Department of Pulmonary and Critical Care Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Shanghai Engineering Research Center of Internet of Things for Respiratory Medicine, 180 Fenglin Road, Shanghai 200032, China; Shanghai Key Laboratory of Lung Inflammation and Injury, 180 Fenglin Road, Shanghai 200032, China.
Hebei Academy of Integrated Traditional Chinese and Western Medicine, Shijiazhuang 050091, Hebei, China.
Int Immunopharmacol. 2024 Mar 10;129:111585. doi: 10.1016/j.intimp.2024.111585. Epub 2024 Feb 6.
Cuproptosis, a novel mode of cell death, is strongly associated with a variety of diseases. However, the contribution of cuproptosis to the onset or progression of chronic obstructive pulmonary disease (COPD), the third most common chronic cause of mortality, is not yet clear. To investigate the potential role of cuproptosis in COPD, raw datasets from multiple public clinical COPD databases (including RNA-seq, phenotype, and lung function data) were used. For further validation, mice exposed to cigarette smoke for three months were used as in vivo models, and iBMDMs (immortalized bone marrow-derived macrophages) and RAW264.7 cells stimulated with cigarette smoke extract were used as in vitro models. For the first time, the expression of the cuproptosis-related gene glutaminase (GLS) was found to be decreased in COPD, and the low expression of GLS was significantly associated with the grade of pulmonary function. In vivo experiments confirmed the decreased expression of GLS in COPD, particularly in alveolar macrophages. Furthermore, in vitro studies revealed that copper ions accumulated in alveolar macrophages, leading to a substantially decreased amount of cell activity of macrophages when stimulated with cigarette extract. In summary, we demonstrate the high potential of GLS as an avenue for diagnosis and therapy in COPD.
铜死亡是一种新的细胞死亡方式，与多种疾病密切相关。然而，铜死亡在慢性阻塞性肺疾病（COPD）发病或进展中的作用尚不清楚。COPD 是第三大常见的致死性慢性疾病。为了研究铜死亡在 COPD 中的潜在作用，本研究使用了多个公共临床 COPD 数据库（包括 RNA-seq、表型和肺功能数据）的原始数据集。为了进一步验证，我们使用了三个月烟熏暴露的小鼠作为体内模型，以及用香烟烟雾提取物刺激的永生化骨髓源性巨噬细胞（iBMDMs）和 RAW264.7 细胞作为体外模型。首次发现，COPD 中与铜死亡相关的基因谷氨酰胺酶（GLS）的表达降低，并且 GLS 的低表达与肺功能的严重程度显著相关。体内实验证实了 COPD 中 GLS 的表达降低，特别是在肺泡巨噬细胞中。此外，体外研究表明，铜离子在肺泡巨噬细胞中积累，导致当用香烟提取物刺激时，巨噬细胞的细胞活性显著降低。综上所述，我们证明了 GLS 作为 COPD 诊断和治疗新靶点的巨大潜力。
