Thymosinβ4 alleviates cholestatic liver fibrosis in mice through downregulating PDGF/PDGFR and TGFβ/Smad pathways

Liver fibrosis is an important health problem without adequate and effective therapeutics. In this study, effects of thymosin beta 4 (T beta 4) on hepatic fibrogenesis and the underlying molecular mechanisms were explored in bile duct ligation (BDL)-induced mice cholestatic liver fibrosis model. Results showed exogenous T beta 4 significantly reduced the mortality and liver/body weight ratio in BDL mice. Histological examinations and biochemical analyses demonstrated that BDL induced evident portal fibrosis and a significant increase in hepatic collagen contents. However, these changes were significantly attenuated by exogenous T beta 4. Quantitative real-time PCR assays showed that T beta 4 suppressed BDL-induced increases in many fibrotic genes expression including alpha-smooth muscle actin (alpha-SMA), collagen I, III and fibronectin, TGF beta 1, TGF beta R II, Smad2, Smad3, and PDGFR beta. Results from immunohistochemistry and Western blots also showed that T beta 4 reduced TGF beta 1 and PDGFR beta protein levels in the liver tissues of BDL mice. In vitro studies using LX-2 cells demonstrated that T beta 4 could decrease PDGFR beta and TGF beta R II levels in hepatic stellate cells. Taken together, findings in our present studies suggested that exogenous T beta 4 alleviated BDL-induced cholestatic liver fibrosis through downregulating PDGF/PDGFR and TGF beta/Smad pathways. (C) 2019 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.