BOTH IN-VITRO AND IN-VIVO IRRADIATION ARE ASSOCIATED WITH INDUCTION OF MACROPHAGE-DERIVED FIBROBLAST GROWTH-FACTORS

Fibrosis in the lung directly underlying the field of irradiation is a n almost universal long term sequelae of thoracic irradiation. It is a ssumed to represent the consequence of direct damage to local tissues and/or vascular endothelium by ionizing radiation. This view, however, is not in keeping with our current understanding of fibrotic processe s, which suggest that growth factors for fibroblasts (including platel et-derived growth factor (PDGF), insulin-like growth factor I (IGF-I)) and cytokines stimulating collagen synthesis (notably transforming gr owth factor-beta) are largely responsible for this process. Since a ma jor source of these factors is the macrophage, present in large number s within the lung, it appeared possible that radiation-induced fibrosi s might be mediated by similar mechanisms. Therefore, a study was desi gned to determine, first, whether in vitro irradiation of mononuclear phagocytes could induce the release of growth factors for fibroblasts. Second, we wished to ascertain whether these same growth factors migh t also be secreted by bronchoalveolar cells from humans who had underg one in vivo thoracic irradiation. The results of this study indicate t hat irradiation of a number of different types of mononuclear phagocyt es resulted in the dose-dependent synthesis and release of several gro wth factors for fibroblasts, including PDGF, tumour necrosis factor-al pha (TNF-alpha) and IGF-I. Further, cells obtained by bronchoalveolar lavage from patients undergoing thoracic radiation spontaneously relea sed PDGF following irradiation. These findings strongly support the co ntention that synthesis and release of macrophage-derived growth facto rs for fibroblasts (particularly PDGF and IGF-I) occur after thoracic irradiation and play a significant role in the pathogenesis of irradia tion-induced pulmonary fibrosis in humans.