背景:慢性阻塞性肺疾病(COPD)是一种在全球范围内与高发病率和死亡率相关的慢性炎症性肺疾病。气道上皮的氧化损伤和线粒体功能障碍是COPD进展的主要事件。
结果:在本研究中在体内和体外研究了孕酮(P4)的治疗作用。在体内,在香烟烟雾(CS)暴露诱导的COPD小鼠模型中,P4治疗显著改善CS暴露诱导的生理和病理特征,包括炎症细胞浸润和氧化损伤,以剂量依赖的方式。c-MYC/SIRT1/PGC-1α通路参与P4对CS诱导的COPD的保护功能。体外,P4共同处理通过促进细胞增殖显著改善H2O2诱导的氧化损伤和线粒体功能障碍,增加线粒体膜电位,降低ROS水平和细胞凋亡,增加ATP含量。此外,P4共同处理部分减弱了H2O2对Nrf1、Tfam、Mfn1,PGR-B,c-MYC,SIRT1和PGC-1α水平。在BEAS-2B和ASM细胞中,c-MYC/SIRT1轴调节P4对H2O2诱导的氧化损伤和线粒体功能障碍的保护作用。
结论:P4激活c-MYC/SIRT1轴,改善CS诱导的COPD并保护气道上皮细胞和平滑肌细胞免受H2O2诱导的氧化损伤。PGC-1α和下游线粒体信号通路可能参与其中。
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with high morbidity and mortality worldwide. Oxidative injury and mitochondrial dysfunction in the airway epithelium are major events in COPD progression.
RESULTS: The therapeutic effects of Progesterone (P4) were investigated in vivo and in vitro in this study. In vivo, in a cigarette smoke (CS) exposure-induced COPD mouse model, P4 treatment significantly ameliorated CS exposure-induced physiological and pathological characteristics, including inflammatory cell infiltration and oxidative injury, in a dose-dependent manner. The c-MYC/SIRT1/PGC-1α pathway is involved in the protective function of P4 against CS-induced COPD. In vitro, P4 co-treatment significantly ameliorated H2O2-induced oxidative injury and mitochondrial dysfunctions by promoting cell proliferation, increasing mitochondrial membrane potential, decreasing ROS levels and apoptosis, and increasing ATP content. Moreover, P4 co-treatment partially attenuated H2O2-caused inhibition in Nrf1, Tfam, Mfn1, PGR-B, c-MYC, SIRT1, and PGC-1α levels. In BEAS-2B and ASM cells, the c-MYC/SIRT1 axis regulated P4\'s protective effects against H2O2-induced oxidative injury and mitochondrial dysfunctions.
CONCLUSIONS: P4 activates the c-MYC/SIRT1 axis, ameliorating CS-induced COPD and protecting both airway epithelial cells and smooth muscle cells against H2O2-induced oxidative damage. PGC-1α and downstream mitochondrial signaling pathways might be involved.