Dual activation of CFTR and CLCN2 by lubiprostone in murine nasal epithelia

作者：Schiffhauer Eric S; Vij Neeraj; Kovbasnjuk Olga; Kang Po Wei; Walker Doug; Lee Seakwoo; Zeitlin Pamela L^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2013, 304(5): L324-L331.

DOI：10.1152/ajplung.00277.2012

• CFTR
• CLCN2
• lubiprostone
• cystic fibrosis
• confocal microscopy
• chloride channels
• electrophysiology
• airway epithelium

Schiffhauer ES, Vij N, Kovbasnjuk O, Kang PW, Walker D, Lee S, Zeitlin PL. Dual activation of CFTR and CLCN2 by lubiprostone in murine nasal epithelia. Am J Physiol Lung Cell Mol Physiol 304: L324-L331, 2013. First published January 11, 2013; doi:10.1152/ajplung.00277.2012.-Multiple sodium and chloride channels on the apical surface of nasal epithelial cells contribute to periciliary fluid homeostasis, a function that is disrupted in patients with cystic fibrosis (CF). Among these channels is the chloride channel CLCN2, which has been studied as a potential alternative chloride efflux pathway in the absence of CFTR. The object of the present study was to use the nasal potential difference test (NPD) to quantify CLCN2 function in an epithelial-directed TetOn CLCN2 transgenic mouse model (TGN-K18rtTA-hCLCN2) by using the putative CLCN2 pharmacological agonist lubiprostone and peptide inhibitor GaTx2. Lubiprostone significantly increased chloride transport in the CLCN2-overexpressing mice following activation of the transgene by doxycycline. This response to lubiprostone was significantly inhibited by GaTx2 after CLCN2 activation in TGN-CLCN2 mice. Cftr(-/-) and Clc2(-/-) mice showed hyperpolarization indicative of chloride efflux in response to lubiprostone, which was fully inhibited by GaTx2 and CFTR inhibitor 172 + GlyH-101, respectively. Our study reveals lubiprostone as a pharmacological activator of both CFTR and CLCN2. Overexpression and activation of CLCN2 leads to improved mouse NPD readings, suggesting it is available as an alternative pathway for epithelial chloride secretion in murine airways. The utilization of CLCN2 as an alternative chloride efflux channel could provide clinical benefit to patients with CF, especially if the pharmacological activator is administered as an aerosol.

• 出版日期2013-3