Cellular and Molecular Life Sciences

, Volume 71, Issue 5, pp 831–845 | Cite as

Carbon dioxide-sensing in organisms and its implications for human disease

  • Eoin P. Cummins
  • Andrew C. Selfridge
  • Peter H. Sporn
  • Jacob I. Sznajder
  • Cormac T. Taylor


The capacity of organisms to sense changes in the levels of internal and external gases and to respond accordingly is central to a range of physiologic and pathophysiologic processes. Carbon dioxide, a primary product of oxidative metabolism is one such gas that can be sensed by both prokaryotic and eukaryotic cells and in response to altered levels, elicit the activation of multiple adaptive pathways. The outcomes of activating CO2-sensitive pathways in various species include increased virulence of fungal and bacterial pathogens, prey-seeking behavior in insects as well as taste perception, lung function, and the control of immunity in mammals. In this review, we discuss what is known about the mechanisms underpinning CO2 sensing across a range of species and consider the implications of this for physiology, disease progression, and the possibility of developing new therapeutics for inflammatory and infectious disease.


Carbon dioxide (CO2Hypercapnia Physiological gases Immune regulation NF-kappaB 



C.T. Taylor, E.P. Cummins and A.C. Selfridge are supported by a Science Foundation Ireland (SFI) P.I award to C.T. Taylor. P.H. Sporn (HL-72891) and J.I. Sznajder (HL-85534, HL-48129 and HL 71643) are supported as indicated.


  1. 1.
    Taylor CT, McElwain JC (2010) Ancient atmospheres and the evolution of oxygen sensing via the hypoxia-inducible factor in metazoans. Physiology (Bethesda) 25(5):272–279Google Scholar
  2. 2.
    Monastersky R (2013) Global carbon dioxide levels near worrisome milestone. Nature 497(7447):13–14PubMedGoogle Scholar
  3. 3.
    Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30(4):393–402PubMedGoogle Scholar
  4. 4.
    López-Barneo J et al (2008) Carotid body oxygen sensing. Eur Respir J Off J Eur Soc Clin Respir Physiol 32(5):1386–1398Google Scholar
  5. 5.
    Poulos T (2006) Soluble guanylate cyclase. Curr Opin Struct Biol 16(6):736–743PubMedGoogle Scholar
  6. 6.
    Cooper GM (2000) The cell: a molecular approach, 2nd edn. In: Transport of small molecules. Sinauer Associates, SunderlandGoogle Scholar
  7. 7.
    Perry SF et al (2010) Do zebrafish Rh proteins act as dual ammonia-CO2 channels? J Exp Zool A Ecol Genet Physiol 313(9):618–621PubMedGoogle Scholar
  8. 8.
    Missner A et al (2008) Carbon dioxide transport through membranes. J Biol Chem 283(37):25340–25347PubMedGoogle Scholar
  9. 9.
    Hachez C, Chaumont F (2010) Aquaporins: a family of highly regulated multifunctional channels. Adv Exp Med Biol 679:1–17PubMedGoogle Scholar
  10. 10.
    Musa-Aziz R et al (2009) Relative CO2/NH3 selectivities of AQP1, AQP4, AQP5, AmtB, and RhAG. Proc Natl Acad Sci USA 106(13):5406–5411PubMedGoogle Scholar
  11. 11.
    Uehlein N et al (2003) The tobacco aquaporin NtAQP1 is a membrane CO2 pore with physiological functions. Nature 425(6959):734–737PubMedGoogle Scholar
  12. 12.
    Nakhoul NL et al (1998) Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes. Am J Physiol 274(2 Pt 1):C543–C548PubMedGoogle Scholar
  13. 13.
    Yang B et al (2000) Carbon dioxide permeability of aquaporin-1 measured in erythrocytes and lung of aquaporin-1 null mice and in reconstituted proteoliposomes. J Biol Chem 275(4):2686–2692PubMedGoogle Scholar
  14. 14.
    Boron W et al (2011) Intrinsic CO2 permeability of cell membranes and potential biological relevance of CO2 channels. Chemphyschem Eur J Chem Phys Phys Chem 12(5):1017–1019Google Scholar
  15. 15.
    Kaplan A, Lieman-Hurwitz J, Tchernov D (2004) Resolving the biological role of the Rhesus (Rh) proteins of red blood cells with the aid of a green alga. Proc Natl Acad Sci USA 101(20):7497–7498PubMedGoogle Scholar
  16. 16.
    Soupene E et al (2002) Rhesus expression in a green alga is regulated by CO(2). Proc Natl Acad Sci USA 99(11):7769–7773PubMedGoogle Scholar
  17. 17.
    Wright PA, Wood CM (2009) A new paradigm for ammonia excretion in aquatic animals: role of Rhesus (Rh) glycoproteins. J Exp Biol 212(Pt 15):2303–2312PubMedGoogle Scholar
  18. 18.
    Kustu S, Inwood W (2006) Biological gas channels for NH3 and CO2: evidence that Rh (Rhesus) proteins are CO2 channels. Transfus Clin Biol 13(1–2):103–110PubMedGoogle Scholar
  19. 19.
    Wang XG, Peracchia C (1997) Positive charges of the initial C-terminus domain of Cx32 inhibit gap junction gating sensitivity to CO2. Biophys J 73(2):798–806PubMedCentralPubMedGoogle Scholar
  20. 20.
    Dean JB et al (2002) Role of gap junctions in CO(2) chemoreception and respiratory control. Am J Physiol Lung Cell Mol Physiol 283(4):L665–L670PubMedGoogle Scholar
  21. 21.
    Solomon IC et al (2001) Localization of connexin26 and connexin32 in putative CO(2)-chemosensitive brainstem regions in rat. Respir Physiol 129(1–2):101–121PubMedGoogle Scholar
  22. 22.
    Huckstepp RT et al (2010) CO2-dependent opening of connexin 26 and related beta connexins. J Physiol 588(Pt 20):3921–3931PubMedGoogle Scholar
  23. 23.
    Hester SE et al (2012) Identification of a CO2 responsive regulon in Bordetella. PLoS ONE 7(10):e47635PubMedCentralPubMedGoogle Scholar
  24. 24.
    Skinner JA et al (2004) Bordetella type III secretion and adenylate cyclase toxin synergize to drive dendritic cells into a semimature state. J Immunol 173(3):1934–1940PubMedGoogle Scholar
  25. 25.
    Passalacqua KD et al (2009) Comparative transcriptional profiling of Bacillus cereus sensu lato strains during growth in CO2-bicarbonate and aerobic atmospheres. PLoS ONE 4(3):e4904PubMedCentralPubMedGoogle Scholar
  26. 26.
    Bongiorni C et al (2008) Dual promoters control expression of the Bacillus anthracis virulence factor AtxA. J Bacteriol 190(19):6483–6492PubMedCentralPubMedGoogle Scholar
  27. 27.
    Gohar M et al (2008) The PlcR virulence regulon of Bacillus cereus. PLoS ONE 3(7):e2793PubMedCentralPubMedGoogle Scholar
  28. 28.
    Gilmore RD Jr, Mbow ML, Stevenson B (2001) Analysis of Borrelia burgdorferi gene expression during life cycle phases of the tick vector Ixodes scapularis. Microbes Infect 3(10):799–808PubMedGoogle Scholar
  29. 29.
    Hyde JA, Trzeciakowski JP, Skare JT (2007) Borrelia burgdorferi alters its gene expression and antigenic profile in response to CO2 levels. J Bacteriol 189(2):437–445PubMedCentralPubMedGoogle Scholar
  30. 30.
    Shimamura T, Watanabe S, Sasaki S (1985) Enhancement of enterotoxin production by carbon dioxide in Vibrio cholerae. Infect Immun 49(2):455–456PubMedCentralPubMedGoogle Scholar
  31. 31.
    Abuaita BH, Withey JH (2009) Bicarbonate induces Vibrio cholerae virulence gene expression by enhancing ToxT activity. Infect Immun 77(9):4111–4120PubMedCentralPubMedGoogle Scholar
  32. 32.
    Lotlikar S et al (2013) Three functional β-carbonic anhydrases in P. aeruginosa PAO1. Role in survival in ambient air. Microbiology (Reading, England) (in press)Google Scholar
  33. 33.
    Feller U, Anders I, Mae T (2008) Rubiscolytics: fate of Rubisco after its enzymatic function in a cell is terminated. J Exp Bot 59(7):1615–1624PubMedGoogle Scholar
  34. 34.
    Hu H, Boisson-Dernier A, Israelsson-Nordström M, Böhmer M, Xue S, Ries A, Godoski J, Kuhn JM, Schroeder JI (2010) Carbonic anhydrases are upstream regulators of CO2-controlled stomatal movements in guard cells. Nat Cell Biol 12(1):87–93Google Scholar
  35. 35.
    Xue S et al (2011) Central functions of bicarbonate in S-type anion channel activation and OST1 protein kinase in CO2 signal transduction in guard cell. EMBO J 30(8):1645–1658PubMedGoogle Scholar
  36. 36.
    Frommer WB (2010) Biochemistry. CO2mmon sense. Science 327(5963):275–276PubMedCentralPubMedGoogle Scholar
  37. 37.
    Kim T-H et al (2010) Guard cell signal transduction network: advances in understanding abscisic acid, CO2, and Ca2+ signaling. Annu Rev Plant Biol 61:561–591PubMedCentralPubMedGoogle Scholar
  38. 38.
    Young J et al (2006) CO(2) signaling in guard cells: calcium sensitivity response modulation, a Ca(2+)-independent phase, and CO(2) insensitivity of the gca2 mutant. Proc Natl Acad Sci USA 103(19):7506–7511PubMedGoogle Scholar
  39. 39.
    Du H et al (2012) The transcription factor Flo8 mediates CO2 sensing in the human fungal pathogen Candida albicans. Mol Biol Cell 23(14):2692–2701PubMedCentralPubMedGoogle Scholar
  40. 40.
    Hall RA et al (2010) CO(2) acts as a signalling molecule in populations of the fungal pathogen Candida albicans. PLoS Pathog 6(11):e1001193PubMedCentralPubMedGoogle Scholar
  41. 41.
    Kadosh D, Johnson AD (2001) Rfg1, a protein related to the Saccharomyces cerevisiae hypoxic regulator Rox1, controls filamentous growth and virulence in Candida albicans. Mol Cell Biol 21(7):2496–2505PubMedCentralPubMedGoogle Scholar
  42. 42.
    Allen AM, King RD (1978) Occlusion, carbon dioxide, and fungal skin infections. Lancet 1(8060):360–362PubMedGoogle Scholar
  43. 43.
    Huang G et al (2009) CO(2) regulates white-to-opaque switching in Candida albicans. Curr Biol 19(4):330–334PubMedCentralPubMedGoogle Scholar
  44. 44.
    Mogensen EG et al (2006) Cryptococcus neoformans senses CO2 through the carbonic anhydrase Can2 and the adenylyl cyclase Cac1. Eukaryot Cell 5(1):103–111PubMedCentralPubMedGoogle Scholar
  45. 45.
    Bahn YS et al (2005) Carbonic anhydrase and CO2 sensing during Cryptococcus neoformans growth, differentiation, and virulence. Curr Biol 15(22):2013–2020PubMedGoogle Scholar
  46. 46.
    Granger DL, Perfect JR, Durack DT (1985) Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide. J Clin Invest 76(2):508–516PubMedCentralPubMedGoogle Scholar
  47. 47.
    Zaragoza O, Fries BC, Casadevall A (2003) Induction of capsule growth in Cryptococcus neoformans by mammalian serum and CO(2). Infect Immun 71(11):6155–6164PubMedCentralPubMedGoogle Scholar
  48. 48.
    Ravi S et al (2009) Biofilm formation by Cryptococcus neoformans under distinct environmental conditions. Mycopathologia 167(6):307–314PubMedGoogle Scholar
  49. 49.
    Bahn YS, Muhlschlegel FA (2006) CO2 sensing in fungi and beyond. Curr Opin Microbiol 9(6):572–578PubMedGoogle Scholar
  50. 50.
    Elleuche S, Poggeler S (2010) Carbonic anhydrases in fungi. Microbiology 156(Pt 1):23–29PubMedGoogle Scholar
  51. 51.
    Klengel T et al (2005) Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence. Curr Biol 15(22):2021–2026PubMedCentralPubMedGoogle Scholar
  52. 52.
    Hallem EA, Sternberg PW (2008) Acute carbon dioxide avoidance in Caenorhabditis elegans. Proc Natl Acad Sci USA 105(23):8038–8043PubMedGoogle Scholar
  53. 53.
    Guillermin ML, Castelletto ML, Hallem EA (2011) Differentiation of carbon dioxide-sensing neurons in Caenorhabditis elegans requires the ETS-5 transcription factor. Genetics 189(4):1327–1339PubMedGoogle Scholar
  54. 54.
    Hallem E et al (2011) Receptor-type guanylate cyclase is required for carbon dioxide sensation by Caenorhabditis elegans. Proc Natl Acad Sci USA 108(1):254–259PubMedGoogle Scholar
  55. 55.
    Hallem E et al (2011) A sensory code for host seeking in parasitic nematodes. Curr Biol 21(5):377–383PubMedCentralPubMedGoogle Scholar
  56. 56.
    Bretscher A et al (2011) Temperature, oxygen, and salt-sensing neurons in C. elegans are carbon dioxide sensors that control avoidance behavior. Neuron 69(6):1099–1113PubMedCentralPubMedGoogle Scholar
  57. 57.
    Sharabi K et al (2009) Elevated CO2 levels affect development, motility, and fertility and extend life span in Caenorhabditis elegans. Proc Natl Acad Sci USA 106(10):4024–4029PubMedGoogle Scholar
  58. 58.
    Stange G, Stowe S (1999) Carbon-dioxide sensing structures in terrestrial arthropods. Microsc Res Tech 47(6):416–427PubMedGoogle Scholar
  59. 59.
    Jones WD et al (2007) Two chemosensory receptors together mediate carbon dioxide detection in Drosophila. Nature 445(7123):86–90PubMedGoogle Scholar
  60. 60.
    Dekker T, Geier M, Cardé R (2005) Carbon dioxide instantly sensitizes female yellow fever mosquitoes to human skin odours. J Exp Biol 208(Pt 15):2963–2972PubMedGoogle Scholar
  61. 61.
    Turner S et al (2011) Ultra-prolonged activation of CO2-sensing neurons disorients mosquitoes. Nature 474(7349):87–91PubMedCentralPubMedGoogle Scholar
  62. 62.
    Robertson HM, Kent LB (2009) Evolution of the gene lineage encoding the carbon dioxide receptor in insects. J Insect Sci 9:19PubMedCentralPubMedGoogle Scholar
  63. 63.
    Suh G et al (2004) A single population of olfactory sensory neurons mediates an innate avoidance behaviour in Drosophila. Nature 431(7010):854–859PubMedGoogle Scholar
  64. 64.
    Wasserman S, Salomon A, Frye M (2013) Drosophila tracks carbon dioxide in flight. Curr Biol 23(Pt 4):301–306Google Scholar
  65. 65.
    Suver M, Mamiya A, Dickinson M (2012) Octopamine neurons mediate flight-induced modulation of visual processing in Drosophila. Curr Biol 22(24):2294–2302PubMedGoogle Scholar
  66. 66.
    Helenius IT et al (2009) Elevated CO2 suppresses specific Drosophila innate immune responses and resistance to bacterial infection. Proc Natl Acad Sci USA 106(44):18710–18715PubMedGoogle Scholar
  67. 67.
    Roelofs J, Van Haastert P (2002) Deducing the origin of soluble adenylyl cyclase, a gene lost in multiple lineages. Mol Biol Evol 19(12):2239–2246PubMedGoogle Scholar
  68. 68.
    Perry S, Abdallah S (2012) Mechanisms and consequences of carbon dioxide sensing in fish. Respir Physiol Neurobiol 184(3):309–315PubMedGoogle Scholar
  69. 69.
    Qin Z, Lewis J, Perry S (2010) Zebrafish (Danio rerio) gill neuroepithelial cells are sensitive chemoreceptors for environmental CO2. J Physiol 588(Pt 5):861–872PubMedGoogle Scholar
  70. 70.
    Munday P, McCormick M, Nilsson G (2012) Impact of global warming and rising CO2 levels on coral reef fishes: what hope for the future? J Exp Biol 215(Pt 22):3865–3873PubMedGoogle Scholar
  71. 71.
    Huckstepp R, Dale N (2011) Redefining the components of central CO2 chemosensitivity—towards a better understanding of mechanism. J Physiol 589(Pt 23):5561–5579PubMedGoogle Scholar
  72. 72.
    Forster H et al (2008) The carotid chemoreceptors are a major determinant of ventilatory CO2 sensitivity and of PaCO2 during eupneic breathing. Adv Exp Med Biol 605:322–326PubMedGoogle Scholar
  73. 73.
    Nattie E, Forster H (2010) Special issue on central chemoreception. Foreword. Respir Physiol Neurobiol 173(3):193–194PubMedGoogle Scholar
  74. 74.
    Blain G et al (2010) Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO(2). J Physiol 588(Pt 13):2455–2471PubMedGoogle Scholar
  75. 75.
    Haldane J, Priestley J (1905) The regulation of the lung-ventilation. J Physiol 32(3–4):225–266PubMedGoogle Scholar
  76. 76.
    Ramanantsoa N et al (2011) Breathing without CO(2) chemosensitivity in conditional Phox2b mutants. J Neurosci Off J Soc Neurosci 31(36):12880–12888Google Scholar
  77. 77.
    Briva A et al (2007) High CO2 levels impair alveolar epithelial function independently of pH. PLoS One 2(Pt 11):e1238Google Scholar
  78. 78.
    Vadász I et al (2008) AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and human cells by promoting Na,K-ATPase endocytosis. J Clin Investig 118(2):752–762PubMedGoogle Scholar
  79. 79.
    Welch L et al (2010) Extracellular signal-regulated kinase (ERK) participates in the hypercapnia-induced Na,K-ATPase downregulation. FEBS Lett 584(18):3985–3989PubMedCentralPubMedGoogle Scholar
  80. 80.
    Vadász I et al (2012) Evolutionary conserved role of c-Jun-N-terminal kinase in CO2-induced epithelial dysfunction. PLoS One 7(10):e46696Google Scholar
  81. 81.
    Lecuona E et al (2013) PKA Iα regulates Na,K-ATPase endocytosis in alveolar epithelial cells exposed to high CO2 levels. Am J Respir Cell Mol Biol 48(Pt 5):626–634Google Scholar
  82. 82.
    Chen J et al (2008) Carbonic anhydrase II and alveolar fluid reabsorption during hypercapnia. Am J Respir Cell Mol Biol 38(1):32–37PubMedGoogle Scholar
  83. 83.
    Hu J et al (2007) Detection of near-atmospheric concentrations of CO2 by an olfactory subsystem in the mouse. Science 317(5840):953–957PubMedGoogle Scholar
  84. 84.
    Sun L et al (2009) Guanylyl cyclase-D in the olfactory CO2 neurons is activated by bicarbonate. Proc Natl Acad Sci USA 106(6):2041–2046PubMedGoogle Scholar
  85. 85.
    Chandrashekar J et al (2009) The taste of carbonation. Science (N Y) 326(5951):443–445Google Scholar
  86. 86.
    Vohwinkel CU et al (2012) Elevated CO2 levels cause mitochondrial dysfunction and impair cell proliferation. J Biol Chem 286(Pt 43):37067–37076Google Scholar
  87. 87.
    O’Toole D et al (2009) Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-kappaB-dependent mechanism. Thorax 64(11):976–982PubMedGoogle Scholar
  88. 88.
    Jaitovich ADL, Welch L, Gusorava GA, Sznajder JI (2012) Role of AMP-activated protein kinase (AMPK) in hypercapnia-induced muscle atrophy. Am J Respir Crit Care Med 185:A2013Google Scholar
  89. 89.
    West MA et al (1997) Mechanism of decreased in vitro murine macrophage cytokine release after exposure to carbon dioxide: relevance to laparoscopic surgery. Ann Surg 226(2):179–190PubMedGoogle Scholar
  90. 90.
    Lang CJ et al (2005) Effect of CO2 on LPS-induced cytokine responses in rat alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 289(1):L96–L103PubMedGoogle Scholar
  91. 91.
    Wang N et al (2010) Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage. FASEB J 24(7):2178–2190PubMedGoogle Scholar
  92. 92.
    Hayden MS, Ghosh S (2012) NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26(3):203–234PubMedGoogle Scholar
  93. 93.
    Takeshita K et al (2003) Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation. Am J Respir Cell Mol Biol 29(1):124–132PubMedGoogle Scholar
  94. 94.
    Abolhassani M et al (2009) Carbon dioxide inhalation causes pulmonary inflammation. Am J Physiol Lung Cell Mol Physiol 296(4):L657–L665PubMedGoogle Scholar
  95. 95.
    Li AM et al (2010) Effects of therapeutic hypercapnia on inflammation and apoptosis after hepatic ischemia–reperfusion injury in rats. Chin Med J (Engl) 123(16):2254–2258Google Scholar
  96. 96.
    Oliver KM et al (2012) Hypercapnia induces cleavage and nuclear localization of RelB protein, giving insight into CO2 sensing and signaling. J Biol Chem 287(17):14004–14011PubMedGoogle Scholar
  97. 97.
    Cummins EP et al (2010) NF-kappaB links CO2 sensing to innate immunity and inflammation in mammalian cells. J Immunol 185(7):4439–4445PubMedGoogle Scholar
  98. 98.
    Taylor CT, Cummins EP (2011) Regulation of gene expression by carbon dioxide. J Physiol 589(Pt 4):797–803PubMedGoogle Scholar
  99. 99.
    Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148(3):399–408PubMedCentralPubMedGoogle Scholar
  100. 100.
    Greer SN et al (2012) The updated biology of hypoxia-inducible factor. EMBO J 31(11):2448–2460PubMedGoogle Scholar
  101. 101.
    Broccard AF et al (2001) Protective effects of hypercapnic acidosis on ventilator-induced lung injury. Am J Respir Crit Care Med 164(5):802–806PubMedGoogle Scholar
  102. 102.
    Sinclair SE et al (2002) Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med 166(3):403–408PubMedGoogle Scholar
  103. 103.
    Laffey JG et al (2004) Hypercapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit Care Med 169(1):46–56PubMedGoogle Scholar
  104. 104.
    O’Croinin DF et al (2005) Hypercapnic acidosis does not modulate the severity of bacterial pneumonia-induced lung injury. Crit Care Med 33(11):2606–2612PubMedGoogle Scholar
  105. 105.
    O’Croinin DF et al (2008) Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury. Crit Care Med 36(7):2128–2135PubMedGoogle Scholar
  106. 106.
    Chonghaile MN et al (2008) Hypercapnic acidosis attenuates lung injury induced by established bacterial pneumonia. Anesthesiology 109(5):837–848PubMedGoogle Scholar
  107. 107.
    Nichol AD et al (2009) Infection-induced lung injury is worsened after renal buffering of hypercapnic acidosis. Crit Care Med 37(11):2953–2961PubMedGoogle Scholar
  108. 108.
    Ni Chonghaile M et al (2008) Hypercapnic acidosis attenuates severe acute bacterial pneumonia-induced lung injury by a neutrophil-independent mechanism. Crit Care Med 36(12):3135–3144PubMedGoogle Scholar
  109. 109.
    Gates KL et al (2013) Hypercapnia impairs lung neutrophil function and increases mortality in murine Pseudomonas Pneumonia. Am J Respir Cell Mol Biol (in press)Google Scholar
  110. 110.
    Lindskog S (1997) Structure and mechanism of carbonic anhydrase. Pharmacol Ther 74(1):1–20PubMedGoogle Scholar
  111. 111.
    Lindskog S, Coleman J (1973) The catalytic mechanism of carbonic anhydrase. Proc Natl Acad Sci USA 70(9):2505–2508PubMedGoogle Scholar
  112. 112.
    Aggarwal M et al (2013) Structural annotation of human carbonic anhydrases. J Enzyme Inhib Med Chem 28(2):267–277PubMedGoogle Scholar
  113. 113.
    Kamenetsky M et al (2006) Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol 362(4):623–639PubMedCentralPubMedGoogle Scholar
  114. 114.
    Gehring C (2010) Adenyl cyclases and cAMP in plant signaling—past and present. Cell Commun Signal 8:15PubMedCentralPubMedGoogle Scholar
  115. 115.
    Sassone-Corsi P (2012) The cyclic AMP pathway. Cold Spring Harb Perspect Biol 4(Pt 12):a011148Google Scholar
  116. 116.
    Cook Z, Gray M, Cann M (2012) Elevated carbon dioxide blunts mammalian cAMP signaling dependent on inositol 1,4,5-triphosphate receptor-mediated Ca2+ release. J Biol Chem 287(31):26291–26301PubMedGoogle Scholar
  117. 117.
    Townsend P et al (2009) Stimulation of mammalian G-protein-responsive adenylyl cyclases by carbon dioxide. J Biol Chem 284(2):784–791PubMedGoogle Scholar
  118. 118.
    Buck J, Levin L (2011) Physiological sensing of carbon dioxide/bicarbonate/pH via cyclic nucleotide signaling. Sensors (Basel, Switzerland) 11(2):2112–2128Google Scholar
  119. 119.
    Chen Y et al (2000) Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. Science (N Y) 289(5479):625–628Google Scholar
  120. 120.
    Moser KM, Shibel EM, Beamon AJ (1973) Acute respiratory failure in obstructive lung disease. Long-term survival after treatment in an intensive care unit. JAMA 225(7):705–707PubMedGoogle Scholar
  121. 121.
    Martin TR, Lewis SW, Albert RK (1982) The prognosis of patients with chronic obstructive pulmonary disease after hospitalization for acute respiratory failure. Chest 82(3):310–314PubMedGoogle Scholar
  122. 122.
    Goel A, Pinckney RG, Littenberg B (2003) APACHE II predicts long-term survival in COPD patients admitted to a general medical ward. J Gen Intern Med 18(10):824–830PubMedCentralPubMedGoogle Scholar
  123. 123.
    Groenewegen KH, Schols AM, Wouters EF (2003) Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest 124(2):459–467PubMedGoogle Scholar
  124. 124.
    Sin DD, Man SF, Marrie TJ (2005) Arterial carbon dioxide tension on admission as a marker of in-hospital mortality in community-acquired pneumonia. Am J Med 118(2):145–150PubMedGoogle Scholar
  125. 125.
    Laserna E et al (2012) Hypocapnia and hypercapnia are predictors for ICU admission and mortality in hospitalized patients with community-acquired pneumonia. Chest 142(5):1193–1199PubMedGoogle Scholar
  126. 126.
    Belkin RA et al (2006) Risk factors for death of patients with cystic fibrosis awaiting lung transplantation. Am J Respir Crit Care Med 173(6):659–666PubMedGoogle Scholar
  127. 127.
    Dreyfuss D et al (1988) High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am Rev Respir Dis 137(5):1159–1164PubMedGoogle Scholar
  128. 128.
    Corbridge TC et al (1990) Adverse effects of large tidal volume and low PEEP in canine acid aspiration. Am Rev Respir Dis 142(2):311–315PubMedGoogle Scholar
  129. 129.
    Amato MB et al (1998) Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338(6):347–354PubMedGoogle Scholar
  130. 130.
    ARDSnet (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 342(18):1301–1308Google Scholar
  131. 131.
    Laffey JG, Kavanagh BP (1999) Carbon dioxide and the critically ill—too little of a good thing? Lancet 354(9186):1283–1286PubMedGoogle Scholar
  132. 132.
    Curley GF, Laffey JG, Kavanagh BP (2013) CrossTalk proposal: there is added benefit to providing permissive hypercapnia in the treatment of ARDS. J Physiol 591(Pt 11):2763–2765PubMedGoogle Scholar
  133. 133.
    Curley GF, Laffey JG, Kavanagh BP (2013) Rebuttal from Gerard F. Curley, John G. Laffey and Brian P. Kavanagh. J Physiol 591(Pt 11):2771–2772PubMedGoogle Scholar
  134. 134.
    Beitler JR, Hubmayr RD, Malhotra A (2013) CrossTalk opposing view: there is not added benefit to providing permissive hypercapnia in the treatment of ARDS. J Physiol 591(Pt 11):2767–2769PubMedGoogle Scholar
  135. 135.
    Beitler JR, Hubmayr RD, Malhotra A (2013) Rebuttal from Jeremy R. Beitler, Rolf D. Hubmayr and Atul Malhotra. J Physiol 591(Pt 11):2773PubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Eoin P. Cummins
    • 1
  • Andrew C. Selfridge
    • 1
  • Peter H. Sporn
    • 3
  • Jacob I. Sznajder
    • 3
  • Cormac T. Taylor
    • 1
    • 2
  1. 1.School of Medicine and Medical Science, UCD Conway InstituteUniversity College DublinDublin 4Ireland
  2. 2.Systems Biology IrelandDublin 4Ireland
  3. 3.Division of Pulmonary and Critical Care Medicine, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

Personalised recommendations