Autocrine activation of fibroblasts following irradiation.

BACKGROUND: The most important limitation of thoracic radiotherapy is radio-toxicity of the normal lung. We distinguish the pneumonitis with acute clinical onset, histologically characterised by infiltration of inflammatory cells to alveoli and interstitium, from fibrosis, which is slowly progressive and characterised by fibroblast proliferation and collagen deposition in the interstitium. Radiogenetic fibrosis can occur without evidence of alveolitis, an active role of mesenchymal lung cells in the pathogenesis of this special disorder is assumed. METHODS: Human lung fibrobasts were irradiated in vitro with single doses of 4, 7 and 10 Gy and afterwards observed or incubated together with non-irradiated cells in a co-culture system. After 3, 6, 9, and 12 days cells were counted, and TGF beta 1 and fibronectin was measured in supernatants. RESULTS: Cell growth of irradiated fibroblasts was inhibited as expected. In contrast, we observed a significant stimulation of cell growth of the non-irradiated fibroblasts, which were incubated together with the irradiated cells. This effect was obvious from day 1 until day 9 following irradiation and was dose dependent. In irradiated cells TBF beta 1 was increased in culture supernatants up to five-fold compared to sham-irradiated cells from day 6 until day 12. Fibronectin was elevated in dose dependent manner. CONCLUSION: Irradiation of fibroblasts in vitro induces synthesis of substances which stimulate cell growth. TGF beta 1 and fibronectin may be involved in this act of "self-activation".