The lung is a radiosensitive organ, which imposes limits on the therapeutic dose in thoracic radiotherapy. Irradiated alveolar epithelial cells promote radiation-related pneumonitis and fibrosis. However, the role of lung stem cells (LSCs) in the development of radiation-induced lung injury is still unclear. In this study, we found that both LSCs and LSC-derived type II alveolar epithelial cells (AECII) can repair radiation-induced DNA double-strand breaks, but the irradiated LSCs underwent growth arrest and cell differentiation faster than the irradiated AECII cells. Moreover, radiation drove LSCs to fibrosis as shown with the elevated levels of markers for epithelial-mesenchymal transition and myofibroblast (α-smooth muscle actin (α-SMA)) differentiation in in vitro and ex vivo studies. Increased gene expressions of connective tissue growth factor and α-SMA were found in both irradiated LSCs and alveolar cells, suggesting that radiation could induce the fibrogenic differentiation of LSCs. Irradiated LSCs showed an increase in the expression of surfactant protein C (SP-C), the AECII cell marker, and α-SMA, and irradiated AECII cells expressed SP-C and α-SMA. These results indicated that radiation induced LSCs to differentiate into myofibroblasts and AECII cells; then, AECII cells differentiated further into either myofibroblasts or type I alveolar epithelial cells (AECI). In conclusion, our results revealed that LSCs are sensitive to radiation-induced cell damage and may be involved in radiation-induced lung fibrosis.

中文翻译：

---

辐射通过促进肺泡干细胞的纤维化分化诱导肺纤维化

肺是放射敏感器官，胸部放射治疗的治疗剂量受到限制。受辐射的肺泡上皮细胞促进辐射相关肺炎和纤维化。然而，肺干细胞（LSC）在辐射引起的肺损伤发展中的作用仍不清楚。在这项研究中，我们发现LSC和LSC衍生的II型肺泡上皮细胞（AECII）都可以修复辐射引起的DNA双链断裂，但受辐射的LSC比受辐射的AECII细胞经历生长停滞和细胞分化更快。此外，在体外和离体研究中，辐射促使 LSC 纤维化，上皮-间质转化和肌成纤维细胞（ α-平滑肌肌动蛋白（α -SMA））分化的标记物水平升高。在受辐射的LSCs和肺泡细胞中发现结缔组织生长因子和α -SMA基因表达增加，表明辐射可以诱导LSCs的纤维化分化。受辐射的LSC显示表面活性剂蛋白C（SP-C）、AECII细胞标记物和α -SMA的表达增加，并且受辐射的AECII细胞表达SP-C和α -SMA。这些结果表明辐射诱导LSCs分化为肌成纤维细胞和AECII细胞；然后，AECII 细胞进一步分化为肌成纤维细胞或 I 型肺泡上皮细胞 (AECI)。总之，我们的结果表明，LSC 对辐射引起的细胞损伤敏感，并可能参与辐射引起的肺纤维化。