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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-03-13

AUTHORS

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

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. More... »

PAGES

405-408

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41586-019-1018-5

DOI

http://dx.doi.org/10.1038/s41586-019-1018-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112734622

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30867598


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34 schema:description 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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