title: Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway.
abstract: 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 μM) 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.
authors.affiliation: 2Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester 14642, NY, USA. irfan_rahman@urmc.rochester.edu.
authors.forename: Jae-Woong
authors.initials: JW
authors.lastname: Hwang
authors.forename: Isaac K
authors.initials: IK
authors.lastname: Sundar
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Michael T
authors.initials: MT
authors.lastname: Sellix
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D014028:Tobacco Smoke Pollution; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: chronic obstructive pulmonary disease; cytokines; emphysema; locomotor activity; mouse; oxidative stress
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