Increased apical Na+ permeability in cystic fibrosis is supported by a quantitative model of epithelial ion transport

Key points •  Cystic fibrosis (CF) is a common genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator gene, which encodes a channel protein, selective for anions. •  In the lungs, the site of the most severe symptoms, CF causes abnormal electrolyte transport in epithelial cells which line the airways. •  Airway epithelial ion transport can be assessed by measuring the trans-epithelial potential difference (Vt) which shows characteristic changes in CF individuals. We developed a biophysical model of ion transport in human nasal epithelia, in order to investigate quantitatively which transport parameters underlie these observed bioelectric changes. •  We found that loss of apical Cl− permeability alone is insufficient to explain the bioelectric properties of CF epithelia. An increase of apical Na+ permeability must also occur. •  This insight has important implications for our understanding of the physiology of CF disease, and hence for potential therapies aimed at correcting the CF ion transport defect. Abstract  Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an anion channel. In the human lung CFTR loss causes abnormal ion transport across airway epithelial cells. As a result CF individuals produce thick mucus, suffer persistent bacterial infections and have a much reduced life expectancy. Trans-epithelial potential difference (Vt) measurements are routinely carried out on nasal epithelia of CF patients in the clinic. CF epithelia exhibit a hyperpolarised basal Vt and a larger Vt change in response to amiloride (a blocker of the epithelial Na+ channel, ENaC). Are these altered bioelectric properties solely a result of electrical coupling between the ENaC and CFTR currents, or are they due to an increased ENaC permeability associated with CFTR loss? To examine these issues we have developed a quantitative mathematical model of human nasal epithelial ion transport. We find that while the loss of CFTR permeability hyperpolarises Vt and also increases amiloride-sensitive Vt, these effects are too small to account for the magnitude of change observed in CF epithelia. Instead, a parallel increase in ENaC permeability is required to adequately fit observed experimental data. Our study provides quantitative predictions for the complex relationships between ionic permeabilities and nasal Vt, giving insights into the physiology of CF disease that have important implications for CF therapy.