放射治疗（RT）是肺癌的常见治疗方法。尽管如此，它仍可能导致不可逆转的肺功能丧失，并显着降低三分之一患者的生活质量。肺癌患者常患有慢性阻塞性肺病 (COPD) 等既往合并症，这进一步增加了并发症的风险。由于肺干细胞对于损伤后肺组织的再生至关重要，因此我们假设患有肺癌的慢性阻塞性肺病患者的气道干细胞可能有助于增加辐射敏感性。我们使用气液界面模型（一种三维 (3D) 培养系统）来比较健康人和慢性阻塞性肺病患者的原代人气道干细胞的辐射反应。我们发现，与健康气道干细胞培养物相比，慢性阻塞性肺病衍生的气道干细胞表现出不成比例的病理性粘膜纤毛分化、异常的细胞周期检查点、残留的DNA损伤、干细胞存活率和自我更新的降低以及辐射后细胞的终末分化。 ，这可以通过使用小分子 γ-分泌酶抑制剂阻断 Notch 通路来逆转。我们的研究结果揭示了 COPD 辐射敏感性增加的潜在机制，并表明气道干细胞反映了接受胸部放疗的肺癌患者肺组织中观察到的部分病理重塑。© 作者 2024 年。牛津大学出版大学出版社。

Radiation therapy (RT) is a common treatment for lung cancer. Still, it can lead to irreversible loss of pulmonary function and a significant reduction in quality of life for one-third of patients. Preexisting comorbidities, such as chronic obstructive pulmonary disease (COPD), are frequent in patients with lung cancer and further increase the risk of complications. Because lung stem cells are crucial for the regeneration of lung tissue following injury, we hypothesized that airway stem cells from patients with COPD with lung cancer might contribute to increased radiation sensitivity. We used the air-liquid interface model, a three-dimensional (3D) culture system, to compare the radiation response of primary human airway stem cells from healthy and patients with COPD. We found that COPD-derived airway stem cells, compared to healthy airway stem cell cultures, exhibited disproportionate pathological mucociliary differentiation, aberrant cell cycle checkpoints, residual DNA damage, reduced survival of stem cells and self-renewal, and terminally differentiated cells post-irradiation, which could be reversed by blocking the Notch pathway using small-molecule γ-secretase inhibitors. Our findings shed light on the mechanisms underlying the increased radiation sensitivity of COPD and suggest that airway stem cells reflect part of the pathological remodeling seen in lung tissue from patients with lung cancer receiving thoracic RT.© The Author(s) 2024. Published by Oxford University Press.