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. Stress-mediated 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-ERBα and retinoic acid receptor-related orphan receptor α (ROR α), 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-ERBα axis, as novel targets for chronopharmacological management of chronic airway diseases.

Keywords: Bmal1; REV-ERBα; asthma; chronic obstructive pulmonary disease; sirtuin 1.

Figure 1.

Impact of environmental agents on molecular clock function in the lung. Various environmental stressors, including cigarette smoke (oxidative/carbonyl stress), viral and bacterial infections, and chronic circadian misalignment (CCM) (chronic jet lag) alter molecular clock functions in the lungs. Circadian disruption of the daily timing system can affect the rhythmic expression of clock output genes in the lung that may influence lung pathophysiology. Activation of sirtuin 1 (SIRT1) and REV-ERBα by pharmacological activators/agonists may have beneficial effects against altered lung phenotypes caused by molecular clock dysfunction in chronic airway diseases. BMAL1, brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1; Clock, circadian locomotor output cycles protein kaput; E-box, enhancer box; RORα, retinoic acid receptor–related orphan receptor α; RORE, retinoic acid receptor–related orphan receptor response element.