Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid secretion in airway epithelia

Raised arterial blood CO2 (hypercapnia) is a feature of many lung diseases. CO2 has been shown to act as a cell signalling molecule in human cells, notably by influencing the levels of cell signalling second messengers: cAMP and Ca2+. Hypercapnia reduced cAMP‐stimulated cystic fibrosis transmembrane conductance regulator‐dependent anion and fluid transport in Calu‐3 cells and primary human airway epithelia but did not affect cAMP‐regulated HCO3− transport via pendrin or Na+/HCO3− cotransporters. These results further support the role of CO2 as a cell signalling molecule and suggests CO2‐induced reductions in airway anion and fluid transport may impair innate defence mechanisms of the lungs.

[1]  L. Galietta,et al.  Modulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activity and Genistein Binding by Cytosolic pH* , 2010, The Journal of Biological Chemistry.

[2]  J. Wine,et al.  Evidence that Calu-3 human airway cells secrete bicarbonate. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[3]  Seiko F. Okada,et al.  Coordinated release of nucleotides and mucin from human airway epithelial Calu‐3 cells , 2007, The Journal of physiology.

[4]  P. Marques,et al.  Inorganic plasma with physiological CO2/HCO3- buffer. , 2003, Biomaterials.

[5]  F. Abboud,et al.  Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. , 1989, Journal of applied physiology.

[6]  P. Quinton,et al.  Cytosolic pH regulates G Cl through control of phosphorylation states of CFTR. , 1998, American journal of physiology. Cell physiology.

[7]  E. Chi,et al.  Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. , 2002, American journal of respiratory and critical care medicine.

[8]  J. Sznajder,et al.  Protein kinase A-Iα regulates Na,K-ATPase endocytosis in alveolar epithelial cells exposed to high CO(2) concentrations. , 2013, American journal of respiratory cell and molecular biology.

[9]  J. Sznajder,et al.  AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and human cells by promoting Na,K-ATPase endocytosis. , 2008, The Journal of clinical investigation.

[10]  Robert T. R. Huckstepp,et al.  CO2-dependent opening of an inwardly rectifying K+ channel , 2011, Pflügers Archiv - European Journal of Physiology.

[11]  J. Lordan,et al.  Primary airway epithelial cell culture from lung transplant recipients , 2005, European Respiratory Journal.

[12]  P. Hegyi,et al.  Novel Role for Pendrin in Orchestrating Bicarbonate Secretion in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-expressing Airway Serous Cells* , 2011, The Journal of Biological Chemistry.

[13]  S R Sprang,et al.  Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. , 1997 .

[14]  R. Boucher,et al.  Evidence for airway surface dehydration as the initiating event in CF airway disease , 2007, Journal of internal medicine.

[15]  S. Alper,et al.  Basolateral chloride loading by the anion exchanger type 2: role in fluid secretion by the human airway epithelial cell line Calu‐3 , 2012, The Journal of physiology.

[16]  M. Welsh,et al.  cAMP stimulation of HCO3- secretion across airway epithelia. , 2001, JOP : Journal of the pancreas.

[17]  J. Garrison,et al.  Ionic mechanism of forskolin-induced liquid secretion by porcine bronchi. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[18]  J. Clancy,et al.  Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells. , 2003, American journal of respiratory cell and molecular biology.

[19]  D. Sheppard,et al.  Direct Sensing of Intracellular pH by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl− Channel*♦ , 2009, The Journal of Biological Chemistry.

[20]  J. Sznajder,et al.  High CO2 Levels Impair Alveolar Epithelial Function Independently of pH , 2007, PloS one.

[21]  R. Whyte,et al.  Absent Secretion to Vasoactive Intestinal Peptide in Cystic Fibrosis Airway Glands* , 2002, The Journal of Biological Chemistry.

[22]  J. Wine,et al.  Calu-3: a human airway epithelial cell line that shows cAMP-dependent Cl- secretion. , 1994, The American journal of physiology.

[23]  P. Quinton,et al.  Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. , 2009, The Journal of clinical investigation.

[24]  M. Cann,et al.  A Defined Subset of Adenylyl Cyclases Is Regulated by Bicarbonate Ion* , 2003, Journal of Biological Chemistry.

[25]  S. Fahrenkrug,et al.  Bicarbonate‐dependent chloride transport drives fluid secretion by the human airway epithelial cell line Calu‐3 , 2012, The Journal of physiology.

[26]  Robert T. R. Huckstepp,et al.  CO2‐dependent opening of connexin 26 and related β connexins , 2010, The Journal of physiology.

[27]  G. Livera,et al.  Phosphodiesterase 4D Forms a cAMP Diffusion Barrier at the Apical Membrane of the Airway Epithelium* , 2005, Journal of Biological Chemistry.

[28]  R. Stornetta,et al.  Central CO2 chemoreception and integrated neural mechanisms of cardiovascular and respiratory control. , 2010, Journal of applied physiology.

[29]  J. Liao,et al.  The buffer capacity of airway epithelial secretions , 2014, Front. Physiol..

[30]  O. Soehnlein,et al.  Contribution of Neutrophils to Acute Lung Injury , 2011, Molecular medicine.

[31]  David R. W. Hodgson,et al.  Regulation of prokaryotic adenylyl cyclases by CO2. , 2006, The Biochemical journal.

[32]  Jae Young Choi,et al.  Mucus secretion by single tracheal submucosal glands from normal and cystic fibrosis transmembrane conductance regulator knockout mice , 2007, The Journal of physiology.

[33]  R. Lee,et al.  cAMP-activated Ca2+ signaling is required for CFTR-mediated serous cell fluid secretion in porcine and human airways. , 2010, The Journal of clinical investigation.

[34]  J. Astermark.  Overview of inhibitors. , 2006, Seminars in hematology.

[35]  K. Chergui,et al.  Ability and safety of a heated humidifier to control hypercapnic acidosis in severe ARDS , 2002, Intensive Care Medicine.

[36]  J. Laffey,et al.  Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-&kgr;B–dependent mechanism , 2012, Critical care medicine.

[37]  M. Ishii,et al.  Effects of hypercapnia and hypocapnia on [Ca2+]i mobilization in human pulmonary artery endothelial cells. , 2001, Journal of applied physiology.

[38]  J. Sznajder,et al.  Carbon dioxide-sensing in organisms and its implications for human disease , 2013, Cellular and Molecular Life Sciences.

[39]  W. Brand,et al.  Atmospheric CO 2 , δ(O 2 /N 2 ) and δ 13 CO 2 measurements at Jungfraujoch, Switzerland: results from a flask sampling intercomparison program , 2012 .

[40]  Ashvani K. Singh,et al.  Bicarbonate and Chloride Secretion in Calu-3 Human Airway Epithelial Cells , 1999, The Journal of general physiology.

[41]  C. Supuran,et al.  Bicarbonate‐dependent chloride secretion in Calu‐3 epithelia in response to 7,8‐benzoquinoline , 2003, The Journal of physiology.

[42]  R. V. Lourenço,et al.  Drive and performance of the ventilatory apparatus in chronic obstructive lung disease. , 1968, The New England journal of medicine.

[43]  A. Verkman,et al.  Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis. , 2006, American journal of physiology. Cell physiology.

[44]  J. Wine,et al.  Compartmentalized Cyclic Adenosine 3′,5′-Monophosphate at the Plasma Membrane Clusters PDE3A and Cystic Fibrosis Transmembrane Conductance Regulator into Microdomains , 2010, Molecular biology of the cell.

[45]  N. Joo,et al.  Acid and base secretion in the Calu-3 model of human serous cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[46]  Scott H Randell,et al.  Well-differentiated human airway epithelial cell cultures. , 2005, Methods in molecular medicine.

[47]  T. Kotsimbos,et al.  Metabolic alkalosis contributes to acute hypercapnic respiratory failure in adult cystic fibrosis. , 2003, Chest.

[48]  Robert T. R. Huckstepp,et al.  Connexin hemichannel‐mediated CO2‐dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity , 2010, The Journal of physiology.

[49]  M. Cann,et al.  Elevated Carbon Dioxide Blunts Mammalian cAMP Signaling Dependent on Inositol 1,4,5-Triphosphate Receptor-mediated Ca2+ Release , 2012, The Journal of Biological Chemistry.

[50]  B. Masereel,et al.  An overview of inhibitors of Na(+)/H(+) exchanger. , 2003, European journal of medicinal chemistry.

[51]  N. Wang,et al.  CO2-induced ion and fluid transport in human retinal pigment epithelium , 2009, The Journal of general physiology.

[52]  P. Quinton,et al.  A new role for bicarbonate in mucus formation. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[53]  J. Hurley,et al.  Structure of the adenylyl cyclase catalytic core , 1997, Nature.

[54]  R. Vender,et al.  Severe Hypercapnia in Critically Ill Adult Cystic Fibrosis Patients , 2011, Journal of clinical medicine research.

[55]  M. Johansson,et al.  Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype , 2012, The Journal of experimental medicine.

[56]  W. Boron,et al.  An increase in intracellular calcium concentration that is induced by basolateral CO2 in rabbit renal proximal tubule. , 2003, American journal of physiology. Renal physiology.

[57]  K. Mikoshiba,et al.  IRBIT coordinates epithelial fluid and HCO3- secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct. , 2008, The Journal of clinical investigation.

[58]  R. A. Johnson,et al.  Determination of adenylyl cyclase catalytic activity using single and double column procedures. , 1994, Methods in enzymology.

[59]  Richard C Boucher,et al.  Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[60]  M. Post,et al.  Hypercapnia attenuates ventilator‐induced lung injury via a disintegrin and metalloprotease‐17 , 2014, The Journal of physiology.

[61]  N. Dale,et al.  CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits , 2013, eLife.

[62]  M. Cann,et al.  Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[63]  P. Hegyi,et al.  Substance P inhibits bicarbonate secretion from guinea pig pancreatic ducts by modulating an anion exchanger. , 2003, American journal of physiology. Cell physiology.

[64]  Arturo Briva,et al.  Adenosine triphosphate–dependent calcium signaling during ventilator-induced lung injury is amplified by hypercapnia , 2011, Experimental lung research.

[65]  E. Hickman,et al.  Protein phosphatase 1 coordinates CFTR‐dependent airway epithelial HCO3− secretion by reciprocal regulation of apical and basolateral membrane Cl−‐HCO3− exchangers , 2013, British journal of pharmacology.

[66]  J. Laffey,et al.  Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. , 2000, American journal of respiratory and critical care medicine.

[67]  M. Welsh,et al.  Reduced Airway Surface pH Impairs Bacterial Killing in the Porcine Cystic Fibrosis Lung , 2012, Nature.

[68]  N. Wang,et al.  CO 2-induced ion and fluid transport in human retinal pigment epithelium , 2009 .

[69]  Philip D. Townsend,et al.  Stimulation of Mammalian G-protein-responsive Adenylyl Cyclases by Carbon Dioxide , 2009, Journal of Biological Chemistry.

[70]  J. Laffey,et al.  Hypercapnia Induces Cleavage and Nuclear Localization of RelB Protein, Giving Insight into CO2 Sensing and Signaling* , 2012, The Journal of Biological Chemistry.

[71]  M. Cann,et al.  Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. , 2000, Science.

[72]  A. Bersten,et al.  Hypercapnic acidosis modulates inflammation, lung mechanics, and edema in the isolated perfused lung. , 2007, Journal of critical care.

[73]  R. Boucher,et al.  Receptor‐promoted exocytosis of airway epithelial mucin granules containing a spectrum of adenine nucleotides , 2010, The Journal of physiology.

[74]  W F Boron,et al.  Intracellular pH. , 1981, Physiological reviews.