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

放射性肺损伤是肺癌、乳腺癌等胸部恶性肿瘤放射治疗的主要剂量限制因素之一。辐射引起的肺纤维化在辐射暴露后几个月到几年内发生，至少在照射区域内是这样。此外，发生泛发性肺纤维化还有不可忽视的严重风险，通常是危及生命的。虽然许多研究试图分析放射性肺纤维化的发病机制，但其机制仍不清楚。因此，尽管人们对放射性肺纤维化进行了广泛的探索，但在临床上预防放射性肺纤维化是困难的。本研究检测了乌司他丁是否能减轻C57BL/6J小鼠的放射性肺纤维化，C57BL/6J小鼠是研究放射性纤维化病理生理学的标准品系。此外，还分析了乌司他丁在延长大剂量照射诱导肺纤维化小鼠寿命方面的治疗潜力。本研究清楚地表明，乌司他丁可减轻放射性肺纤维化小鼠的肺纤维化，乌司他丁的照射时机和给药时机是重要的。值得注意的是，乌司他丁给药期间对肺纤维化有正向抑制作用，与照射后转化生长因子-β水平升高相对应，尤其是在转化生长因子-β达到峰值之前。提示乌司他丁抑制肺纤维化的作用可能与抑制转化生长因子-β有关。

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.