatocyte Growth Factor / genetics* Humans Liver Cirrhosis, Experimental / surgery Liver Cirrhosis, Experimental / therapy* Protein Serine-Threonine Kinases Rats Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta / genetics*
IF 3.356
Times Cited 22
DNA material AxCA rat HGF (RDB1553)