Department of Respiratory Medicine, Yantai Yuhuangding Hospital, Yantai, Shandong, China.
Department of Respiratory Medicine, Muping Hospital of Traditional Chinese Medicine, Yantai, Shandong, China.
Biosci Rep. 2020 Mar 27;40(3). doi: 10.1042/BSR20192567.
Chronic obstructive pulmonary disease (COPD) is a common airway disease characterized by an exaggerated pulmonary inflammatory response. Long noncoding MIR155 host gene (lncRNA MIR155HG) has been identified to be related to the macrophage polarization in COPD. However, the detailed function of MIR155HG in cigarette smoke (CS)-mediated COPD remains largely unknown. The expression level of MIR155HG was elevated while miR-218-5p was decreased in lung tissues of smokers without or with COPD, especially in smokers with COPD, and cigarette smoke extract (CSE)-treated human pulmonary microvascular endothelial cell (HPMECs) in a dose- and time-dependent manner. Then, functional experiments showed that MIR155HG deletion could reverse CSE exposure-induced apoptosis and inflammation in HPMECs. MiR-218-5p was confirmed to be a target of MIR155HG and rescue assay showed miR-218-5p inhibitor attenuated the inhibitory action of MIR155HG knockdown on CSE-induced HPMECs. Subsequently, miR-218-5p was found to target bromodomain containing 4 (BRD4) directly, and miR-218-5p overexpression overturned CSE-induced injury of HPMECs via regulating BRD4. Additionally, co-expression analysis indicated MIR155HG indirectly regulated BRD4 expression in HPMECs via miR-218-5p. Thus, we concluded that MIR155HG contributed to the apoptosis and inflammation of HPMECs in smoke-related COPD by regulating miR-128-5p/BRD4 axis, providing a novel insight on the pathogenesis of COPD and a therapeutic strategy on COPD treatments.
慢性阻塞性肺疾病（COPD）是一种常见的气道疾病，其特征为过度的肺部炎症反应。长链非编码 MIR155 宿主基因（lncRNA MIR155HG）已被确定与 COPD 中的巨噬细胞极化有关。然而，MIR155HG 在香烟烟雾（CS）介导的 COPD 中的详细功能在很大程度上仍然未知。在没有或患有 COPD 的吸烟者的肺组织中，MIR155HG 的表达水平升高，而 miR-218-5p 降低，尤其是在患有 COPD 的吸烟者中，并且以剂量和时间依赖性方式降低了香烟烟雾提取物（CSE）处理的人肺微血管内皮细胞（HPMEC）中的表达水平。然后，功能实验表明，MIR155HG 缺失可以逆转 CSE 暴露诱导的 HPMEC 凋亡和炎症。MiR-218-5p 被确认为 MIR155HG 的靶标，挽救实验表明 miR-218-5p 抑制剂减弱了 MIR155HG 敲低对 CSE 诱导的 HPMEC 的抑制作用。随后，发现 miR-218-5p 直接靶向溴结构域包含 4（BRD4），并且 miR-218-5p 过表达通过调节 BRD4 逆转了 CSE 诱导的 HPMEC 损伤。此外，共表达分析表明，MIR155HG 通过 miR-218-5p 间接调节 HPMECs 中的 BRD4 表达。因此，我们得出结论，MIR155HG 通过调节 miR-128-5p/BRD4 轴促进与吸烟有关的 COPD 中 HPMEC 的凋亡和炎症，为 COPD 的发病机制提供了新的见解，并为 COPD 的治疗提供了一种治疗策略。
