TY - JOUR
T1 - Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia
AU - Muraglia, Katrina A.
AU - Chorghade, Rajeev S.
AU - Kim, Bo Ram
AU - Tang, Xiao Xiao
AU - Shah, Viral S.
AU - Grillo, Anthony S.
AU - Daniels, Page N.
AU - Cioffi, Alexander G.
AU - Karp, Philip H.
AU - Zhu, Lingyang
AU - Welsh, Michael J.
AU - Burke, Martin D.
N1 - Funding Information:
Acknowledgements We acknowledge M. Sivaguru at the Carl R. Woese Institute for Genomic Biology for assistance with confocal microscopy, S. E. Denmark and C. Delaney for assistance with rapid injection NMR and D. J. Blair for helpful discussions. Support was provided by NIH (5R35GM118185 to M.D.B. and HL091842 to M.J.W.), and by Emily’s Entourage. M.J.W. is an HHMI Investigator. K.A.M. is a Medical Scholars Fellow.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/3/21
Y1 - 2019/3/21
N2 - Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3− and Cl− secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis1–3. Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3− secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+, K+-ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in vivo. Thus, unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.
AB - Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3− and Cl− secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis1–3. Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3− secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+, K+-ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in vivo. Thus, unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.
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U2 - 10.1038/s41586-019-1018-5
DO - 10.1038/s41586-019-1018-5
M3 - Article
C2 - 30867598
AN - SCOPUS:85063040454
VL - 567
SP - 405
EP - 408
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7748
ER -