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Cystic fibrosis transmembrane conductance regulator activation by the solvent ethanol: implications for topical drug delivery
Author(s) -
Cho DoYeon,
Skinner Daniel,
Zhang Shaoyan,
Fortenberry James,
Sorscher Eric J.,
Dean Nichole R.,
Woodworth Bradford A.
Publication year - 2016
Publication title -
international forum of allergy and rhinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.503
H-Index - 46
eISSN - 2042-6984
pISSN - 2042-6976
DOI - 10.1002/alr.21638
Subject(s) - cystic fibrosis transmembrane conductance regulator , mucociliary clearance , cystic fibrosis , ussing chamber , transepithelial potential difference , medicine , ethanol , pharmacology , stimulation , mucus , respiratory epithelium , secretion , endocrinology , chemistry , respiratory system , biochemistry , ion transporter , lung , biology , membrane , ecology
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).

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