title: [Reversal of liver fibrosis through AG490 inhibitor-mediated inhibition of the TGFbeta1-STAT3 pathway].
abstract: OBJECTIVE
  To investigate the role of TGF-beta1 and STAT3 signaling in liver fibrosis using a rat model system and to determine the therapeutic mechanism of AG490 in relation to this signaling pathway.
  
  
  METHODS
  Rats were randomly divided into a control group and DENA-induced liver fibrosis model group, and then subdivided into AG490 treatment groups. During fibrosis development, liver tissue samples were collected at different time points (0, 4 and 8 weeks) and evaluated according to the Scheuer scoring system. Expression of STAT3, TGFbeta1, alpha-SMA, E-cadherin, MMP2 and TIMP1 was measured by PCR (mRNA) and immunohistochemistry and western blotting (protein).
  
  
  RESULTS
  Increasing degrees of inflammation and fibrosis were observed in liver tissues of DENA-treated rats throughout model establishment. The mRNA expression of TGFbeta1 and STAT3 was significantly increased in DENA-induced rats with advanced fibrosis (AF) compared to those with early fibrosis (EF) (P = 0.034 and P = 0.012 respectively). The protein expression of TGF-beta1, phospho-Smad2, alpha-SMA, E-cadherin, STAT3 and phospho-STAT3 was significantly increased in DENA-induced rats with AF compared to the unmodeled control group (P = 0.048, P = 0.003, P = 0.002, P = 0.028, P = 0.009 and P = 0.039). The protein expression of E-cadherin was lower in the DENA-induced rats with AF than in those with EF (P = 0.026). STAT3 and TGF-beta1 co-expression was detected in AF tissues. DENA-induced AG490-treated rats with AF showed substantially lower protein expression of STAT3, TGF-beta1, MMP2 and TIMP1 compared to DENA-induced untreated rats with AF (P = 0.006, P = 0.018, P = 0.010 and P = 0.005); in addition, the degrees of fibrosis and inflammation were also greatly reduced in the DENA-induced AG490-treated rats with AF compared to DENA-induced untreated rats with AF (P = 0.042 and P = 0.021). Conclusions STAT3 signal transduction may regulate the TGF-beta1 pathway and affect liver fibrosis, especially in the advanced phase. AG490 can inhibit TGFbeta1-STAT3 signaling, resulting in reversal of liver fibrosis.
authors.affiliation: Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University of Medicine, Shanghai 200080, China.
authors.forename: Shengzheng
authors.initials: S
authors.lastname: Luo
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Li
authors.forename: Mingyi
authors.initials: M
authors.lastname: Xu
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.forename: Lungen
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide