Circadian Rhythms in the Larynx and Trachea under the Control of the Molecular Clock

Abstract

Some symptoms of laryngeal and tracheal diseases are associated with specific times of the day. For example, cough aggravation in the middle of the night is frequent complaint of patients with airway inflammation. We speculated that these symptoms were under the control of the circadian clock, and the clock genes in the airway epithelium played some important roles. The present study addresses the role of the circadian system in day-night changes of the respiratory functions in mice. In all airway tissues investigated (i.e. laryngeal, tracheal, bronchial, and lung), we observed clear rhythmic expression of the clock genes. Oscillations were abolished in arrhythmic Cry1⁄Cry2 knock out mice and after lesioning of the master clock in the suprachiasmatic nucleus (SCN) in the wild-type. These findings indicate that respiratory cells contain a functional peripheral oscillator that is controlled by the SCN. Signals from SCN are mainly transmitted by the vagal nerve since performing a unilateral vagotomy completely abolished rhythms in Per2 protein levels in the ipsilateral side of the submucosal glands, but not in the contralateral side. Furthermore, we found that the muscarinic acethylcholine receptor genes Chrm2, Chrm3, Chrm4 are expressed in a circadian manner. Thus, laryngeal and tracheal clocks mediated circadian expression of muscarinic acethylcholine receptors and parasympathetic signaling between SCN and airways are essential pathways in conferring circadian time information to the larynx and the trachea. We consider that airway clocks could be the key in solving the nocturnal aggravation of respiratory symptoms.