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


CONCLUSIONS
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.
Ozawa
Satoru
S
Second Department of Surgery, Wakayama Medical University, Wakayama, Japan.
Uchiyama
Kazuhisa
K
Nakamori
Mikihito
M
Ueda
Kentaro
K
Iwahashi
Makoto
M
Ueno
Hikaru
H
Muragaki
Yasuteru
Y
Ooshima
Akira
A
Yamaue
Hiroki
H
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003131:Combined Modality Therapy; D004128:Dimethylnitrosamine; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000601:surgery / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*
D018125:Receptors, Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D004128:Dimethylnitrosamine