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

•  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.

[1]  E. Hoffman,et al.  Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs. , 2013, The Journal of clinical investigation.

[2]  S. Randell,et al.  Loss of Cftr function exacerbates the phenotype of Na(+) hyperabsorption in murine airways. , 2013, American journal of physiology. Lung cellular and molecular physiology.

[3]  M. Althaus.  ENaC inhibitors and airway re-hydration in cystic fibrosis: state of the art. , 2013, Current molecular pharmacology.

[4]  M. Butterworth,et al.  Proteases, cystic fibrosis and the epithelial sodium channel (ENaC) , 2013, Cell and Tissue Research.

[5]  T. Chinet,et al.  Effect of nitric oxide on epithelial ion transports in noncystic fibrosis and cystic fibrosis human proximal and distal airways. , 2012, American journal of physiology. Lung cellular and molecular physiology.

[6]  D. Baines,et al.  AMP‐activated protein kinase (AMPK)–dependent and –independent pathways regulate hypoxic inhibition of transepithelial Na+ transport across human airway epithelial cells , 2012, British journal of pharmacology.

[7]  J. Sheehan,et al.  Molecular organization of the mucins and glycocalyx underlying mucus transport over mucosal surfaces of the airways , 2012, Mucosal Immunology.

[8]  C. Schultz,et al.  CFTR Regulates Early Pathogenesis of Chronic Obstructive Lung Disease in βENaC-Overexpressing Mice , 2012, PloS one.

[9]  M. Myerburg,et al.  Activation of the Epithelial Sodium Channel (ENaC) by the Alkaline Protease from Pseudomonas aeruginosa* , 2012, The Journal of Biological Chemistry.

[10]  D. Pearce,et al.  Organization of the ENaC-regulatory machinery , 2012, Critical reviews in biochemistry and molecular biology.

[11]  S. Matalon,et al.  The CFTR and ENaC debate: how important is ENaC in CF lung disease? , 2012, American journal of physiology. Lung cellular and molecular physiology.

[12]  T. Kleyman,et al.  Epithelial Na(+) channel regulation by cytoplasmic and extracellular factors. , 2012, Experimental cell research.

[13]  Y. Qadri,et al.  ENaCs and ASICs as therapeutic targets. , 2012, American journal of physiology. Cell physiology.

[14]  L. Palmer,et al.  Regulation and dysregulation of epithelial Na+ channels , 2012, Clinical and Experimental Nephrology.

[15]  L. Ostrowski,et al.  Transgenic hCFTR expression fails to correct β-ENaC mouse lung disease. , 2012, American journal of physiology. Lung cellular and molecular physiology.

[16]  L. Bingle,et al.  Distribution of human PLUNC/BPI fold-containing (BPIF) proteins. , 2011, Biochemical Society transactions.

[17]  C. Schultz,et al.  The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease. , 2011, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[18]  D. Rotin,et al.  Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease , 2011, Proceedings of the National Academy of Sciences.

[19]  M. Welsh,et al.  Loss of Anion Transport without Increased Sodium Absorption Characterizes Newborn Porcine Cystic Fibrosis Airway Epithelia , 2010, Cell.

[20]  L. Bakaletz,et al.  The Multifunctional Host Defense Peptide SPLUNC1 Is Critical for Homeostasis of the Mammalian Upper Airway , 2010, PloS one.

[21]  Seiko F. Okada,et al.  Human Alveolar Type II Cells Secrete and Absorb Liquid in Response to Local Nucleotide Signaling* , 2010, The Journal of Biological Chemistry.

[22]  M. Gentzsch,et al.  CFTR's Proteolysis Protection♦ , 2010, Journal of Biological Chemistry.

[23]  S. Pradervand,et al.  Airway Surface Liquid Volume Regulation Determines Different Airway Phenotypes in Liddle Compared with βENaC-overexpressing Mice* , 2010, The Journal of Biological Chemistry.

[24]  N. Dokholyan,et al.  Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases , 2010, Pflügers Archiv - European Journal of Physiology.

[25]  D. Kentrup,et al.  Characterization of the epithelial sodium channel delta-subunit in human nasal epithelium. , 2010, American journal of respiratory cell and molecular biology.

[26]  J. Dötsch,et al.  A mutation of the epithelial sodium channel associated with atypical cystic fibrosis increases channel open probability and reduces Na+ self inhibition , 2010, The Journal of physiology.

[27]  M. Myerburg,et al.  Acute regulation of the epithelial sodium channel in airway epithelia by proteases and trafficking. , 2010, American journal of respiratory cell and molecular biology.

[28]  J. Olsen,et al.  SPLUNC1 regulates airway surface liquid volume by protecting ENaC from proteolytic cleavage , 2009, Proceedings of the National Academy of Sciences.

[29]  L. Koulischer,et al.  Genetic analysis of Rwandan patients with cystic fibrosis-like symptoms: identification of novel cystic fibrosis transmembrane conductance regulator and epithelial sodium channel gene variants. , 2009, Chest.

[30]  M. Mall.  Role of the amiloride‐sensitive epithelial Na+ channel in the pathogenesis and as a therapeutic target for cystic fibrosis lung disease , 2009, Experimental physiology.

[31]  N. Alexis,et al.  Tracheobronchial air-liquid interface cell culture: a model for innate mucosal defense of the upper airways? , 2008, American journal of physiology. Lung cellular and molecular physiology.

[32]  D. Meyerholz,et al.  Disruption of the CFTR Gene Produces a Model of Cystic Fibrosis in Newborn Pigs , 2008, Science.

[33]  D. Silverthorn,et al.  Insight toward epithelial Na+ channel mechanism revealed by the acid‐sensing ion channel 1 structure , 2008, IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology.

[34]  R. Tarran,et al.  Liquid movement across the surface epithelium of large airways , 2007, Respiratory Physiology & Neurobiology.

[35]  D. Benos,et al.  Molecular Proximity of Cystic Fibrosis Transmembrane Conductance Regulator and Epithelial Sodium Channel Assessed by Fluorescence Resonance Energy Transfer* , 2007, Journal of Biological Chemistry.

[36]  S. Cross,et al.  Differential epithelial expression of the putative innate immune molecule SPLUNC1 in Cystic Fibrosis , 2007, Respiratory research.

[37]  A. Robay,et al.  Regulatory interactions of N1303K-CFTR and ENaC in Xenopus oocytes: evidence that chloride transport is not necessary for inhibition of ENaC. , 2007, American journal of physiology. Cell physiology.

[38]  M. Myerburg,et al.  Airway Surface Liquid Volume Regulates ENaC by Altering the Serine Protease-Protease Inhibitor Balance , 2006, Journal of Biological Chemistry.

[39]  R. Tarran,et al.  Soluble Mediators, Not Cilia, Determine Airway Surface Liquid Volume in Normal and Cystic Fibrosis Superficial Airway Epithelia , 2006, The Journal of general physiology.

[40]  S. Matalon,et al.  δ-Subunit Confers Novel Biophysical Features to αβγ-Human Epithelial Sodium Channel (ENaC) via a Physical Interaction* , 2006, Journal of Biological Chemistry.

[41]  D. Baines,et al.  Forskolin-induced Cell Shrinkage and Apical Translocation of Functional Enhanced Green Fluorescent Protein-Human αENaC in H441 Lung Epithelial Cell Monolayers* , 2006, Journal of Biological Chemistry.

[42]  M. Knowles,et al.  Mucus clearance and lung function in cystic fibrosis with hypertonic saline. , 2006, The New England journal of medicine.

[43]  Richard C Boucher,et al.  Normal and Cystic Fibrosis Airway Surface Liquid Homeostasis , 2005, Journal of Biological Chemistry.

[44]  R. Schreiber,et al.  Cl– Interference with the Epithelial Na+ Channel ENaC* , 2005, Journal of Biological Chemistry.

[45]  R. Boucher,et al.  Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[46]  D. Sheppard,et al.  Transepithelial electrical measurements with the Ussing chamber. , 2004, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[47]  Richard C Boucher,et al.  Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice , 2004, Nature Medicine.

[48]  Richard C Boucher,et al.  Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. , 2002, The Journal of clinical investigation.

[49]  R. Schreiber,et al.  The cystic fibrosis transmembrane conductance regulator (CFTR) inhibits ENaC through an increase in the intracellular Cl− concentration , 2001, EMBO reports.

[50]  J. Gatzy,et al.  The Relative Roles of Passive Surface Forces and Active Ion Transport in the Modulation of Airway Surface Liquid Volume and Composition , 2001, The Journal of general physiology.

[51]  R. Tarran,et al.  The CF salt controversy: in vivo observations and therapeutic approaches. , 2001, Molecular cell.

[52]  J. Pilewski,et al.  Na+ transport in normal and CF human bronchial epithelial cells is inhibited by BAY 39-9437. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[53]  B. Stanton,et al.  Gating of amiloride-sensitive Na(+) channels: subunit-subunit interactions and inhibition by the cystic fibrosis transmembrane conductance regulator. , 2000, Biophysical journal.

[54]  P. Quinton,et al.  Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl- channel function , 1999, Nature.

[55]  R. Schreiber,et al.  Cystic Fibrosis Transmembrane Conductance Regulator Inhibits Epithelial Na+ Channels Carrying Liddle’s Syndrome Mutations* , 1999, The Journal of Biological Chemistry.

[56]  R. Schreiber,et al.  The first-nucleotide binding domain of the cystic-fibrosis transmembrane conductance regulator is important for inhibition of the epithelial Na+ channel. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[57]  S. Randell,et al.  Evidence for Periciliary Liquid Layer Depletion, Not Abnormal Ion Composition, in the Pathogenesis of Cystic Fibrosis Airways Disease , 1998, Cell.

[58]  R. Schreiber,et al.  The amiloride-inhibitable Na+ conductance is reduced by the cystic fibrosis transmembrane conductance regulator in normal but not in cystic fibrosis airways. , 1998, The Journal of clinical investigation.

[59]  L. Schild,et al.  A mutation causing pseudohypoaldosteronism type 1 identifies a conserved glycine that is involved in the gating of the epithelial sodium channel , 1997, The EMBO journal.

[60]  L. Schild,et al.  Identification of a PY motif in the epithelial Na channel subunits as a target sequence for mutations causing channel activation found in Liddle syndrome. , 1996, The EMBO journal.

[61]  J C Olsen,et al.  CFTR as a cAMP-dependent regulator of sodium channels , 1995, Science.

[62]  B. Abella,et al.  Generation and characterization of a ΔF508 cystic fibrosis mouse model , 1995, Nature Genetics.

[63]  B. Grubb,et al.  Ion transport across the jejunum in normal and cystic fibrosis mice. , 1995, The American journal of physiology.

[64]  M. Konstan,et al.  Bronchoalveolar lavage findings in cystic fibrosis patients with stable, clinically mild lung disease suggest ongoing infection and inflammation. , 1994, American journal of respiratory and critical care medicine.

[65]  C. Cotton,et al.  Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr(-/-) mice. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[66]  J. Widdicombe,et al.  Altered fluid transport across airway epithelium in cystic fibrosis. , 1993, Science.

[67]  B. Koller,et al.  An Animal Model for Cystic Fibrosis Made by Gene Targeting , 1992, Science.

[68]  M. Yacoub,et al.  Effect of heart-lung transplantation on airway potential difference in patients with and without cystic fibrosis. , 1991, The European respiratory journal.

[69]  M. Knowles,et al.  Evidence for reduced Cl‐ and increased Na+ permeability in cystic fibrosis human primary cell cultures. , 1988, The Journal of physiology.

[70]  M. Knowles,et al.  Oxygen Consumption and Ouabain Binding Sites in Cystic Fibrosis Nasal Epithelium , 1986, Pediatric Research.

[71]  L. Cantley,et al.  Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation. , 1986, The Journal of clinical investigation.

[72]  M. Knowles,et al.  Abnormal ion permeation through cystic fibrosis respiratory epithelium. , 1983, Science.

[73]  M. Knowles,et al.  Relative ion permeability of normal and cystic fibrosis nasal epithelium. , 1983, The Journal of clinical investigation.

[74]  M. Knowles,et al.  Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. , 1981, The New England journal of medicine.

[75]  H H USSING,et al.  Active transport of sodium as the source of electric current in the short-circuited isolated frog skin. , 1951, Acta physiologica Scandinavica.

[76]  H. Sticht,et al.  A mutation in the β-subunit of ENaC identified in a patient with cystic fibrosis-like symptoms has a gain-of-function effect. , 2013, American journal of physiology. Lung cellular and molecular physiology.

[77]  D. Baines,et al.  Cleavage of endogenous γENaC and elevated abundance of αENaC are associated with increased Na+ transport in response to apical fluid volume expansion in human H441 airway epithelial cells , 2011, Pflügers Archiv - European Journal of Physiology.

[78]  S. Matalon,et al.  Delta-subunit confers novel biophysical features to alpha beta gamma-human epithelial sodium channel (ENaC) via a physical interaction. , 2006, The Journal of biological chemistry.

[79]  Boxer,et al.  An Animal Model , 2005 .

[80]  A. Konstas,et al.  cAMP-dependent activation of CFTR inhibits the epithelial sodium channel (ENaC) without affecting its surface expression , 2002, Pflügers Archiv.

[81]  Ichael,et al.  PULMONARY EPITHELIAL SODIUM-CHANNEL DYSFUNCTION AND EXCESS AIRWAY LIQUID IN PSEUDOHYPOALDOSTERONISM , 2000 .

[82]  R. Boucher,et al.  Pathophysiology of gene-targeted mouse models for cystic fibrosis. , 1999, Physiological reviews.

[83]  J. Gatzy,et al.  Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice. , 1996, Nature genetics.

[84]  B. Abella,et al.  Generation and characterization of a delta F508 cystic fibrosis mouse model. , 1995, Nature genetics.

[85]  M. King,et al.  Aerosolized amiloride as treatment of cystic fibrosis lung disease: a pilot study. , 1991, Advances in experimental medicine and biology.

[86]  M. Knowles,et al.  Abnormal apical cell membrane in cystic fibrosis respiratory epithelium. An in vitro electrophysiologic analysis. , 1987, The Journal of clinical investigation.

[87]  J. A. Acree.  On mutation , 1980 .

[88]  E. Egan,et al.  Changes in non‐electrolyte permeability of alveoli and the absorption of lung liquid at the start of breathing in the lamb. , 1975, The Journal of physiology.