Abstract
Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO 3 − and Cl − secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis 1–3 . Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO 3 − 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 language | English (US) |
|---|---|
| Pages (from-to) | 405-408 |
| Number of pages | 4 |
| Journal | Nature |
| Volume | 567 |
| Issue number | 7748 |
| DOIs | |
| State | Published - Mar 21 2019 |
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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.
In: Nature, Vol. 567, No. 7748, 21.03.2019, p. 405-408.Research output: Contribution to journal › Letter
}
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
PY - 2019/3/21
Y1 - 2019/3/21
N2 - Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO 3 − and Cl − secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis 1–3 . Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO 3 − 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 HCO 3 − and Cl − secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis 1–3 . Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO 3 − 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 - Letter
VL - 567
SP - 405
EP - 408
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7748
ER -