Recombinant soluble transforming growth factor beta type II receptor ameliorates radiation enteropathy in mice.
OBJECTIVE
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 (TbetaR-II) protein ameliorates intestinal radiation injury (radiation enteropathy).


METHODS
A recombinant fusion protein, consisting of the extracellular portion of mouse TbetaR-II and the Fc portion of mouse immunoglobulin (Ig) G, was produced. A 5-cm segment of mouse ileum was exposed to 19 Gy x-radiation. TbetaR-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, TbetaR-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 TbetaR-II:Fc-treated mice, whereas TGF-beta immunoreactivity decreased. TbetaR-II:Fc treatment increased crypt cell proliferation but otherwise did not affect unirradiated intestine.


CONCLUSIONS
Long-term modulation of TGF-beta with a TbetaR-II:Fc fusion protein is feasible and ameliorates radiation enteropathy. These data confirm the putative role of TGF-beta in intestinal radiation fibrosis.
Zheng
H
H
Departments of Surgery and Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA.
Wang
J
J
Koteliansky
V E
VE
Gotwals
P J
PJ
Hauer-Jensen
M
M
D000818:Animals; D016466:CHO Cells; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D007410:Intestinal Diseases / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011832:Radiation Injuries / Q000188:drug therapy* / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D020033:Protein Isoforms; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen