doi: 10.1111/j.1472-8206.2011.01020.x ORIGINAL ARTICLE Trolox mitigates fibrosis in a bile duct ligation model Marina Galicia-Moreno, Liliana Favari, Pablo Muriel* Departamento de Farmacologı ´a, CINVESTAV-IPN., Apdo Postal 14-740 Me ´xico, DF 07000, Me ´xico INTRODUCTION Cirrhosis can be defined as a pathologic state character- ized by increased deposition and altered composition of extracellular matrix (ECM), mainly of collagens I, III, and IV, and where architecture and normal liver function are lost completely [1]. This disease is caused by a variety of etiological factors, including viral hepatitis (mainly hepatitis B and C), alcohol abuse, drugs, or bile duct obstruction [2]. Currently, some studies indicate that cirrhosis is associated with oxidative stress, lipid peroxidation pro- cess, and the activation of hepatic stellate cells (HSC) [2,3]. HSC comprise 15% of total number of resident liver cells. In normal conditions, HSC produced controlled amounts of collagens type III and IV [4]. The activation of HSC results in transdifferentiation of this fibrogenic precursor cell type to the ECM producing myofibroblastic phenotype (MFB) [5]; therefore, during the fibrogenesis, these cells play a key role in the pathogenesis of fibrosis and cirrhosis [6–9]. On the other hand, various studies have identified the transforming growth factor-b (TGF-b) as the major profibrogenic master cytokine, which in concert with other growth factors promotes transdifferentiaton of HSC into MFB. Stimulation of matrix gene expression, down regulation of matrix degradation, and induction of hepatocellular apoptosis are promoted by the numerical expansion of MFB [10–14]. Recent studies showed how TGF-b stimulates the production of reactive oxygen Keywords cirrhosis, cytokines, fibrosis, oxidative stress, TGF-b1 Received 15 April 2011; revised 1 November 2011; accepted 22 November 2011 *Correspondence and reprints: pamuriel@cinvestav.mx ABSTRACT Several studies suggest that free radicals may play a role in cholestatic liver injury. The aim of this work was to evaluate the role of trolox in chronic bile duct ligation (BDL). Liver injury was induced by 28-day BDL to male Wistar rats. Animals were divided in four groups of six rats. Trolox was administered daily (50 mg/kg, p.o.). Alanine aminotransferase (ALT) was quantified in serum. Fibrosis was assessed measuring liver hydroxyproline content. Reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, catalase (CAT), and glutathione peroxidase (GPx) activities were measured in liver. Transforming growth factor-b (TGF-b), interleukin- 6 (IL-6), and interleukin-10 (IL-10) were determined by western blot and quantified densitometrically. Our results show that trolox treatment in BDL rats prevented the increase in ALT. Collagen was increased by chronic BDL, but trolox administration preserved the normal collagen concentration. BDL produced high levels of the cytokine TGF-b1, IL-6, and IL-10 levels. Trolox administration was effective to partially prevent the increase of TGF-b1 and IL-6, and it was able to further augment the levels of IL-10. Oxidative stress (assessed by lipid peroxidation and liver glutathione content) was increased by BDL; this process was normalized by trolox. The activities of CAT and GPx were altered by BDL, and trolox prevented these events. We found that there is a close relationship between cholestatic liver damage and oxidative stress generation, and this was effectively prevented by trolox. Our study shows that the beneficial effects of trolox are because of its important antioxidant and immunomodulatory properties. ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Socie ´ te ´ Franc ¸aise de Pharmacologie et de The ´ rapeutique Fundamental & Clinical Pharmacology 1 Fundamental & Clinical Pharmacology