Regulation of lung epithelial cell senescence in smoking-induced COPD/emphysema by microR-125a-5p via Sp1 mediation of SIRT1/HIF-1a

Abstract

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.

Liquiritin alleviates alpha‐naphthylisothiocyanate‐induced intrahepatic cholestasis through the Sirt1/FXR/Nrf2 pathway

“…Further, HCA and KEGG functional enrichment analysis results demonstrated that ANIT‐induced cholestasis in mice led to a global alteration in hepatic gene expression, possibly mainly related to bile acids metabolic pathways, which was obviously reverted by LQ pretreatment. Among the 94 miRNAs, certain miRNAs, such as miR‐34a (Castro et al, 2013), miR‐155 (Wang et al, 2021), miR‐221 (Peng et al, 2018), and miR‐125a (Wu et al, 2022), participate in regulating the expression of Sirt1, which is involved in the physiological processes of apoptosis, inflammatory response and cell senescence. Besides, our previous study found that miR‐155 functions act as a significant regulatory factor in the Nrf2 signaling pathway (Li et al, 2021).…”

Resveratrol attenuates cigarette smoke extract induced cellular senescence in human airway epithelial cells by regulating the miR-34a/SIRT1/NF-κB pathway

“…A variety of miRNAs, termed senescence-related miRNAs, can act as senescence inducers. [ 36 ] Philipot et al identified that miR-24 negatively regulates p16 expression and promotes cellular senescence in human chondrocytes. [ 37 ] Afanasyeva et al reported that miR-885-5p exertes antitumor effects by interfering with cell cycle progression and cell survival.…”

Hypoxia-inducible factor 1-alpha is a driving mechanism linking chronic obstructive pulmonary disease to lung cancer

“…Additionally, miR-199-5p expression was elevated in HPMVECs transfected with miR-34a precursor gene. In a recent study, Wu et al (110) found that miR-125a-5p levels were higher in normal smokers and COPD smokers than in the healthy population. Furthermore, researchers have used smoke to induce COPD in mouse models.…”