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, Martin D. Burke

Research output: Contribution to journalLetter

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.

Original languageEnglish (US)
Pages (from-to)405-408
Number of pages4
JournalNature
Volume567
Issue number7748
DOIs
StatePublished - Mar 21 2019

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Cystic Fibrosis Transmembrane Conductance Regulator
Ion Channels
Cystic Fibrosis
Amphotericin B
Epithelium
Mutation
Viscosity
Anions
Fibrosis
Swine
Genotype

ASJC Scopus subject areas

  • General

Cite this

Muraglia, K. A., Chorghade, R. S., Kim, B. R., Tang, X. X., Shah, V. S., Grillo, A. S., ... Burke, M. D. (2019). Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia. Nature, 567(7748), 405-408. https://doi.org/10.1038/s41586-019-1018-5

Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia. / Muraglia, Katrina A.; Chorghade, Rajeev S.; Kim, Bo Ram; Tang, Xiao Xiao; Shah, Viral S.; Grillo, Anthony S.; Daniels, Page N.; Cioffi, Alexander G.; Karp, Philip H.; Zhu, Lingyang; Welsh, Michael J.; Burke, Martin D.

In: Nature, Vol. 567, No. 7748, 21.03.2019, p. 405-408.

Research output: Contribution to journalLetter

Muraglia, KA, Chorghade, RS, Kim, BR, Tang, XX, Shah, VS, Grillo, AS, Daniels, PN, Cioffi, AG, Karp, PH, Zhu, L, Welsh, MJ & Burke, MD 2019, 'Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia', Nature, vol. 567, no. 7748, pp. 405-408. https://doi.org/10.1038/s41586-019-1018-5
Muraglia KA, Chorghade RS, Kim BR, Tang XX, Shah VS, Grillo AS et al. Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia. Nature. 2019 Mar 21;567(7748):405-408. https://doi.org/10.1038/s41586-019-1018-5
Muraglia, Katrina A. ; Chorghade, Rajeev S. ; Kim, Bo Ram ; Tang, Xiao Xiao ; Shah, Viral S. ; Grillo, Anthony S. ; Daniels, Page N. ; Cioffi, Alexander G. ; Karp, Philip H. ; Zhu, Lingyang ; Welsh, Michael J. ; Burke, Martin D. / Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia. In: Nature. 2019 ; Vol. 567, No. 7748. pp. 405-408.
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