Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia

Katrina A. Muraglia, Rajeev S. Chorghade, Bo Ram Kim, Xiao Xiao Tang, Viral S. Shah, Anthony S. Grillo, Page N. Daniels, Alexander G. Cioffi, Philip H. Karp, Lingyang Zhu, Michael J. Welsh and Martin D. Burke ()
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Katrina A. Muraglia: University of Illinois at Urbana-Champaign
Rajeev S. Chorghade: University of Illinois at Urbana-Champaign
Bo Ram Kim: University of Iowa
Xiao Xiao Tang: University of Iowa
Viral S. Shah: University of Iowa
Anthony S. Grillo: University of Illinois at Urbana-Champaign
Page N. Daniels: University of Illinois at Urbana-Champaign
Alexander G. Cioffi: University of Illinois at Urbana-Champaign
Philip H. Karp: University of Iowa
Lingyang Zhu: University of Illinois at Urbana-Champaign
Michael J. Welsh: University of Iowa
Martin D. Burke: University of Illinois at Urbana-Champaign

Nature, 2019, vol. 567, issue 7748, 405-408

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1018-5

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