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

AbstractBACKGROUND & 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 (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.
AuthorsH Zheng, J Wang, V E Koteliansky, P J Gotwals, M Hauer-Jensen
JournalGastroenterology (Gastroenterology) Vol. 119 Issue 5 Pg. 1286-96 (Nov 2000) ISSN: 0016-5085 [Print] United States
PMID11054386 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Collagen
Topics
  • Animals
  • CHO Cells
  • Collagen (metabolism)
  • Cricetinae
  • Ileum (drug effects, metabolism, pathology, radiation effects)
  • Immunoglobulin Fc Fragments (genetics)
  • Immunoglobulin G (genetics)
  • Intestinal Diseases (drug therapy, pathology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Isoforms (chemistry, genetics)
  • RNA, Messenger (metabolism)
  • Radiation Injuries (drug therapy, pathology)
  • Receptors, Transforming Growth Factor beta (chemistry, genetics)
  • Recombinant Fusion Proteins (therapeutic use)
  • Solubility
  • Transforming Growth Factor beta (genetics, metabolism)
  • Transforming Growth Factor beta1

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