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

放射性肺损伤是胸部恶性肿瘤（如肺癌和乳腺癌）放射治疗的主要剂量限制因素之一。辐射诱导的肺纤维化在辐射暴露后数月至数年发展，至少在照射野中。此外，存在发展通常危及生命的全身性肺纤维化的不可忽视的关键风险。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，在临床环境中难以实现放射诱导的肺纤维化的预防，尽管在探索这种病症方面已经进行了广泛的努力。本研究检测了乌司他丁是否减少C57 BL/6 J小鼠中辐射诱导的肺纤维化，C57 BL/6 J小鼠是研究辐射诱导的纤维化的病理生理学的标准小鼠品系。此外，分析了乌司他丁延长用显著剂量辐照诱导肺纤维化的小鼠寿命的治疗潜力。本研究清楚地表明，乌司他丁给药可减少小鼠放射诱导的肺纤维化，并且乌司他丁的照射时间和注射时间很重要。值得注意的是，引起肺纤维化积极抑制的乌司他丁给药期对应于照射导致TGF-β水平升高的时期，特别是在达到TGF-β峰值水平之前。因此，乌司他丁抑制肺纤维化可能是由于抑制TGF-β。

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.