Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway
Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway
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DOI：
10.1096/fj.13-232629
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发表时间：
2014-01-01
期刊：
影响因子：
4.8
通讯作者：
Rahman, Irfan
中科院分区：
文献类型：
--
作者：
Hwang, Jae-Woong;Sundar, Isaac K.;Rahman, Irfan
阻塞性肺疾病患者的肺功能表现出异常的昼夜节律。我们确定了环境烟草/香烟烟雾(CS)通过Sirtuin1(SIRT1)脱乙酰酶在肺部炎症和损伤反应中调节核心时钟基因BMAL1表达的机制。将成年C57BL6/J和不同SIRT1和BMAL1基因突变的小鼠暴露于慢性(6mo)和急性(3d和10d)CS，检测时钟基因的节律性表达、运动活动的昼夜节律、肺功能以及肺部的炎症和肺气肿反应。CS暴露(100-300 mg/m(3)颗粒物)通过扰乱中枢和外周时钟，改变时钟基因的表达，减少运动活动，增加肺部炎症，导致小鼠肺气肿。与不吸烟对照组相比，暴露于CS的小鼠和慢性阻塞性肺疾病(COPD)患者的肺中BMal1被乙酰化和降解，从机械上将其与CS诱导的SIRT1减少联系在一起。选择性SIRT1激活剂SRT1720(EC50=0.16M)不能减轻CS对肺上皮细胞中BMal1的靶向缺失所致的炎症反应。因此，生物钟，特别是上皮细胞中的增强子BMAL1，在调节CS诱导的肺炎症和损伤反应中发挥着关键作用，这种作用是由SIRT1依赖的BMAL1介导的。Hwang，J.-W.，Sundar，I.K.，姚，H.，Sellix，M.T.，Rahman，I.生物钟功能被环境烟草/香烟烟雾扰乱，通过SIRT1-BMAL1途径导致肺部炎症和损伤。
Patients with obstructive lung diseases display abnormal circadian rhythms in lung function. We determined the mechanism whereby environmental tobacco/cigarette smoke (CS) modulates expression of the core clock gene BMAL1, through Sirtuin1 (SIRT1) deacetylase during lung inflammatory and injurious responses. Adult C57BL6/J and various mice mutant for SIRT1 and BMAL1 were exposed to both chronic (6 mo) and acute (3 and 10 d) CS, and we measured the rhythmic expression of clock genes, circadian rhythms of locomotor activity, lung function, and inflammatory and emphysematous responses in the lungs. CS exposure (100-300 mg/m(3) particulates) altered clock gene expression and reduced locomotor activity by disrupting the central and peripheral clocks and increased lung inflammation, causing emphysema in mice. BMAL1 was acetylated and degraded in the lungs of mice exposed to CS and in patients with chronic obstructive pulmonary disease (COPD), compared with lungs of the nonsmoking controls, linking it mechanistically to CS-induced reduction of SIRT1. Targeted deletion of Bmal1 in lung epithelium augmented inflammation in response to CS, which was not attenuated by the selective SIRT1 activator SRT1720 (EC50=0.16 M) in these mice. Thus, the circadian clock, specifically the enhancer BMAL1 in epithelium, plays a pivotal role, mediated by SIRT1-dependent BMAL1, in the regulation of CS-induced lung inflammatory and injurious responses. Hwang, J.-W., Sundar, I. K., Yao, H., Sellix, M. T., Rahman, I. Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway.