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

Transforming growth factor (TGF) beta isoforms (in particular, TGF-beta1) play a central role in the fibrogenic response to injury in many organs, including the liver. Although TGF-beta is clearly important in fibrogenesis, a number of issues related to therapeutic antagonism have emerged. For example, the long-term effect of TGF-beta antagonism is unknown; furthermore, controversy exists as to appropriate levels of TGF-beta inhibition. Therefore, we aimed to examine TGF-beta in models of chronic liver injury and to determine whether an in vivo dose-response relationship exists for inhibition of TGF-beta. Liver injury was induced in BALB/c mice by administering carbon tetrachloride for 4 or 8 weeks. TGF-P binding was inhibited with a soluble TGF-beta type H 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-beta 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-beta.