Hua Jianlan, Liu Li, He Binfeng, Hu Weiping, Wu Yixing, Han Yaopin, Zhang Jing
Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Department of General Practice, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
Int Immunopharmacol. 2025 Aug 28;161:115062. doi: 10.1016/j.intimp.2025.115062. Epub 2025 Jun 13.
Airway epithelial apoptosis is a key in the development and progression of COPD, but the mechanism remains unclear. HIF-1α is a major regulatory factor for maintaining cellular redox homeostasis in the body, promoting cellular adaptive responses in hypoxic conditions and regulating cellular metabolism, immune inflammation, cell proliferation, and cell apoptosis. It is worth exploring whether and how HIF-1α regulates airway epithelial apoptosis in COPD. Here, apoptosis was evaluated by flow cytometry, TUNEL staining, measuring expression of pro-apoptotic proteins including Bcl-2-associated X protein (Bax) and cleaved Caspase-3, and anti-apoptotic protein Bcl-2 in the human bronchial epithelial cell line (BEAS-2B) in vitro. The results revealed that HIF-1α knockdown significantly amplified cigarette-induced apoptosis. Analogously, cigarette exposure induced a significant increase of REDD1, a downstream effector of HIF-1α. Noteworthy, REDD1 overexpression prevented the amplified effects of HIF-1α knockdown on CSE-induced apoptosis. In in vivo study, we established the chronic obstructive pulmonary disease (COPD) model in HIF-1α heterozygous knockdown mice (HIF-1α). It was found that HIF-1α knockdown significantly enhanced cigarette-induced apoptosis in murine airway epithelial cells. In conclusion, our study demonstrated that HIF-1a/REDD1 plays a protective role through inhibition of airway epithelium apoptosis in cigarette-induced COPD.
气道上皮细胞凋亡是慢性阻塞性肺疾病（COPD）发生发展的关键因素，但其机制尚不清楚。缺氧诱导因子-1α（HIF-1α）是维持机体细胞氧化还原稳态的主要调节因子，可促进细胞在缺氧条件下的适应性反应，并调节细胞代谢、免疫炎症、细胞增殖和细胞凋亡。HIF-1α是否以及如何调节COPD中的气道上皮细胞凋亡值得探讨。在此，通过流式细胞术、TUNEL染色、检测促凋亡蛋白（包括Bcl-2相关X蛋白（Bax）和裂解的半胱天冬酶-3）以及抗凋亡蛋白Bcl-2在人支气管上皮细胞系（BEAS-2B）中的表达，在体外评估细胞凋亡。结果显示，敲低HIF-1α可显著放大香烟诱导的细胞凋亡。类似地，香烟暴露可导致HIF-1α的下游效应物REDD1显著增加。值得注意的是，REDD1过表达可阻止HIF-1α敲低对香烟烟雾提取物（CSE）诱导的细胞凋亡的放大作用。在体内研究中，我们在HIF-1α杂合敲低小鼠中建立了慢性阻塞性肺疾病（COPD）模型。发现敲低HIF-1α可显著增强香烟诱导的小鼠气道上皮细胞凋亡。总之，我们的研究表明，HIF-1α/REDD1通过抑制香烟诱导的COPD中的气道上皮细胞凋亡发挥保护作用。
