Circadian molecular clock disruption in chronic pulmonary diseases

Abstract

The circadian clock is the biochemical oscillator with a near 24-h period that is responsible for generating the circadian rhythms in peripheral organs including the lung. Mounting evidence suggests that circadian clock disruption during chronic lung diseases plays an essential role in augmented oxidative stress, inflammatory response, metabolic imbalances, hypoxia/hyperoxia, mucus secretion, dysregulated autophagy, and alters pulmonary function. Here, we review circadian clock disruption and discuss candidate clock genes that are altered at the transcriptional or translational level in chronic pulmonary diseases. This review aims to provide the current knowledge and understanding of the circadian molecular clock disruption in chronic pulmonary diseases which will further advance the development of novel clock-based therapeutics in the future.

Keywords: COPD; asthma; circadian rhythms; clock disruption; lung pathophysiology; pulmonary arterial hypertension; pulmonary fibrosis.

Figure 1.. Molecular mechanism of circadian clock machinery in the lung.

The schematic of the trilateral transcriptional-translation feedback loop system that drives the periodic oscillation of circadian clock genes at the cellular level in the lung. The overview of the molecular clock machinery in the lung comprises the first core loop, second loop, and the third loop along with their associated core clock targets is summarized in great detail within Box 1. This figure was created using BioRender (BioRender.com). Abbreviations: ARNTL: Aryl Hydrocarbon Receptor Nuclear Translocator Like; BMAL1: Brain and Muscle ARNT-Like 1; CCGs: Core Clock Genes; CLOCK: Circadian Locomotor Output Cycles Kaput; CRY: Cryptochrome; DBP: D-box Binding Protein; HLF: Hepatic Leukemia Factor; NFIL3: Nuclear Factor, Interleukin 3 Regulated or E4 promoter-binding protein 4; PER: Period; REV-ERBα/β or Nr1d1/2: Nuclear Receptor Subfamily 1 Group D Member 1/2; ROR: Retinoic Acid Receptor-Related Orphan Receptor; RORE: ROR Response Elements; TEF: Thyrotroph Embryonic Factor.

Figure 2.. Circadian molecular clock disruption in chronic pulmonary diseases.

Schematic representation of the circadian molecular clock disruption in the lung leading to augmented inflammatory response, airway hyperresponsiveness, mucus hypersecretion, oxidative stress, cytokine response, autoimmune phenotype, ECM remodeling, fibrogenesis, dysregulated autophagy and apoptosis, and altered lung function in chronic pulmonary diseases. The bordered yellow circles with a wave inside represent the alterations of the circadian clock targets. The upward and downward arrows depict the pathophysiological phenotypes affected (increased or decreased) during chronic pulmonary diseases as a consequence of lung circadian clock disruption. This figure was created using BioRender (BioRender.com) and Smart Servier Medical Art (https://smart.servier.com/). Abbreviations: BMAL1: Brain and Muscle ARNT-Like 1; CLOCK: Circadian Locomotor Output Cycles Kaput; CRY1–2: Cryptochrome 1–2; DBP: D-box Binding Protein; ECM: Extracellular matrix; FMT: Fibroblast to myofibroblast transition; IL-6: Interleukin 6; NFIL3: Nuclear Factor, Interleukin 3 Regulated or E4 promoter-binding protein 4, NK cells: Natural killer cells; PER1–3: Period 1–3; REV-ERBα/β or Nr1d1/2: Nuclear Receptor Subfamily 1 Group D Member 1/2; ROR: Retinoic Acid Receptor-Related Orphan Receptor; TGF-β: Transforming growth factor-beta; Th2: T helper 2 cells; Th17: T helper 17 cells.