Unselective small-molecule ion channels can restore host defenses in the airway epithelia of patients with cystic fibrosis (CF) using a mechanism that is independent of CF transmembrane conductance regulator (CFTR) and is thus independent of genotype, according to a study published in Nature.
Investigators reported that apical addition of amphotericin B (AmB) — a small molecule that forms unselective ion channels — restored bicarbonate secretion and increased airway surface liquid pH in the cultured airway epithelia obtained from individuals with CF. They speculated that although AmB is likely to mobilize ions other than bicarbonate, the compensatory actions of other pumps, channels, carriers, and the paracellular pathway may help to establish airway surface liquid ion concentrations at steady state.
Secretion of ions through apical channels depends on an electrochemical gradient that is generated, in large part, by basolateral transport proteins. It has been shown that AmB-mediated growth rescue in Trk-deficient yeast is reduced by chemical inhibition of H+ ATPases that drive secondary K+ influx.
The researchers also evaluated whether AmB could restore key features of airway host defense in differentiated primary cultures of human airway epithelia. They examined epithelia derived from 9 donors with CF that represented different CFTR mutations, which included some that produce no CFTR. It was shown that apical AmB increased airway surface liquid pH by approximately 0.2 pH units — an effect that was sustained for ≥48 hours.
The apical addition of AmB required the basolateral Na+, K+, and ATPase, which implies that apical AmB channels interface functionally with this driver of anion secretion. Moreover, AmB also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures obtained from patients with CF caused by different mutations, including those that do not yield CFTR.
The investigators concluded that in individuals with CF, unselective small-molecule ion channels can restore host defenses in the airway epithelia using a method that is unrelated to CFTR and is therefore independent of a patient’s genotype.
Disclosures: Several authors report that they are inventors on patent applications PCT/US15/58806, PCT/US18/55435, and/or PCT/US2017/26806 submitted by University of Illinois Urbana-Champaign which cover use of AmB and AmB-cholesterol to treat CF.
Muraglia KA, Chorghade RS, Kim BR, et al. Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia. Nature. 2019;567(7748):405-408.