Expression of pro-fibrotic and anti-fibrotic molecules in dimethylnitrosamine-induced hepatic fibrosis

Abstract

BackgroundHepatic fibrosis is characterized by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins, produced by activated myofibroblasts which are modulated by both profibrotic and antifibrotic factors. ObjectiveTo evaluate in vivo the expression of pro-fibrotic molecules like avβ6 integrin, transforming growth factor-β (TGF-β), Smad3, connective tissue growth factor (CTGF) and mammalian target of Rapamycin (mTOR), as well as anti-fibrotic peroxisome proliferator-activated receptor-γ (PPARγ) in an experimental model of chronic hepatitis-associated fibrosis induced by intraperitoneal administration of dimethylnitrosamine (DMN) in mice. MethodsChronic hepatitis was induced in 12 Smad3 wild-type (WT) and 12 knock-out (KO) mice by intraperitoneal DMN administration. Histological, morphometric and immunohistochemical analyses using α-smooth muscle actin (α-SMA), collagen types I–III, TGF-β1, Smad3, avβ6 integrin, CTGF, mTOR and PPARγ antibodies were performed. ResultsThe liver of DMN-treated Smad3 WT mice showed a higher degree of hepatic accumulation of connective tissue compared to KO mice. The expression of α-SMA, collagen I–III and CTGF was increased in Smad3 WT compared to KO mice treated with DMN, associated with a concomitant up-regulation of avβ6, TGFβ, Smad3, and mTOR and a reduction in PPARγ expression. ConclusionsThese results suggest a possible interaction between pro-fibrotic and anti-fibrotic molecules in the development of hepatic fibrosis.