Transforming growth factor-beta receptor-II up-regulation during wound healing in previously irradiated graft beds in vivo.
Wound healing disorders may often present in patients with head and neck cancer after surgical interventions, particularly in preirradiated tissue. Inflammatory changes and the expression of cytokines can lead to induction of fibrosis. The isoforms of the transforming growth factor beta (TGFbeta1-3) play a key role for this process. It has been shown that radiation treatment associated fibrosis is induced by TGFbeta1 and TGFbeta2, although the influence of radiation on the expression of the TGFbeta receptor-II (TGFbetaR-II) involved in the signal transduction of TGFbeta remains elusive. The objective of this in vivo study was to analyze the expression profile of TGFbetaR-II in the graft bed and in the transition area between graft and graft bed after surgery with and without prior radiation treatment to compare with the expression profiles of activated TGFbeta1 and latency-associated peptide. A total of 48 Wistar rats (male, weight 300-500 g) were used in the study. Eighteen rats were irradiated in the neck region (3 x 10 Gy) without transplantation. A free myocutaneous gracilis flap was transplanted in 30 rats, of which 16 animals were preirradiated in the neck region (3 x 10 Gy) and 14 animals were not irradiated at all. Tissue samples were taken postoperatively from the transition area between the graft and the graft bed and from the graft bed itself after 3, 7, 14, and 28 days. Tissue samples were taken from the irradiated neck region and the non-irradiated groin region 0, 4, 7, 11, 14, and 28 days after the end of the exposure. The expression of TGFbetaR-II, activated TGFbeta1 and latency-associated peptide was analyzed immunohistochemically both qualitatively and quantitatively (labeling index). The success rate for graft healing was 75% in the previously irradiated group with 30 Gy, and 86% in the non-irradiated group. Following radiation alone a significantly (p = 0.04) increased TGFbetaR-II expression in the neck was revealed 2-4 weeks following irradiation compared to non-irradiated skin. Whereas only minor differences in TGFbetaR-II expression were observed following surgery between the groups with and without prior radiation in the transition area between the graft and the graft bed, the group undergoing prior radiation and subsequent grafting showed significantly increased expression in the bed compared to the non-preirradiated group with a maximum on postoperative day 7 (week 1, p = 0.003; week 2-4, p < 0.001). In irradiated tissues the up-regulation of TGFbetaR-II expression correlated with an increase of activated TGFbeta1 and latency-associated peptide expression compared to non-irradiated tissues. After irradiation, a significantly increased TGFbetaR-II expression was identified in the irradiated graft bed, which may be the reason for delayed reepithelialization and fibrosis. Exogenous blocking or TGFbetaR-II inhibitors could therefore represent a new therapeutic approach for improving wound healing after preoperative radiotherapy.
Schultze-Mosgau
Stefan
S
Department of Oral and Maxillofacial Surgery, University of Erlangen-Nuremberg, Erlangen, Germany. stefan.schultze-mosgau@mkg.imed.uni-erlangen.de
Wehrhan
Falk
F
Rödel
Franz
F
Amann
Kerstin
K
Radespiel-Tröger
Martin
M
Grabenbauer
Gerhard G
GG
D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism / Q000528:radiation effects; D011498:Protein Precursors / Q000378:metabolism / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017208:Rats, Wistar; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism* / Q000528:radiation effects*; D016038:Skin Transplantation; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000528:radiation effects; D053773:Transforming Growth Factor beta1; D019737:Transplants; D015854:Up-Regulation / Q000528:radiation effects*; D014945:Wound Healing / Q000528:radiation effects*
D010446:Peptide Fragments; D011498:Protein Precursors; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II