Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-β soluble receptor: Implications for antifibrotic therapy

Abstract

Transforming growth factor (TGF) β isoforms (in particular, TGF-β1) play a central role in the fibrogenic response to injury in many organs, including the liver. Although TGF-β is clearly important in fibrogenesis, a number of issues related to therapeutic antagonism have emerged. For example, the long-term effect of TGF-β antagonism is unknown; furthermore, controversy exists as to appropriate levels of TGF-β inhibition. Therefore, we aimed to examine TGF-β in models of chronic liver injury and to determine whether an in vivo dose-response relationship exists for inhibition of TGF-β. Liver injury was induced in BALB/c mice by administering carbon tetrachloride for 4 or 8 weeks. TGF-β binding was inhibited with a soluble TGF-β type II receptor (STR) construct, administered intraperitoneally over a dose range of 4.0, 1.0, 0.4, or 0.1 mg/kg twice weekly during fibrogenesis. Fibrogenesis was assessed by measurement of type I collagen messenger RNA (mRNA) expression and by quantitative morphometric analysis. In the 4-week study, STR at concentrations of 4.0, 1.0, and 0.1 mg/kg reduced type I collagen mRNA expression by 31%, 49%, and 60% compared with immunoglobulin (Ig) G controls, respectively. In the 8-week study, lower concentrations of STR (0.1 mg/kg) also had the greatest effect on type I collagen mRNA expression. Quantitative morphometrics similarly showed that lower concentrations of STR were the most antifibrogenic. In conclusion, the results confirm the antifibrotic effect of inhibiting TGF-β in chronic hepatic wounding and, moreover, show that its in vivo effect in the mouse is dose dependent. Such findings have major translational implications for therapeutic strategies aimed at TGF-β.