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

辐射诱发的肺损伤是肺癌、乳腺癌等胸部恶性肿瘤放疗的主要剂量限制因素之一。至少在辐射场中，辐射诱发的肺纤维化在辐射暴露后数月至数年发生。此外，发生全身性肺纤维化的危险不可忽视，通常会危及生命。尽管许多研究试图分析辐射诱发肺纤维化的发病机制，但其机制仍不清楚。因此，预防辐射引起的肺纤维化很难在临床环境中实现，尽管在探索这种情况方面已经进行了广泛的努力。本研究检测乌司他丁是否能减轻C57BL/6J小鼠（研究辐射纤维化病理生理的标准小鼠品系）辐射诱导的肺纤维化。此外，我们还分析了乌司他丁在显著剂量诱导肺纤维化照射小鼠的寿命延长方面的治疗潜力。本研究明确表明，给药乌司他丁可以减轻小鼠辐射诱导的肺纤维化，乌司他丁的照射时间和注射时间很重要。值得注意的是，引起肺纤维化阳性抑制的乌司他丁给药期与照射后TGF-β水平升高的时期相对应，尤其是在TGF-β达到峰值之前。因此，我们认为乌司他丁对肺纤维化的抑制可能与抑制TGF-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.