Cellular sources of transforming growth factor-beta isoforms in early and chronic radiation enteropathy

Am J Pathol. 1998 Nov;153(5):1531-40. doi: 10.1016/s0002-9440(10)65741-0.


The three mammalian transforming growth factor (TGF)-beta isoforms (TGF-beta1, TGF-beta2, and TGF-beta3) differ in their putative roles in radiation-induced fibrosis in intestine and other organs. Furthermore, tissue specificity of TGF-beta action may result from temporal or spatial changes in production and/or activation. The present study examined shifts in the cell types expressing TGF-beta mRNA relative to TGF-beta immunoreactivity and histopathological injury during radiation enteropathy development. A 4-cm loop of rat small intestine was locally exposed to O, 12, or 21-Gy single doses of x-irradiation. Sham-irradiated and irradiated intestine were procured 2 and 26 weeks after irradiation. Cells expressing the TGF-beta1, TGF-beta2, or TGF-beta3 transcripts were identified by in situ hybridization with digoxigenin-labeled riboprobes. Intestinal wall TGF-beta immunoreactivity was measured using computerized image analysis, and structural radiation injury was assessed by quantitative histopathology. Normal intestinal epithelium expressed transcripts for all three TGF-beta isoforms. Two weeks after irradiation, regenerating crypts, inflammatory cells, smooth muscle cells, and mesothelium exhibited increased TGF-beta1 expression and, to a lesser degree, TGF-beta2 and TGF-beta3 expression. Twenty-six weeks after irradiation, TGF-beta2 and TGF-beta3 expression had returned to normal. In contrast, TGF-beta1 expression remained elevated in smooth muscle, mesothelium, endothelium, and fibroblasts in regions of chronic fibrosis. Extracellular matrix-associated TGF-beta1 immunoreactivity was significantly increased at both observation times, whereas, TGF-beta2 and TGF-beta3 immunoreactivity exhibited minimal postradiation changes. Intestinal radiation injury is associated with overexpression of all three TGF-beta isoforms in regenerating epithelium. Radiation enteropathy was also associated with sustained shifts in the cellular sources of TGF-beta1 from epithelial cells to cells involved in the pathogenesis of chronic fibrosis. TGF-beta2 and TGF-beta3 did not exhibit consistent long-term changes. TGF-beta1 appears to be the predominant isoform in radiation enteropathy and may be more important in the mechanisms of chronicity than TGF-beta2 and TGF-beta3.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biomarkers / analysis
  • Dose-Response Relationship, Radiation
  • Extracellular Matrix / metabolism
  • In Situ Hybridization
  • Intestinal Diseases / etiology*
  • Intestinal Diseases / metabolism
  • Intestinal Diseases / pathology
  • Intestinal Mucosa / metabolism
  • Intestines / pathology
  • Intestines / radiation effects*
  • Male
  • Oligonucleotides, Antisense / metabolism
  • RNA, Messenger / metabolism
  • Radiation Injuries, Experimental / metabolism*
  • Radiation Injuries, Experimental / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*


  • Biomarkers
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Transforming Growth Factor beta