Adenovirus-mediated transfer of siRNA against PAI-1 mRNA ameliorates hepatic fibrosis in rats.
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.
Hu
Ping-Fang
PF
Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Chen
Han
H
Zhong
Wei
W
Lin
Yong
Y
Zhang
Xin
X
Chen
Yue-Xiang
YX
Xie
Wei-Fen
WF
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
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