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

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.

SUBMITTER: Muraglia KA

PROVIDER: S-EPMC6492938 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Muraglia Katrina A KA Chorghade Rajeev S RS Kim Bo Ram BR Tang Xiao Xiao XX Shah Viral S VS Grillo Anthony S AS Daniels Page N PN Cioffi Alexander G AG Karp Philip H PH Zhu Lingyang L Welsh Michael J MJ Burke Martin D MD

Nature 20190313 7748

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 airw ...[more]

PMID: 30867598

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Project description:Key pointsCl- and HCO3 - had similar paracellular permeabilities in human airway epithelia. PCl /PNa of airway epithelia was unaltered by pH 7.4 vs. pH 6.0 solutions. Under basal conditions, calculated paracellular HCO3 - flux was secretory. Cytokines that increased airway surface liquid pH decreased or reversed paracellular HCO3 - flux. HCO3 - flux through the paracellular pathway may counterbalance effects of cellular H+ and HCO3 - secretion.AbstractAirway epithelia control the pH of airway surface liquid (ASL), thereby optimizing respiratory defences. Active H+ and HCO3 - secretion by airway epithelial cells produce an ASL that is acidic compared with the interstitial space. The paracellular pathway could provide a route for passive HCO3 - flux that also modifies ASL pH. However, there is limited information about paracellular HCO3 - flux, and it remains uncertain whether an acidic pH produced by loss of cystic fibrosis transmembrane conductance regulator anion channels or proinflammatory cytokines might alter the paracellular pathway function. To investigate paracellular HCO3 - transport, we studied differentiated primary cultures of human cystic fibrosis (CF) and non-CF airway epithelia. The paracellular pathway was pH-insensitive at pH 6.0 vs. pH 7.4 and was equally permeable to Cl- and HCO3 - . Under basal conditions at pH ∼6.6, calculated paracellular HCO3 - flux was weakly secretory. Treating epithelia with IL-17 plus TNFα alkalinized ASL pH to ∼7.0, increased paracellular HCO3 - permeability, and paracellular HCO3 - flux was negligible. Applying IL-13 increased ASL pH to ∼7.4 without altering paracellular HCO3 - permeability, and calculated paracellular HCO3 - flux was absorptive. These results suggest that HCO3 - flux through the paracellular pathway counterbalances, in part, changes in the ASL pH produced via cellular mechanisms. As the pH of ASL increases towards that of basolateral liquid, paracellular HCO3 - flux becomes absorptive, tempering the alkaline pH generated by transcellular HCO3 - secretion.

Project description:Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a plasma membrane protein expressed on the apical surface of secretory epithelia of the airways. In the airways, defective or absent function of the CFTR protein determines abnormalities of chloride and bicarbonate secretion and, in general, of the transepithelial homeostasis that lead to alterations of airway surface liquid (ASL) composition and properties. The reduction of ASL volume impairs ciliary beating with the consequent accumulation of a sticky mucus. This situation prevents normal mucociliary clearance, favoring the survival and proliferation of bacteria and contributing to the genesis of the CF pulmonary disease. We explored the potential of some CFTR modulators, namely ivacaftor, tezacaftor, elexacaftor and their combination KaftrioTM, capable of partially recovering the basic defects of the CFTR protein, to ameliorate the transepithelial fluid transport and the viscoelastic properties of the mucus when used singly or in combination. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of correctors tezacaftor, elexacaftor and their combination with potentiator ivacaftor on the key properties of ASL, such as fluid reabsorption, viscosity, protein content and pH. The treatment of airway epithelia bearing the deletion of a phenylalanine at position 508 (F508del) in the CFTR gene with tezacaftor and elexacaftor significantly improved the pericilial fluid composition, reducing the fluid reabsorption, correcting the ASL pH and reducing the viscosity of the mucus. KaftrioTM was more effective than single modulators in improving all the evaluated parameters, demonstrating once more that this combination recently approved for patients 6 years and older with cystic fibrosis who have at least one F508del mutation in the CFTR gene represents a valuable tool to defeat CF.

Dataset Information

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

Publications

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

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