Carbocisteine stimulated an increase in ciliary bend angle via a decrease in [Cl-](i) in mouse airway cilia

摘要

Carbocisteine (CCis), a mucoactive agent, is widely used to improve respiratory diseases. This study demonstrated that CCis increases ciliary bend angle (CBA) by 30% and ciliary beat frequency (CBF) by 10% in mouse airway ciliary cells. These increases were induced by an elevation in intracellular pH (pH(i); the pH(i) pathway) and a decrease in the intracellular Cl- concentration ([Cl-](i); the Cl- pathway) stimulated by CCis. The Cl- pathway, which is independent of CO2/HCO3-, increased CBA by 20%. This pathway activated Cl- release via activation of Cl- channels, leading to a decrease in [Cl-](i), and was inhibited by Cl- channel blockers (5-nitro-2-(3-phenylpropylamino) benzoic acid and CFTR(inh)-172). Under the CO2/HCO3--free condition, the CBA increase stimulated by CCis was mimicked by the Cl--free NO3- solution. The pH(i) pathway, which depends on CO2/HCO3-, increased CBF and CBA by 10%. This pathway activated HCO3- entry via Na+/HCO3- cotransport (NBC), leading to a pH(i) elevation, and was inhibited by 4,4-diisothiocyano-2,2-stilbenedisulfonic acid. The effects of CCis were not affected by a protein kinase A inhibitor (1M PKI-A) or Ca2+-free solution. Thus, CCis decreased [Cl-](i) via activation of Cl- channels including CFTR, increasing CBA by 20%, and elevated pH(i) via NBC activation, increasing CBF and CBA by 10%.