Department of Biology, Georgia State University, Atlanta, GA, United States.
Department of Nutrition, Georgia State University, Atlanta, GA, United States.
Front Immunol. 2024 Jun 14;15:1429946. doi: 10.3389/fimmu.2024.1429946. eCollection 2024.
Chronic obstructive pulmonary disease (COPD) is currently listed as the 3 leading cause of death in the United States. Accumulating data shows the association between COPD occurrence and the usage of electronic nicotine delivery systems (ENDS) in patients. However, the underlying pathogenesis mechanisms of COPD have not been fully understood.
In the current study, bENaC-overexpressing mice (bENaC mice) were subjected to whole-body ENDS exposure. COPD related features including emphysema, mucus accumulation, inflammation and fibrosis are examined by tissue staining, FACS analysis, cytokine measurement. Cell death and ferroptosis of alveolar epithelial cells were further evaluated by multiple assays including staining, FACS analysis and lipidomics.
ENDS-exposed mice displayed enhanced emphysema and mucus accumulation, suggesting that ENDS exposure promotes COPD features. ENDS exposure also increased immune cell number infiltration in bronchoalveolar lavage and levels of multiple COPD-related cytokines in the lungs, including CCL2, IL-4, IL-13, IL-10, M-CSF, and TNF-α. Moreover, we observed increased fibrosis in ENDS-exposed mice, as evidenced by elevated collagen deposition and a-SMA+ myofibroblast accumulation. By investigating possible mechanisms for how ENDS promoted COPD, we demonstrated that ENDS exposure induced cell death of alveolar epithelial cells, evidenced by TUNEL staining and Annexin V/PI FACS analysis. Furthermore, we identified that ENDS exposure caused lipid dysregulations, including TAGs (9 species) and phospholipids (34 species). As most of these lipid species are highly associated with ferroptosis, we confirmed ENDS also enhanced ferroptosis marker CD71 in both type I and type II alveolar epithelial cells.
Overall, our data revealed that ENDS exposure exacerbates features of COPD in bENaC mice including emphysema, mucus accumulation, abnormal lung inflammation, and fibrosis, which involves the effect of COPD development by inducing ferroptosis in the lung.
慢性阻塞性肺疾病（COPD）目前被列为美国第三大致死原因。越来越多的数据表明，COPD 的发生与患者使用电子尼古丁传送系统（ENDS）之间存在关联。然而，COPD 的发病机制尚未完全阐明。
在本研究中，过表达钠离子通道（bENaC）的小鼠（bENaC 小鼠）接受全身 ENDS 暴露。通过组织染色、FACS 分析、细胞因子测定等方法检测肺气肿、黏液积聚、炎症和纤维化等 COPD 相关特征。进一步通过染色、FACS 分析和脂质组学等多种方法评估肺泡上皮细胞的细胞死亡和铁死亡。
暴露于 ENDS 的小鼠表现出增强的肺气肿和黏液积聚，提示 ENDS 暴露促进 COPD 特征的发生。ENDS 暴露还增加了支气管肺泡灌洗液中免疫细胞的数量和肺部中多种 COPD 相关细胞因子的水平，包括 CCL2、IL-4、IL-13、IL-10、M-CSF 和 TNF-α。此外，我们观察到暴露于 ENDS 的小鼠中纤维化增加，这表现在胶原蛋白沉积增加和 α-SMA+肌成纤维细胞积聚。通过研究 ENDS 促进 COPD 的可能机制，我们发现 ENDS 暴露诱导肺泡上皮细胞死亡，这可以通过 TUNEL 染色和 Annexin V/PI FACS 分析来证明。此外，我们发现 ENDS 暴露导致脂质失调，包括 TAG（9 种）和磷脂（34 种）。由于这些脂质物种中的大多数与铁死亡高度相关，我们证实 ENDS 还增强了 I 型和 II 型肺泡上皮细胞中的铁死亡标志物 CD71。
总的来说，我们的数据显示，ENDA 暴露在 bENaC 小鼠中加剧了 COPD 的特征，包括肺气肿、黏液积聚、异常的肺部炎症和纤维化，这涉及通过在肺部诱导铁死亡来影响 COPD 的发展。
