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2015 ; 309
(10
): L1056-75
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Circadian molecular clock in lung pathophysiology
#MMPMID26361874
Sundar IK
; Yao H
; Sellix MT
; Rahman I
Am J Physiol Lung Cell Mol Physiol
2015[Nov]; 309
(10
): L1056-75
PMID26361874
show ga
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-ERB? and ROR? 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-ERB? and ROR? 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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