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

Abstract

Key points Lung hydration and mucus clearance rates are set by a balance between CFTR‐mediated Cl− secretion and ENaC‐led Na+ absorption. In CF airways, CFTR is diminished, and ENaC is upregulated, leading to mucus dehydration and increased chance of infection. Evidence for ENaC upregulation in CF airways includes electrophysiological evidence, increased ASL absorption rates, increased cleavage of CF ENaC and increased basolateral Na+/K+ ATPase activity in CF airways. The mechanism of Na+ 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. Abstract Airway epithelia absorb Na+ through the epithelial Na+ channel (ENaC) and secrete Cl− 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 CFTR 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−/HCO3− and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O 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 in vivo and in vitro, 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.

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+ Channel

“…In contrast, an increase in Na + absorption by ENaC overexpression in a genetic mouse model leads to a cystic fibrosis lung phenotype (Mall et al, 2010). In airway epithelia of cystic fibrosis patients, the loss of cystic fibrosis transmembrane conductance regulator (CFTR) activity is accompanied by an increased ENaC activity resulting in Na + hyperabsorption, suggesting that ENaC upregulation may contribute to the cystic fibrosis lung phenotype (Mall et al, 2010;Hobbs et al, 2013). A cystic fibrosis-like lung phenotype, however, has not been consistently observed in Liddle patients.…”

“…Functional and structural parallels and differences are discussed in the perspective of ENaC and ASICs as targets for pharmacological ligands. Other recent reviews cover relevant aspects of ASIC and ENaC function in more detail than this review: physiologic and pathologic roles of ASICs (Wemmie et al, 2013), regulation of ASIC function , physiology and regulation of ENaC Rossier, 2014), and ENaC's role in cystic fibrosis (Hobbs et al, 2013). Information on ASIC and ENaC properties and pharmacology can be found in the IUPHAR/BPS Guide to PHARMACOLOGY (www.guidetopharmacology.…”

NRA-2, a Nicalin Homolog, Regulates Neuronal Death by Controlling Surface Localization of Toxic Caenorhabditis elegans DEG/ENaC Channels

“…Considering structural and functional similarities along with our clear demonstration of NRA-2 influence on MEC-10(d) surface expression, we speculate that the mammalian Nicalin/NOMO complex might also influence DEG/ENaC surface expression (and possibly other channels). If so, this step might be considered for therapeutic modulation of DEG/ENaC channel activity in cystic fibrosis (45), renal disease (46), pain management, and possibly ischemic stroke (21).…”

Origins of Cystic Fibrosis Lung Disease

“…Studies of cultured human airway epithelia, as well as mouse fibroblast and dog kidney cell lines expressing recombinant CFTR and ENaC suggest that without CFTR, ENaC-mediated sodium transport increases. In addition, mice overexpressing ENaC show decreased airway surface liquid height and reduced mucociliary clearance 9,46,47 , suggesting that increased ENaC activity can alter airway surface liquid. In contrast to the hypothesis that sodium hyperabsorption initiates disease, newborn porcine cystic fibrosis airway epithelia do not hyperabsorb sodium 44 .…”

“…A widely held hypothesis is that CFTR inhibits ENaC, and loss of that effect causes amiloride-inhibitable sodium hyperabsorption, which dehydrates airways, reduces the height of periciliary liquid, and disrupts mucociliary clearance 9,46,47 . Studies of cultured human airway epithelia, as well as mouse fibroblast and dog kidney cell lines expressing recombinant CFTR and ENaC suggest that without CFTR, ENaC-mediated sodium transport increases.…”