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

Abstract

Airway diseases are associated with abnormal circadian rhythms of lung function, reflected in daily changes of airway caliber, airway resistance, respiratory symptoms, and abnormal immune-inflammatory responses. Circadian rhythms are generated at the cellular level by an autoregulatory feedback loop of interlocked transcription factors collectively referred to as clock genes. The molecular clock is altered by cigarette smoke, LPS, and bacterial and viral infections in mouse and human lungs and in patients with chronic airway diseases. Stressmediated post-translational modification of molecular clock proteins, brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) and PERIOD 2, is associated with a reduction in the activity/ level of the deacetylase sirtuin 1 (SIRT1). Similarly, the levels of the nuclear receptor REV-ERBa and retinoic acid receptor-related orphan receptor a (ROR a), critical regulators of Bmal1 expression, are altered by environmental stresses. Molecular clock dysfunction is implicated in immune and inflammatory responses, DNA damage response, and cellular senescence. The molecular clock in the lung also regulates the timing of glucocorticoid sensitivity and phasic responsiveness to inflammation. Herein, we review our current understanding of clock-controlled cellular and molecular functions in the lungs, the impact of clock dysfunction in chronic airway disease, and the response of the pulmonary clock to different environmental perturbations.Furthermore, we discuss the evidence for candidate signaling pathways, such as the SIRT1-BMAL1-REV-ERBa axis, as novel targets for chronopharmacological management of chronic airway diseases.

Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment – A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine

“…In addition, Dbp was the most upregulated gene in transgenic silica-exposed lung. These findings link perturbations in circadian clock genes to gremlin-mediated inflammatory and tissue injury responses in the lung [ 38 ].…”

“…Inflammatory responses are known to be affected by perturbations of the molecular clock function, which contributes to lung function in airway diseases. Decline in circadian function has been linked especially to depression of immune responses and exacerbations in asthma and COPD [ 38 ]. Interestingly, gremlin-2 and BMP-signaling was recently suggested to be regulated by circadian rhythms in the fibrous tissue of tendon [ 52 ].…”

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

“…These effects may be due to circadian disruption in peripheral tissues and/or uncoupling between peripheral oscillators and the master clock located in the suprachiasmatic nucleus of the hypothalamus (5)(6)(7)(8). By examining the direct effects of smoking and COPD on molecular clock gene expression in peripheral oscillators, we can dissect the impact of environmental stress on cell-autonomous clocks and begin to describe the mechanism linking clock disruption to enhanced inflammatory responses (9). Sirtuin1 (SIRT1), an NAD 1 -dependent deacetylase, affects clock function by binding with CLOCK:BMAL1 complexes and deacetylating BMAL1 and PER2 proteins (10)(11)(12).…”

Circadian Clock and Sirtuins in Diabetic Lung: A Mechanistic Perspective

“…Conversely, once PER and CRY accumulate to a certain level, they form heterodimer and translocate back to the nucleus to block transcriptional activity of the BMAL1/CLOCK complex and ultimately repress their own transcription. REV-ERB and ROR drive the rhythmic expression of BMAL1 and CLOCK via competitively binding to the REV-ERB/ROR binding site, thus repressing or activating transcription of Bmal1 and Clock, respectively (47,48). In addition, posttranslational modifications have been established to regulate clock gene expression.…”