Testosterone deficiency is common in male patients with chronic obstructive pulmonary disease (COPD) and may correlate with the deterioration of COPD. Clinical research suggests that testosterone replacement therapy m...Testosterone deficiency is common in male patients with chronic obstructive pulmonary disease (COPD) and may correlate with the deterioration of COPD. Clinical research suggests that testosterone replacement therapy may slow the COPD progression, but the specific biological pathway remains unclear. In this study, we explored the effect of testosterone on pulmonary inflammation in male COPD rats. The animals were co-treated with lipopolysaccharide (LPS) and cigarette to induce COPD. In COPD rats, nuclear respiratory factor 1 (NRF1) and NF-κB p65 were upregulated. In cigarette smoke extract (CSE)-, LPS-, or the combination of CSE and LPS-treated L132 cells, NRF1 and p65 were also upregulated. Silencing NRF1 resulted in the downregulation of p65. ChIP‒seq, ChIP‒qPCR, and luciferase results showed that NRF1 transcriptionally regulated p65. Both male and female COPD rats showed an upregulated NRF1 level and similar pulmonary morphology. But NRF1 was further upregulated in male castrated rats. Further supplementing testosterone in castrated male rats significantly reduced NRF1, pulmonary lesions, and inflammation. Supplementation of testosterone also reduced the phosphorylation of p65 and IKKβ induced by LPS or CSE in L132 cells. Our results suggest that testosterone plays a protective role in pulmonary epithelial inflammation of COPD through inhibition of NRF1-derived NF-κB signaling and the phosphorylation of p65.展开更多
除呼吸系统外心脏可能是二氧化氮(NO2)作用的重要靶器官之一,而线粒体是心脏运作高度依赖的细胞器,故通过研究线粒体相关指标的变化,探究空气NO2污染与心血管系统疾病的相关性对有效预防这类污染物暴露和干预由此引发的疾病治疗具有重...除呼吸系统外心脏可能是二氧化氮(NO2)作用的重要靶器官之一,而线粒体是心脏运作高度依赖的细胞器,故通过研究线粒体相关指标的变化,探究空气NO2污染与心血管系统疾病的相关性对有效预防这类污染物暴露和干预由此引发的疾病治疗具有重要意义.建立Wistar大鼠NO2动式吸入染毒模型,考察慢性(对照、1×10-6和2.5×10-6)和急性(对照、2.5×10-6、5×10-6和10×10-6)暴露条件下大鼠心肌细胞线粒体超微结构变化、线粒体膜电位和活性功能水平变化,以及调控线粒体呼吸链组分相关因子PGC-1α、NRF1和TFAM蛋白表达变化.结果显示,长期低浓度NO2暴露致使心肌细胞线粒体数量减少并伴有肿胀;活性均显著降低,分别为对照组的0.79倍(P<0.05)和0.56倍(P<0.05);膜电位较对照组均显著下降,分别为0.89倍(P<0.05)和0.79倍(P<0.05);调控线粒体呼吸链组分相关因子PGC-1α、NRF1和TFAM蛋白表达较对照组下调,并在2.5×10-6时均显现出显著性差距,分别为对照组的0.76倍(P<0.05)、0.85倍(P<0.001)和0.52倍(P<0.05).而急性较高浓度NO2暴露时结果不同,大鼠心肌细胞线粒体数量增加;活性在5×10-6和10×10-6时显著性上升,分别为对照组的1.52倍(P<0.001)和2.12倍(P<0.001);膜电位在各浓度均显著增加,分别为对照组的1.50倍(P<0.05)、1.62倍(P<0.05)和2.25倍(P<0.001);调控线粒体呼吸链组分相关因子PGC-1α、N R F1和TFA M表达依赖性上调,同时在10×10-6下呈现显著增高趋势,分别为对照组的1.51倍(P<0.001)、1.47倍(P<0.05)和1.60倍(P<0.001).本研究表明,长期低浓度NO2暴露会引起心肌细胞线粒体氧化磷酸化功能减弱,进而导致线粒体功能退化;然而,急性较高浓度NO2暴露则引发相反的生物学效应,大鼠心肌细胞线粒体增强相关功能以适应外界刺激,这与线粒体功能代偿作用有关.由于线粒体功能和结构的完整性对于心血管系统疾病的生理机能至关重要,其损伤�展开更多
基金The study was supported by grants from the National Natural Science Foundation of China(31671206,81702874,81873924,and 81971131).
文摘Testosterone deficiency is common in male patients with chronic obstructive pulmonary disease (COPD) and may correlate with the deterioration of COPD. Clinical research suggests that testosterone replacement therapy may slow the COPD progression, but the specific biological pathway remains unclear. In this study, we explored the effect of testosterone on pulmonary inflammation in male COPD rats. The animals were co-treated with lipopolysaccharide (LPS) and cigarette to induce COPD. In COPD rats, nuclear respiratory factor 1 (NRF1) and NF-κB p65 were upregulated. In cigarette smoke extract (CSE)-, LPS-, or the combination of CSE and LPS-treated L132 cells, NRF1 and p65 were also upregulated. Silencing NRF1 resulted in the downregulation of p65. ChIP‒seq, ChIP‒qPCR, and luciferase results showed that NRF1 transcriptionally regulated p65. Both male and female COPD rats showed an upregulated NRF1 level and similar pulmonary morphology. But NRF1 was further upregulated in male castrated rats. Further supplementing testosterone in castrated male rats significantly reduced NRF1, pulmonary lesions, and inflammation. Supplementation of testosterone also reduced the phosphorylation of p65 and IKKβ induced by LPS or CSE in L132 cells. Our results suggest that testosterone plays a protective role in pulmonary epithelial inflammation of COPD through inhibition of NRF1-derived NF-κB signaling and the phosphorylation of p65.
文摘除呼吸系统外心脏可能是二氧化氮(NO2)作用的重要靶器官之一,而线粒体是心脏运作高度依赖的细胞器,故通过研究线粒体相关指标的变化,探究空气NO2污染与心血管系统疾病的相关性对有效预防这类污染物暴露和干预由此引发的疾病治疗具有重要意义.建立Wistar大鼠NO2动式吸入染毒模型,考察慢性(对照、1×10-6和2.5×10-6)和急性(对照、2.5×10-6、5×10-6和10×10-6)暴露条件下大鼠心肌细胞线粒体超微结构变化、线粒体膜电位和活性功能水平变化,以及调控线粒体呼吸链组分相关因子PGC-1α、NRF1和TFAM蛋白表达变化.结果显示,长期低浓度NO2暴露致使心肌细胞线粒体数量减少并伴有肿胀;活性均显著降低,分别为对照组的0.79倍(P<0.05)和0.56倍(P<0.05);膜电位较对照组均显著下降,分别为0.89倍(P<0.05)和0.79倍(P<0.05);调控线粒体呼吸链组分相关因子PGC-1α、NRF1和TFAM蛋白表达较对照组下调,并在2.5×10-6时均显现出显著性差距,分别为对照组的0.76倍(P<0.05)、0.85倍(P<0.001)和0.52倍(P<0.05).而急性较高浓度NO2暴露时结果不同,大鼠心肌细胞线粒体数量增加;活性在5×10-6和10×10-6时显著性上升,分别为对照组的1.52倍(P<0.001)和2.12倍(P<0.001);膜电位在各浓度均显著增加,分别为对照组的1.50倍(P<0.05)、1.62倍(P<0.05)和2.25倍(P<0.001);调控线粒体呼吸链组分相关因子PGC-1α、N R F1和TFA M表达依赖性上调,同时在10×10-6下呈现显著增高趋势,分别为对照组的1.51倍(P<0.001)、1.47倍(P<0.05)和1.60倍(P<0.001).本研究表明,长期低浓度NO2暴露会引起心肌细胞线粒体氧化磷酸化功能减弱,进而导致线粒体功能退化;然而,急性较高浓度NO2暴露则引发相反的生物学效应,大鼠心肌细胞线粒体增强相关功能以适应外界刺激,这与线粒体功能代偿作用有关.由于线粒体功能和结构的完整性对于心血管系统疾病的生理机能至关重要,其损伤�
