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

Abstract

Background & Aims: Transforming growth factor (TGF)-β 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-β type II receptor (TβR-ll) protein ameliorates intestinal radiation injury (radiation enteropathy). Methods: A recombinant fusion protein, consisting of the extracellular portion of mouse TβR-ll and the Fc portion of mouse immunoglobulin (lg) G, was produced. A 5-cm segment of mouse ileum was exposed to 19 Gy x-radiation. TβRll: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-β 1 messenger RNA was assessed with fluorogenic probe reverse-transcription polymerase chain reaction. Results: Compared with IgG controls, TβR-ll:Fc-treated mice exhibited less structural injury, preservation of mucosal surface area, and less intestinal wall fibrosis. Intestinal TGF-β l messenger RNA increased in TβR-ll:Fc-treated mice, whereas TGF-β immunoreactivity decreased. TβR-ll:Fc treatment increased crypt cell proliferation but otherwise did not affect unirradiated intestine. Conclusions: Long-term modulation of TGF-β with a TβR-ll:Fc fusion protein is feasible and ameliorates radiation enteropathy. These data confirm the putative role of TGF-β in intestinal radiation fibrosis. © 2000 by the American Gastroenterological Association.