Trolox down-regulates transforming growth factor-beta and prevents experimental cirrhosis

Cirrhosis is a very common disease and its treatment is limited due to lack of effective drugs. Some studies indicate that this disease is associated with oxidative stress. Therefore, we decided to study the effect of trolox, an effective antioxidant, on experimental cirrhosis. Cirrhosis was induced by CCl4 administration (0.4 g/kg, intraperitoneally, three times per week, for 8 weeks) to Wistar male rats. Trolox was administered daily (50 mg/kg, orally). Fibrosis was assessed histologically and by measuring liver hydroxyproline content. Glutathione, lipid peroxidation and glycogen were measured in liver; serum markers of liver damage were also quantified. Transforming growth factor-beta (TGF-beta) was determined by Western blot and quantified densitometrically. Alkaline phosphatase, gamma-glutamyl transpeptidase and alanine aminotransferase increased in the group receiving CCl4; trolox completely or partially prevented these alterations. Glycogen was almost depleted by CCl4 but was partially preserved by trolox. Lipid peroxidation increased while glutathione decreased by CCl4 administration; trolox corrected both effects. Histology showed thick bands of collagen, necrosis and distortion of the hepatic parenchyma in the CCl4 group, such effects were prevented by trolox. Hydroxyproline content increased 5-fold by CCl4, while the group receiving both CCl4 and trolox showed no significant difference compared to the control group. CCl4 increased 3-fold TGF-beta, while trolox completely prevented this increase. We found that trolox effectively prevented cirrhosis induced with CCl4 in the rat. Our results suggest that the beneficial effects of trolox may be associated to its antioxidant properties and to its ability to reduce the profibrogenic cytokine TGF-beta expression.