title: Gene transfer of c-met confers protection against D-galactosamine/lipopolysaccharide-induced acute liver failure.
abstract: BACKGROUND
  Acute liver failure (ALF) is characterized by impaired regeneration of hepatocytes, partially resulting from the defective signaling between elevated levels of hepatocyte growth factor (HGF) and the downregulation of its receptor, c-met.
  
  
  OBJECTIVE
  In this study, we assess the therapeutic efficacy of in vivo c-met gene transfer in ALF.
  
  
  METHODS
  We established a D: -galactosamine/lipopolysaccharide (D: -GalN/LPS)-induced ALF model in rats. The levels of HGF and c-met in D: -GalN/LPS rats were compared with vehicle-injected rats and those undergoing liver regeneration following partial hepatectomy (PH). To deliver c-met in vivo, pcDNA-c-met was constructed and transfected into the rat liver via hydrodynamic injection. Control rats were transfected with the pcDNA3.1 plasmid. The expressions of c-met in different tissues were examined by immunohistochemistry. Hepatocyte proliferation and apoptosis were determined by PCNA staining and TUNEL assay, respectively. The survival of rats in the control and c-met-expressing rats was compared by Kaplan-Meier analysis.
  
  
  RESULTS
  Compared with control rats, D: -GalN/LPS or PH -treated rats had significantly higher levels of HGF (P < 0.01). D: -GalN/LPS also led to significantly lower c-met expression in the liver (P < 0.01) than PH. The in vivo c-met gene transfer led to its specific expression on hepatocytes, which was accompanied by the enhancement of hepatocyte proliferation, a reduction in apoptosis, as well as significant improvement in overall survival (P < 0.01).
  
  
  CONCLUSIONS
  This study provides the initial evidence that c-met may serve as a novel target for gene therapy, and may be of clinical benefit in the treatment of patients with ALF.
authors.affiliation: Department of Infectious Diseases, Affiliated Provincial Hospital, Anhui Medical University, Hefei 230001, China. zhuchuanlong@yahoo.com.cn
authors.forename: Chuanlong
authors.initials: C
authors.lastname: Zhu
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Li
authors.forename: Wenting
authors.initials: W
authors.lastname: Li
authors.forename: Quan
authors.initials: Q
authors.lastname: Wu
authors.forename: Rentao
authors.initials: R
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005688:Galactosamine; D015316:Genetic Therapy; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000473:pathology; D008070:Lipopolysaccharides; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration; D010053:Ovary; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
chemical_list: D008070:Lipopolysaccharides; D017228:Hepatocyte Growth Factor; D005688:Galactosamine; D019859:Proto-Oncogene Proteins c-met