Recombinant soluble transforming growth factor β type II receptor ameliorates radiation enteropathy in mice

Background & Aims: Transforming growth factor (TGF)-beta has been implicated in many fibrotic conditions. However, its mechanistic role in radiation toxicity is equivocal despite compelling correlative evidence. This study assessed whether in vivo administration of a soluble TGF-beta type II receptor (TPR-II) protein ameliorates intestinal radiation injury (radiation enteropathy). Methods: A recombinant fusion protein, consisting of the extracellular portion of mouse T betaR-II and the Fc portion of mouse immunoglobulin (Ig) G, was produced. A 5cm segment of mouse ileum was exposed to 19 Gy x-radiation. T betaR-II:Fc fusion protein (1 mg/kg every other day) or mouse IgG was administered from 2 days before to 6 weeks after irradiation. Radiation injury was assessed at 6 weeks using quantitative histology, morphometry, and immunohistochemistry. Collagen was measured colorimetrically, and TGF-beta1 messenger RNA was assessed with fluorogenic probe reverse-transcription polymerase chain reaction. Results: Compared with IgG controls, T betaR-II:Fc-treated mice exhibited less structural injury, preservation of mucosal surface area, and less intestinal wall fibrosis. intestinal TGF-beta1 messenger RNA increased in T betaR-II:Fc-treated mice, whereas TGF-beta immunoreactivity decreased, T betaR-II:Fe treatment increased crypt cell proliferation but otherwise did not affect unirradiated intestine. Conclusions: Long-term modulation of TGF-beta with a T betaR-II:Fc fusion protein is feasible and ameliorates radiation enteropathy. These data confirm the putative role of TGF-beta in intestinal radiation fibrosis.