Circadian clock dysfunction of epithelial cells in pulmonary diseases

Highly-differentiated pulmonary epithelial cells are essential for maintaining lung homeostasis by exerting various physiological functions, which are regulated by circadian clock consisted of an autoregulatory feedback loop of clock genes, including Brain-Muscle Aryl-hydrocarbon Receptor Nuclear Translocator-Like 1 (BMAL1) and Nuclear Heme Receptor Reverse Erythroblastosis Virus α (REV-ERB-α). The circadian clock dysfunction of epithelial cells has been increasingly associated with the pulmonary diseases: BMAL1 and REV-ERB-α regulates inflammatory response of club cells induced by lipopolysaccharide and cigarette smoke (CS) respectively; the clock disfunction in alveolar epithelial type2 cells (AEC-II) has been implicated in CS-induced airway inflammation and early-life hyperoxia-related susceptibility to influenza infection; the ciliary beat frequency of ciliated cells also shows circadian rhythms. Here, we review the current knowledge on the circadian regulation of different epithelial-cell subtypes, attempting to provide insights into how clock dysfunction contributes to pulmonary diseases, and explore possible pharmacological therapies and future directions for fundamental studies.