溶剂乙醇对囊性纤维化跨膜传导调节因子的激活作用：对局部给药的影响。
Cystic fibrosis transmembrane conductance regulator activation by the solvent ethanol: implications for topical drug delivery.
作者信息
Cho Do-Yeon, Skinner Daniel, Zhang Shaoyan, Fortenberry James, Sorscher Eric J, Dean Nichole R, Woodworth Bradford A
机构信息
Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL.
Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Birmingham, AL.
出版信息
Int Forum Allergy Rhinol. 2016 Feb;6(2):178-84. doi: 10.1002/alr.21638. Epub 2015 Dec 3.
BACKGROUND
Decreased cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride (Cl) secretion across mucosal surfaces contributes to the development of airway disease by depleting airway surface liquid, increasing mucus viscosity and adhesion, and consequently hindering mucociliary clearance. We serendipitously discovered during testing of drugs solubilized in low concentrations ethanol (0.25%, 43 mM) that the control vehicle produced robust activation of CFTR-mediated Cl(-) transport. The objective of the current study is to investigate low concentrations of ethanol for effects on Cl(-) secretion and ciliary beat frequency (CBF).
METHODS
Wild-type (WT) and transgenic CFTR(-/-) primary murine nasoseptal epithelial (MNSE) cultures and WT and F508del/F508del human sinonasal epithelial (HSNE) cultures were subjected to transepithelial ion transport measurements using pharmacologic manipulation in Ussing chambers. CBF activation was also monitored. Murine nasal potential difference (NPD) was measured in vivo.
RESULTS
Ussing chamber tracings revealed ethanol activated CFTR-mediated Cl transport in a dose-dependent fashion in WT MNSE (n = 4, p < 0.05) and HSNE (n = 4, p < 0.05). Ethanol also significantly increased CBF (fold change) in WT MNSE cultures in a dose-dependent fashion (phosphate-buffered saline [PBS], 1.33 ± 0.04; 0.25% ethanol, 1.37 ± 0.09; 0.5% ethanol, 1.53 ± 0.06 [p < 0.05]; 1% ethanol, 1.62 ± 0.1 [p < 0.05]). Lack of stimulation in CFTR(-/-) and F508del/F508del cultures indicated activity was dependent on the presence of intact functional CFTR. Ethanol perfusion (0.5%) resulted in a significant -3.5-mV mean NPD polarization when compared to control solution (p < 0.05).
CONCLUSION
The observation that brief exposure of ethanol stimulated Cl(-) secretion via CFTR-mediated pathways indicates its possible use as topical aerosol delivered alone or in combination with other CFTR activators for diseases of dysfunctional mucociliary clearance (MCC) in chronic rhinosinusitis (CRS).
背景
囊性纤维化跨膜传导调节因子（CFTR）介导的氯离子（Cl）跨黏膜表面分泌减少，通过消耗气道表面液体、增加黏液黏度和黏附性，进而阻碍黏液纤毛清除功能，促使气道疾病的发生。我们在测试溶解于低浓度乙醇（0.25%，43 mM）中的药物时意外发现，对照溶媒可强力激活CFTR介导的Cl⁻转运。本研究的目的是探究低浓度乙醇对Cl⁻分泌和纤毛摆动频率（CBF）的影响。
方法
使用Ussing室中的药理学操作，对野生型（WT）和转基因CFTR⁻/⁻原代小鼠鼻中隔上皮（MNSE）培养物以及WT和F508del/F508del人鼻窦上皮（HSNE）培养物进行跨上皮离子转运测量。同时监测CBF激活情况。在体内测量小鼠鼻电位差（NPD）。
结果
Ussing室记录显示，乙醇在WT MNSE（n = 4，p < 0.05）和HSNE（n = 4，p < 0.05）中以剂量依赖性方式激活CFTR介导的Cl转运。乙醇还以剂量依赖性方式显著增加WT MNSE培养物中的CBF（倍数变化）（磷酸盐缓冲盐水[PBS]，1.33 ± 0.04；0.25%乙醇，1.37 ± 0.09；0.5%乙醇，1.53 ± 0.06 [p < 0.05]；1%乙醇，1.62 ± 0.1 [p < 0.05]）。CFTR⁻/⁻和F508del/F508del培养物中缺乏刺激表明该活性依赖于完整功能性CFTR的存在。与对照溶液相比，乙醇灌注（0.5%）导致平均NPD极化显著降低-3.5 mV（p < 0.05）。
结论
乙醇短暂暴露通过CFTR介导的途径刺激Cl⁻分泌这一观察结果表明，乙醇可能单独或与其他CFTR激活剂联合用作局部气雾剂，用于治疗慢性鼻窦炎（CRS）中功能失调的黏液纤毛清除（MCC）疾病。
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