title: Disruption of Sirtuin 1-Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease.
abstract: Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBα, REV-ERBβ, and RORα), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-α released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBα was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBα in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-α) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD.
authors.affiliation: Departments of 1 Environmental Medicine, Lung Biology and Disease Program.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.affiliation: Departments of 1 Environmental Medicine, Lung Biology and Disease Program.
authors.forename: Isaac K
authors.initials: IK
authors.lastname: Sundar
authors.affiliation: Departments of 1 Environmental Medicine, Lung Biology and Disease Program.
authors.forename: Yadi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Departments of 1 Environmental Medicine, Lung Biology and Disease Program.
authors.forename: Janice
authors.initials: J
authors.lastname: Gerloff
authors.affiliation: 2 Medicine, Division of Endocrinology, Diabetes and Metabolism; and.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Sellix
authors.affiliation: 3 Medicine, Pulmonary Diseases and Critical Care, University of Rochester Medical Center, Rochester, New York.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.affiliation: Departments of 1 Environmental Medicine, Lung Biology and Disease Program.
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D057906:Circadian Clocks; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000276:immunology; D056564:Sirtuin 1 / Q000502:physiology*; D012907:Smoking / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: BMAL1; REV-ERBα; SIRT1; circadian rhythm; smokers