Regulation of lung epithelial cell senescence in smoking-induced COPD/emphysema by microR-125a-5p via Sp1 mediation of SIRT1/HIF-1a.
Regulation of lung epithelial cell senescence in smoking-induced COPD/emphysema by microR-125a-5p via Sp1 mediation of SIRT1/HIF-1a.
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DOI：
10.7150/ijbs.65861
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发表时间：
2022
影响因子：
9.2
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Wu H;Ma H;Wang L;Zhang H;Lu L;Xiao T;Cheng C;Wang P;Yang Y;Wu M;Wang S;Zhang J;Liu Q
慢性阻塞性肺疾病（COPD）影响全世界3亿多人的健康；目前尚无治疗慢性阻塞性肺病的有效药物。吸烟是最重要的危险因素，但吸烟导致该疾病的分子机制尚不清楚。肺上皮细胞的衰老与COPD的发生发展有关。mirna的调控是与衰老相关的主要表观遗传机制。β-半乳糖染色显示吸烟者肺组织细胞衰老程度较高，miR-125a-5p表达较高。对于患有COPD/肺气肿的吸烟者，这种影响是明显的，并且miR-125a-5p水平与一秒用力呼气量(FEV1)/用力肺活量（FVC）值之间存在负相关。Balb/c小鼠长期暴露于不同浓度的香烟烟雾（CS）后，体积谱显示肺功能受损，肺组织衰老增加，支气管肺泡灌洗液中衰老相关分泌表型（SASP）增加。小鼠肺上皮(MLE)-12细胞经香烟烟雾提取物（CSE）处理后，Sp1和SIRT1水平降低，HIF-1α乙酰化水平升高，细胞衰老和SASP因子分泌增加。miR-125a-5p的下调或Sp1的上调逆转了这些作用。此外，与暴露于CS的小鼠相比，miR-125a-5p的敲低可减少肺上皮细胞衰老和COPD/肺气肿。因此，在吸烟诱导的COPD中，升高的miR-125a-5p通过Sp1/SIRT1/HIF-1α参与肺上皮细胞的衰老。这些发现为慢性吸烟引起的COPD/肺气肿的发病机制提供了证据。
Chronic obstructive pulmonary disease (COPD) affects the health of more than 300 million people worldwide; at present, there is no effective drug to treat COPD. Smoking is the most important risk factor, but the molecular mechanism by which smoking causes the disease is unclear. The senescence of lung epithelial cells is related to development of COPD. Regulation of miRNAs is the main epigenetic mechanism related to aging. β-Galactose staining showed that the lung tissues of smokers have a higher degree of cellular senescence, and the expression of miR-125a-5p is high. This effect is obvious for smokers with COPD/emphysema, and there is a negative correlation between miR-125a-5p levels and values for forced expiratory volume in one second (FEV1)/forced vital capacity (FVC). After Balb/c mice were chronically exposed to various concentrations of cigarette smoke (CS), plethysmography showed that lung function was impaired, lung tissue senescence was increased, and the senescence-associated secretory phenotype (SASP) in bronchoalveolar lavage fluid was increased. For mouse lung epithelial (MLE)-12 cells treated with cigarette smoke extract (CSE), Sp1 and SIRT1 levels were low, HIF-1α acetylation levels were high, and cell senescence and secretion of SASP factors were elevated. Down-regulation of miR-125a-5p or up-regulation of Sp1 reversed these effects. In addition, compared with mice exposed to CS, knockdown of miR-125a-5p reduced lung epithelial cell senescence and COPD/emphysema. Therefore, in smoking-induced COPD, elevated miR-125a-5p participates in the senescence of lung epithelial cells through Sp1/SIRT1/HIF-1α. These findings provide evidence related to the pathogenesis of COPD/emphysema caused by chronic smoking.
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