Analysis of molecular mechanism and development of preventive methods against the radiation-induced lung fibrosis

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Radiation-induced lung injury is one of the major dose-limiting factors of radiotherapy for thoracic malignancies such as lung and breast cancers. Radiation-induced lung fibrosis develops several months to years after radiation exposure at least in the irradiated field. Moreover, there are non-negligible critical risks of developing generalized lung fibrosis that is usually life-threatening. Although many studies have tried to analyze the mechanisms underlying the pathogenesis of radiation-induced lung fibrosis, the mechanisms still remain unclear. Hence, the prevention of radiation-induced lung fibrosis is difficult to realize in a clinical set- ting although extensive efforts have been undertaken in the exploration of this condition. The present study examined whether Ulinastatin reduced radiation-induced lung fibrosis in C57BL/6J mice, the standard mouse strain for studying the pathophysiology of radiation-induced fibrosis. In addition, the therapeutic potential of Ulinastatin was analyzed for prolongation of the lifespan of mice irradiated with a significant dose for inducing lung fibrosis. The present study clearly indicated that administration of Ulinastatin reduced radiation-induced lung fibrosis in mice, and timing and the injection timing of Ulinastatin for irradiation was important. It is noteworthy that the Ulinastatin administration period, which caused positive suppression of lung fibrosis, corresponded to the period of the increase in TGF-β level by irradiation, and especially before reaching the peak level of TGF-β. Therefore, it was suggested that the suppression of lung fibrosis might be due to the suppression of TGF-β by Ulinastatin.