RADIATION-INDUCED LIVER FIBROSIS IS MITIGATED BY GENE THERAPY INHIBITING TRANSFORMING GROWTH FACTOR-β SIGNALING IN THE RAT

Purpose We determined whether anti transforming growth factor beta (TGF-beta) intervention could halt the progression of established radiation-induced liver fibrosis (RILF) Methods and Materials A replication defective adenoviral vector expressing the extracellular portion of human T beta RII and the Fe portion of immunoglobulin G fusion protein (AdT beta RIIFc) was produced The entire rat liver was exposed to 30 Gy irradiation to generate a RILF model (RILFM) Then, RILFM animals were treated with AdT beta RIIFc (1 x 10(11) plaque forming units [PFU] of T beta RII), control virus (1 x 10(11) PFU of AdGFP), or saline Delayed radiation liver injury was assessed by histology and immunohistochemistry Chronic oxidative stress damage, hepatic stellate cell activation, and hepatocyte regeneration were also analyzed Results In rats infected with AdT beta RIIFc, fibrosis was significantly improved compared with rats treated with AdGFP or saline, as assessed by histology, hydroxyproline content, and serum level of hyaluronic acid Compared with AdGFP rats, AdT beta RIIFc-treated rats exhibited decreased oxidative stress damage and hepatic stellate cell activation and preserved liver function Conclusions Our results demonstrate that TGF beta plays a critical role in the progression of liver fibrosis and suggest that anti TGF beta intervention is feasible and ameliorates established liver fibrosis In addition, chronic oxidative stress may be involved in the progression of RILF (C) 2010 Elsevier Inc