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.