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

Background: Hepatic 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. Objective: To evaluate in vivo the expression of pro-fibrotic molecules like av beta 6 integrin, transforming growth factor-beta (TGF-beta), Smad3, connective tissue growth factor (CTGF) and mammalian target of Rapamycin (mTOR), as well as anti-fibrotic peroxiscime proliferator-activated receptor-gamma (PPAR gamma) in an experimental model of chronic hepatitis-associated fibrosis induced by intraperitoneal administration of dimethylnitrosamine (DMN) in mice. Methods: Chronic 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 alpha-smooth muscle actin (alpha-SMA), collagen types I-III, TGF-beta 1, Smad3, av beta 6 integrin, CTGF, mTOR and PPAR gamma antibodies were performed. Results: The liver of DMN-treated Smad3 WT mice showed a higher degree of hepatic accumulation of connective tissue compared to KO mice. The expression of a-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 av beta 6, TGF beta, Smad3, and mTOR and a reduction in PPAR gamma expression. Conclusions: These results suggest a possible interaction between pro-fibrotic and anti-fibrotic molecules in the development of hepatic fibrosis. (C) 2016 Elsevier GmbH. All rights reserved.