New Generation ENaC Inhibitors Detach Cystic Fibrosis Airway Mucus
Bundles via Sodium/Hydrogen Exchanger Inhibition
Abstract
Background and Purpose: Cystic fibrosis (CF) is a recessive inherited
disease caused by mutations affecting anion transport by the epithelial
ion channel cystic fibrosis transmembrane conductance regulator (CFTR).
The disease is characterized by mucus accumulation in the airways and
intestine, but the major cause of mortality in CF is airway mucus
accumulation, leading to bacterial colonization, inflammation and
respiratory failure. One of the drug targets under evaluation to
alleviate airway mucus obstruction in CF is the epithelial sodium
channel, ENaC. Experimental Approach: To explore effects of ENaC
inhibitors on mucus properties, we used two model systems to investigate
mucus characteristics, mucus attachment in mouse ileum and mucus bundle
transport in piglet airways. We quantified mucus attachment in explants
from CFTR null (CF) mice and tracheobronchial explants from newborn CFTR
null (CF) piglets to evaluate effects of ENaC or sodium/hydrogen
exchange (NHE) inhibitors on mucus attachment. Key Results: ENaC
inhibitors detached mucus in the CF mouse ileum, although the ileum
lacks ENaC expression. This effect was mimicked by two sodium/proton
exchange (NHE) inhibitors. Airway mucus bundles were immobile in
untreated newborn CFTR null (CF) piglets but were detached by the
therapeutic drug candidate AZD5634. Conclusion and Implications: These
results suggest that the ENaC inhibitor AZD5634 causes detachment of CF
mucus in the ileum and airway via NHE inhibition and that drug design
should focus on NHE instead of ENaC inhibition.