title: Hepatocyte growth factor gene transfer with naked plasmid DNA ameliorates dimethylnitrosamine-induced liver fibrosis in rats.
abstract: OBJECTIVE
  Hepatocyte growth factor (HGF) has various biological properties, including antifibrogenic activity. In the present study, we tested the efficacy of HGF gene therapy using naked plasmid DNA in dimethylnitrosamine (DMN)-induced liver fibrosis in a rat model.
  
  
  METHODS
  Naked plasmid DNA encoding human HGF was injected once, together with a hypertonic solution, into the hepatic artery after DMN treatment on three consecutive days per week for 3 weeks. Naked plasmid DNA encoding beta-galactosidase was injected similarly in the DMN-treated control rats. DMN treatment was continued once weekly after gene transfer for additional 3 weeks.
  
  
  RESULTS
  The human HGF protein expression was detected in livers transfected with human HGF naked plasmid DNA, gradually decreasing by day 21. The expression of the endogenous rat HGF protein was also upregulated after human HGF gene transfer. Phosphorylation of c-Met, a HGF receptor, was detected only in livers transfected with human HGF plasmid DNA. Fibrosis was attenuated significantly in livers transfected with the human HGF plasmid. Attenuation wasaccompanied by decreased expression of alpha-smooth muscle actin. Increased portal vein pressure after treatment with DMN was suppressed significantly by HGF gene transfer. The upregulated hepatic protein expression of transforming growth factor-beta (TGF-beta) in response to DMN was markedly attenuated by HGF gene transfer accompanied by the increased protein expression for matrix metalloproteinases (MMP)-3 and -13.
  
  
  CONCLUSIONS
  The hepatic arterial injection of human naked plasmid HGF DNA was effective in suppressing liver fibrosis induced in rats by DMN. The mechanisms by which HGF expression attenuated liver fibrosis may include the suppression of hepatic TGF-beta expression and the induction of MMP expression.
authors.affiliation: Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Hironari
authors.initials: H
authors.lastname: Kanemura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iimuro
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ueki
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Hirano
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Horiguchi
authors.forename: Yasukane
authors.initials: Y
authors.lastname: Asano
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto