The production of collagen and the activity of mast-cell chymase increase in human skin after irradiation therapy

Abstract

Fibrosis is a common complication of radiotherapy. The pathogenesis of radiation-induced fibrosis is not known in detail. There is increasing evidence to suggest that mast cells contribute to various fibrotic conditions. Several mast-cell mediators have been proposed to have a role in fibrogenesis. Tryptase and chymase, the predominant proteins in mast cells, have been shown to induce fibroblast proliferation and collagen synthesis in vitro. In order to explore the role of mast cells in irradiation-induced fibrosis, we analyzed skin biopsies and suction blister fluid (SBF) samples from the lesional and healthy-looking skin of 10 patients who had been treated for breast cancer with surgery and radiotherapy. The biopsies were analyzed histochemically for mast-cell tryptase, chymase, kit receptor, and tumor necrosis factor-alpha. Skin collagen synthesis was assessed by determining the levels of type I and III procollagen amino-terminal propeptides (PINP and PIIINP) in SBF and using immunohistochemical staining for PINP. Immunohistochemical stainings for prolyl-4-hydroxylase reflecting collagen synthesis and chymase immunoreactivity in irradiated and control skin were also performed. The mean level of procollagen propeptides in SBF, which reflects actual skin collagen synthesis in vivo, was markedly increased in irradiated skin compared to corresponding healthy control skin areas. The mean number of PINP-positive fibroblasts was also significantly increased in the upper dermis of radiotherapy-treated skin. The number of cells positive for tryptase, chymase and kit receptor was markedly increased in irradiated skin. In addition, using double-staining techniques, it was possible to demonstrate that in some areas of the dermis, tryptase-positive mast cells and fibroblasts are closely associated. These findings suggest a possible role of mast cells in enhanced skin collagen synthesis and fibrosis induced by radiotherapy.