Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?

<jats:title>Key points</jats:title><jats:p><jats:list list-type="explicit-label"> <jats:list-item><jats:p>Lung hydration and mucus clearance rates are set by a balance between CFTR‐mediated Cl<jats:sup>−</jats:sup> secretion and ENaC‐led Na<jats:sup>+</jats:sup> absorption. In CF airways, CFTR is diminished, and ENaC is upregulated, leading to mucus dehydration and increased chance of infection.</jats:p></jats:list-item> <jats:list-item><jats:p>Evidence for ENaC upregulation in CF airways includes electrophysiological evidence, increased ASL absorption rates, increased cleavage of CF ENaC and increased basolateral Na<jats:sup>+</jats:sup>/K<jats:sup>+</jats:sup> ATPase activity in CF airways.</jats:p></jats:list-item> <jats:list-item><jats:p>The mechanism of Na<jats:sup>+</jats:sup> hyperabsorption in CF airways is unknown and it may be due to altered protein‐protein interactions and/or increased proteolysis of ENaC in CF airways. However, inhibition of ENaC is predicted to increase CF mucus hydration/clearance and thus, ENaC remains an important therapeutic target for the treatment of CF lung disease.</jats:p></jats:list-item> </jats:list></jats:p><jats:p><jats:bold>Abstract </jats:bold> Airway epithelia absorb Na<jats:sup>+</jats:sup> through the epithelial Na<jats:sup>+</jats:sup> channel (ENaC) and secrete Cl<jats:sup>−</jats:sup> through the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. This balance maintains sufficient airway surface liquid hydration to permit efficient mucus clearance, which is needed to maintain sterility of the lung. Cystic fibrosis (CF) is a common autosomal recessive inherited disease caused by mutations in the <jats:italic>CFTR</jats:italic> gene that lead to the reduction or elimination of the CFTR protein. CF is a multi‐organ disease that affects epithelia lining the intestines, lungs, pancreas, sweat ducts and vas deferens, among others. CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl<jats:sup>−</jats:sup>/HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup> and H<jats:sub>2</jats:sub>O secretion as well as ENaC hyperactivity and increased Na<jats:sup>+</jats:sup> and H<jats:sub>2</jats:sub>O absorption. Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus. Rehydrating CF mucus has become a recent clinical focus and yields important end‐points for clinical trials. However, while ENaC hyperactivity in CF airways has been detected <jats:italic>in vivo</jats:italic> and <jats:italic>in vitro</jats:italic>, recent data have brought the role of ENaC in CF lung disease pathogenesis into question. This review will focus on our current understanding of the contribution of ENaC to CF pathogenesis.</jats:p>