Transforming growth factor‐β receptor‐II up‐regulation during wound healing in previously irradiated graft beds in vivo
Authors: Schultze‐Mosgau Stefan , Wehrhan Falk , Rödel Franz , Amann Kerstin , Radespiel‐Tröger Martin , Grabenbauer Gerhard G. 
Published: July 2003

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 β (TGFβ1−3) play a key role for this process. It has been shown that radiation treatment associated fibrosis is induced by TGFβ1 and TGFβ2, although the influence of radiation on the expression of the TGFβ receptor‐II (TGFβR‐II) involved in the signal transduction of TGFβ remains elusive. The objective of this in vivo study was to analyze the expression profile of TGFβR‐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 TGFβ1 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 × 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 × 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 TGFβR‐II, activated TGFβ1 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 TGFβR‐II expression in the neck was revealed 2–4 weeks following irradiation compared to non‐irradiated skin. Whereas only minor differences in TGFβR‐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 TGFβR‐II expression correlated with an increase of activated TGFβ1 and latency‐associated peptide expression compared to non‐irradiated tissues. After irradiation, a significantly increased TGFβR‐II expression was identified in the irradiated graft bed, which may be the reason for delayed reepithelialization and fibrosis. Exogenous blocking or TGFβR‐II inhibitors could therefore represent a new therapeutic approach for improving wound healing after preoperative radiotherapy. (WOUND REP REG 2003;11:297–305)