title: Adenovirus-mediated transfer of siRNA against PAI-1 mRNA ameliorates hepatic fibrosis in rats.
abstract: OBJECTIVE
  Plasminogen activator inhibitor-1 (PAI-1) is a potential profibrotic molecule. The aim of this study was to evaluate the therapeutic effect of PAI-1 small interfering RNA (siRNA) on experimental hepatic fibrosis and investigate the intrinsic mechanisms.
  
  
  METHODS
  Hepatic fibrosis in rats was induced by dimethylnitrosamine (DMN) administration or bile duct ligation (BDL). An adenovirus carrying PAI-1 shRNA (AdshPAI) was generated and administered via tail vein injection. The expression of PAI-1 was confirmed by real-time RT-PCR and immunohistochemistry. The effect of AdshPAI on fibrosis was evaluated by histological and immunohistochemical examination.
  
  
  RESULTS
  We found that PAI-1 was downregulated after AdshPAI administration. Liver fibrosis was significantly improved after AdshPAI administration in both DMN and BDL models. AdshPAI treatment facilitated matrix degradation by correcting the levels of matrix metalloproteinases (MMPs) and its inhibitors (TIMPs) through upregulation of MMP9, MMP13 and downregulation of TIMP-1. Moreover, AdshPAI treatment stimulated hepatocellular proliferation and inhibited cellular apoptosis.
  
  
  CONCLUSIONS
  This study suggests that AdshPAI treatment has a protective effect on hepatocytes and ameliorates liver fibrogenesis. Inhibiting the upregulation of PAI-1 during liver fibrosis may be an antifibrotic pathway worth exploiting.
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
authors.forename: Ping-Fang
authors.initials: PF
authors.lastname: Hu
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Yue-Xiang
authors.initials: YX
authors.lastname: Chen
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
mesh_terms: D000199:Actins / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D024042:Collagen Type I / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000502:physiology; D008106:Liver Cirrhosis, Experimental / Q000628:therapy*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D051900:Smad3 Protein / Q000235:genetics; D051906:Smad7 Protein / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D000199:Actins; D024042:Collagen Type I; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D051900:Smad3 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; C497787:Smad3 protein, rat; C497808:Smad7 protein, rat; C498862:Acta2 protein, rat