Department of Radiation Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen, 529030, Guangdong, China.
Mol Med. 2024 Apr 22;30(1):54. doi: 10.1186/s10020-024-00821-y.
Bleomycin, a potent antitumor agent, is limited in clinical use due to the potential for fatal pulmonary toxicity. The accelerated DNA damage and senescence in alveolar epithelial cells (AECs) is considered a key factor in the development of lung pathology. Understanding the mechanisms for bleomycin-induced lung injury is crucial for mitigating its adverse effects.
Human lung epithelial (A549) cells were exposed to bleomycin and subsequently assessed for cellular senescence, DNA damage, and double-strand break (DSB) repair. The impact of Rad51 overexpression on DSB repair and senescence in AECs was evaluated in vitro. Additionally, bleomycin was intratracheally administered in C57BL/6 mice to establish a pulmonary fibrosis model.
Bleomycin exposure induced dose- and time-dependent accumulation of senescence hallmarks and DNA lesions in AECs. These effects are probably due to the inhibition of Rad51 expression, consequently suppressing homologous recombination (HR) repair. Mechanistic studies revealed that bleomycin-mediated transcriptional inhibition of Rad51 might primarily result from E2F1 depletion. Furthermore, the genetic supplement of Rad51 substantially mitigated bleomycin-mediated effects on DSB repair and senescence in AECs. Notably, decreased Rad51 expression was also observed in the bleomycin-induced mouse pulmonary fibrosis model.
Our works suggest that the inhibition of Rad51 plays a pivotal role in bleomycin-induced AECs senescence and lung injury, offering potential strategies to alleviate the pulmonary toxicity of bleomycin.
博来霉素是一种有效的抗肿瘤药物，但由于其可能导致致命性肺毒性，在临床应用中受到限制。肺泡上皮细胞（AECs）中的加速 DNA 损伤和衰老被认为是导致肺病理学发展的关键因素。了解博来霉素诱导肺损伤的机制对于减轻其不良反应至关重要。
将人肺上皮（A549）细胞暴露于博来霉素中，然后评估细胞衰老、DNA 损伤和双链断裂（DSB）修复。体外评估 Rad51 过表达对 AECs 中 DSB 修复和衰老的影响。此外，通过气管内给予博来霉素在 C57BL/6 小鼠中建立肺纤维化模型。
博来霉素暴露诱导 AECs 中衰老标志物和 DNA 损伤的剂量和时间依赖性积累。这些影响可能是由于 Rad51 表达的抑制，从而抑制同源重组（HR）修复。机制研究表明，博来霉素介导的 Rad51 转录抑制可能主要归因于 E2F1 的耗竭。此外，Rad51 的遗传补充可显著减轻博来霉素对 AECs 中 DSB 修复和衰老的影响。值得注意的是，在博来霉素诱导的小鼠肺纤维化模型中也观察到 Rad51 表达降低。
我们的研究表明，Rad51 的抑制在博来霉素诱导的 AECs 衰老和肺损伤中起关键作用，为减轻博来霉素的肺毒性提供了潜在策略。
