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-ERBa, REV-ERBb, and RORa), 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-a released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBa 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-ERBa in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-a) 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.Keywords: circadian rhythm; SIRT1; REV-ERBa; BMAL1; smokers Clinical RelevanceAlthough the circadian clock regulates the inflammatory response, there is no information available regarding the impact of chronic obstructive pulmonary disease (COPD) on molecular clock function in peripheral tissues and its modulation by sirtuin 1 (SIRT1). We report here that clock proteins, including BMAL1 and REV-ERBa, are reduced in peripheral tissues from patients with COPD in part owing to SIRT1 reduction. LPS differently affects the timing and amplitude of cytokine release from peripheral blood mononuclear cells among nonsmokers, smokers, and patients with COPD. The SIRT1 activator SRT1720 is able to inhibit LPS-induced cytokine release in peripheral blood mononuclear cells. This has implications in the pathogenesis and pharmacological chronotherapy of COPD.

Circadian Clock–Coupled Lung Cellular and Molecular Functions in Chronic Airway Diseases

“…We have shown that environmental CS exposure also causes circadian disruption, producing molecular clock dysfunction and enhanced inflammatory responses in the lungs (10). Abundance of clock proteins, such as BMAL1, PER2, and REV-ERBa, are reduced in peripheral blood mononuclear cells, sputum cells and lung tissues associated with inflammatory responses from smokers and patients with COPD when compared to nonsmokers (24). Hence, it is likely that the molecular clock dysfunction can augment lung inflammatory responses to environmental stressors/agents.…”

“…It is possible that oxidative/carbonyl stress (CS)-mediated reduction of SIRT1 level/activity leads to hyperacetylation of clock proteins and/or clock gene-associated histones, culminating in abnormal rhythms of proinflammatory and molecular clock gene expression. Indeed, we have shown that molecular clock dysfunction, along with SIRT1 reduction, contributes to abnormal inflammatory responses in smokers and patients with COPD (24). SIRT1 activation reduces CS-induced acetylation and degradation of BMAL1 in mouse lungs.…”

“…SIRT1 activation reduces CS-induced acetylation and degradation of BMAL1 in mouse lungs. Thus, targeting time-dependent pharmacological activation of SIRT1 may have considerable potential as a novel form of chronopharmacology in chronic airways disease (24). SIRT1 is also implicated in regulation of senescence during DDR (28).…”

Timing Matters: Circadian Rhythm in Sepsis, Obstructive Lung Disease, Obstructive Sleep Apnea, and Cancer

“…Similar to asthma, the diurnal variation in symptom severity has been observed during COPD exacerbations, with elevated risk for intubation during early morning hours in the emergency department (82). Exciting research is emerging showing environmental risks of COPD, such as tobacco smoking, can affect components of the circadian clock (83), which may lead to chronic inflammatory responses (84). As future studies elucidate the interrelationship between circadian rhythm and COPD, new therapeutic targets and approaches may emerge in COPD treatment.…”

Lungs can tell time—a highlight from 2016 ATS session on clock genes, inflammation, immunology, and sleep

“…Cigarette smoking led to decreased Sirtuin-1 activity leading to altered Bmal I: Clock activity (12). This finding may be a contributing factor for increased inflammation seen in smokers with COPD (13).…”