Zeng Zhengpeng, Liu Xuelian, Xiang Fei, He Xue, Li Jiahui, Liu Hanying, Xie Lihua
Health Management Medicine Center, The Third Xiangya Hospital, Central South University, Changsha, China.
Respiratory and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
Tob Induc Dis. 2025 Mar 18;23. doi: 10.18332/tid/202182. eCollection 2025.
Bronchial epithelial cell damage is an important determinant of the severity of chronic obstructive pulmonary (COPD). However, the exact molecular mechanisms underlying this cell death in COPD development are not well understood. This study investigates the involvement of microRNA-21 (miR-21/miRNA-21) in COPD and its underlying molecular mechanism.
A mouse model of COPD was created by exposing the mice to cigarette smoke (CS) and injecting them with cigarette smoke extract (CSE). Both wild-type mice and miR-21 knockout (miR-21-/-) mice were used to investigate the role of microRNA-21 (miR-21) in exacerbating COPD. Various assays and analyses were performed, including HE staining, tunel staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, quantitative real-time polymerase chain reaction (RT-qPCR), and western blotting (WB) to measure outcomes such as the pathological morphological changes, necroptosis, apoptosis, and levels of inflammatory factors.
Our results revealed an upregulation of miR-21 in the lung tissue of COPD model mice. Additionally, knockout of miR-21 resulted in decreased levels of bronchial epithelial cell necroptosis and apoptosis, as evidenced by the downregulation of tumor necrosis factor receptor 1 (TNFR1), phosphoryl-mixed lineage kinase domain-like protein (p-MLKL) and caspase-3. This downregulation of necroptosis and apoptosis ultimately led to a reduction of inflammatory factors and damage-associated molecular patterns (DAMPs), such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL- 1β), and interleukin-6 (IL-6) and high mobility group protein B1(HMGB1) in the lungs, thereby ameliorating COPD.
Our findings suggest that miR-21 contributes to the worsening of chronic obstructive pulmonary disease by modulating necroptosis and apoptosis in bronchial epithelial cells, providing a new theoretical basis for the pathogenesis of chronic obstructive pulmonary disease.
支气管上皮细胞损伤是慢性阻塞性肺疾病（COPD）严重程度的重要决定因素。然而，COPD发展过程中这种细胞死亡的具体分子机制尚不清楚。本研究探讨了微小RNA-21（miR-21/miRNA-21）在COPD中的作用及其潜在分子机制。
通过将小鼠暴露于香烟烟雾（CS）并注射香烟烟雾提取物（CSE）建立COPD小鼠模型。使用野生型小鼠和miR-21基因敲除（miR-21-/-）小鼠来研究微小RNA-21（miR-21）在加重COPD中的作用。进行了各种检测和分析，包括苏木精-伊红（HE）染色、TUNEL染色、酶联免疫吸附测定（ELISA）、流式细胞术、定量实时聚合酶链反应（RT-qPCR）和蛋白质印迹法（WB），以测量病理形态变化、坏死性凋亡、凋亡和炎症因子水平等结果。
我们的结果显示COPD模型小鼠肺组织中miR-21上调。此外，miR-21基因敲除导致支气管上皮细胞坏死性凋亡和凋亡水平降低，肿瘤坏死因子受体1（TNFR1）、磷酸化混合谱系激酶结构域样蛋白（p-MLKL）和半胱天冬酶-3的下调证明了这一点。坏死性凋亡和凋亡的这种下调最终导致肺中炎症因子和损伤相关分子模式（DAMPs）减少，如肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和高迁移率族蛋白B1（HMGB1），从而改善COPD。
我们的研究结果表明，miR-21通过调节支气管上皮细胞的坏死性凋亡和凋亡促进慢性阻塞性肺疾病的恶化，为慢性阻塞性肺疾病的发病机制提供了新的理论依据。
