Circadian molecular clock in lung pathophysiology

Sep 13, 2015American journal of physiology. Lung cellular and molecular physiology

The body’s internal clock and lung disease processes

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Abstract

Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases.

Circadian rhythms are maintained by an autoregulatory feedback loop involving clock gene transcription factors.
Key nuclear receptors and transcription factors, REV-ERBα and RORα, regulate the expression of the Bmal1 gene, contributing to oscillator stability.
Circadian clock dysfunction is linked to immune and inflammatory responses to various environmental and infectious agents.
Molecular clock function can be influenced by factors such as tobacco smoke, allergens, and infections.
Sirtuin 1 (SIRT1) regulates the molecular clock's timing and is affected by environmental stressors.
There is a reciprocal relationship between the molecular clock and inflammation in lung cells, suggesting potential use as a biomarker for disease severity.

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Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology.

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Circadian molecular clock in lung pathophysiology

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