title: Coexpression of Smad7 and UPA attenuates carbon tetrachloride-induced rat liver fibrosis.
abstract: BACKGROUND
  There is a great need for developing novel therapies to treat liver fibrosis. Previous studies showed that both Smad7 and uPA were inhibitors of liver fibrosis. Therefore, we explored the therapeutic effects of combinational gene therapy with Smad7 and uPA on CCl4-induced liver fibrosis.
  
  
  METHODS
  Smad7 and uPA genes were cloned into an adenovirus vector. To observe the therapeutic effects of coexpression of Smad7 and uPA genes, the recombinant adenovirus were delivered into CCL4-induced fibrosis models. Fibrillar collagen, hydroxyproline, α-SMA, TGF-β1, MMP-13, TIMP-1, HGF and PCNA were detected to evaluate the fibrosis and to explore the mechanisms underlying the treatment with Smad7 and uPA.
  
  
  RESULTS
  The results showed that single Smad7 or uPA adenovirus reduced CCL4 induced liver fibrosis significantly; while combination of Smad7 and uPA had more significant therapeutic effect on CCl4 induced liver fibrosis. Then the markers underlying the therapeutic effect of combination of Smad7 and uPA were also explored. Over-expression of Smad7 and uPA inhibited the expression of α-SMA and TGF- β1 significantly. Combinational gene therapy also enhanced extracellular matrix degradation by increasing the expression of MMP-13, inhibiting TIMP-1 expression, and promoted hepatocyte proliferation, while single Smad7 or uPA only induced part of these changes.
  
  
  CONCLUSIONS
  These results suggest that combinational gene therapy with Smad7 and uPA inhibited CCl4-induced rat liver fibrosis by simultaneously targeting multiple pathogenic pathways.
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Baocan
authors.initials: B
authors.lastname: Wang
authors.forename: Wenxi
authors.initials: W
authors.lastname: Li
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Chen
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.forename: Yuanwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Hanming
authors.initials: H
authors.lastname: Lu
authors.forename: Jiangao
authors.initials: J
authors.lastname: Fan
authors.forename: Dingguo
authors.initials: D
authors.lastname: Li
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002251:Carbon Tetrachloride; D049109:Cell Proliferation; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology* / Q000628:therapy*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011995:Recombination, Genetic / Q000235:genetics; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D012333:RNA, Messenger; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D002251:Carbon Tetrachloride; D014568:Urokinase-Type Plasminogen Activator; D053509:Matrix Metalloproteinase 13