Carbocisteine stimulated an increase in ciliary bend angle via a decrease in [Cl-]i in mouse airway cilia
Carbocisteine stimulated an increase in ciliary bend angle via a decrease in [Cl-]i in mouse airway cilia
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DOI：
10.1007/s00424-018-2212-2
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发表时间：
2019-02-01
影响因子：
4.5
通讯作者：
Nakahari, Takashi
中科院分区：
文献类型：
--
作者：
Ikeuchi, Yukiko;Kogiso, Haruka;Nakahari, Takashi
卡西汀（CCis）是一种广泛用于改善呼吸系统疾病的粘液活性药物。本研究表明，CCis使小鼠气道纤毛细胞的纤毛弯曲角（CBA）增加30%，纤毛搏动频率（CBF）增加10%。这些增加是由细胞内pH升高引起的(pH(i)；pH(i)途径)和细胞内Cl-浓度([Cl-](i)的降低；CCis刺激的Cl-通路)。不依赖于CO2/HCO3-的Cl-途径使CBA增加20%。该途径通过激活Cl-通道激活Cl-释放，导致[Cl-]减少(i)，并被Cl-通道阻滞剂（5-硝基-2-（3-苯基丙胺）苯甲酸和CFTR(inh)-172）抑制。在无CO2/HCO3条件下，无Cl- NO3-溶液模拟CCis刺激的CBA增加。依赖于CO2/HCO3-的pH(i)途径使CBF和CBA增加了10%。该途径通过Na+/HCO3-共转运（NBC）激活HCO3-进入，导致pH(i)升高，并被4,4-二异硫氰酸-2,2-二苯乙烯二磺酸抑制。CCis的作用不受蛋白激酶a抑制剂（1M PKI-A）或无Ca2+溶液的影响。因此，CCis通过激活包括CFTR在内的Cl-通道降低[Cl-](i)，使CBA增加20%，并通过NBC激活升高pH(i)，使CBF和CBA增加10%。
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%.