Adenosine Receptors in the Lungs

  • Amir PellegEmail author
  • Riccardo Polosa
Part of the The Receptors book series (REC, volume 34)


The ubiquitous adenine nucleoside adenosine (Ado), which plays an important role in cellular energetics, is released from cells under physiologic and pathophysiologic conditions. Another source of extracellular Ado is rapid degradation of extracellular adenosine 5′-triphosphate (ATP) by ectoenzymes. Extracellular Ado acts as an autocrine and paracrine agent by the activation of G protein-coupled cell surface receptors (GPCRs), designated as A1, A2A, A2B, and A3. Almost four decades ago, published data have indicated that Ado could play a role in immune-mediated histamine release from pulmonary mast cells. Since then, numerous studies have indicated that Ado’s signal transductions are involved in various pulmonary pathologies including asthma and COPD. This chapter is a succinct review of recent studies in this field.


Adenosine Adenosine receptors Lungs Pulmonary mast cells Asthma COPD 


  1. Aeffner F, Woods PS, Davis IC (2014) Activation of A1-adenosine receptors promotes leukocyte recruitment to the lung and attenuates acute lung injury in mice infected with influenza a/Wsn/33 (H1n1). Virus J Virol 88:10214–10227CrossRefPubMedGoogle Scholar
  2. Aggarwal NR, D’alessio FR, Eto Y et al (2013) Macrophage A2a Adenosinergic receptor modulates oxygen-induced augmentation of murine lung injury. Am J Respir Cell Mol Biol 48:635–646CrossRefPubMedPubMedCentralGoogle Scholar
  3. Alfaro TM, Rodrigues DI, Tome AR et al (2017) Adenosine A2a receptors are up-regulated and control the activation of human alveolar macrophages. Pulm Pharmacol Ther 45:90–94CrossRefPubMedGoogle Scholar
  4. Anvari F, Sharma AK, Fernandez LG et al (2010) Tissue-derived Proinflammatory effect of adenosine A2b receptor in lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 140:871–877CrossRefPubMedPubMedCentralGoogle Scholar
  5. Borea PA, Gessi S, Merighi S et al (2016) Adenosine as a multi-Signalling Guardian angel in human diseases: when where and how does it exert its protective effects? Trends Pharmacol Sci 37:419–434CrossRefPubMedGoogle Scholar
  6. Breschi MC, Blandizzi C, Fogli S et al (2007) In vivo adenosine a(2b) receptor desensitization in Guinea-pig airway smooth muscle: implications for asthma. Eur J Pharmacol 575:149–157CrossRefPubMedGoogle Scholar
  7. Burnstock G, Brouns I, Adriaensen D et al (2012) Purinergic signaling in the airways. Pharmacol Rev 64:834–868CrossRefPubMedGoogle Scholar
  8. Caruso M, Holgate ST, Polosa R (2006) Adenosine Signalling in airways. Curr Opin Pharmacol 6:251–256CrossRefPubMedGoogle Scholar
  9. Caruso M, Varani K, Tringali G et al (2009) Adenosine and adenosine receptors: their contribution to airway inflammation and therapeutic potential in asthma. Curr Med Chem 16:3875–3885CrossRefPubMedGoogle Scholar
  10. Chen Y, Yu X, He Y et al (2017) Activation of A2ar attenuates Bleomycin-induced pulmonary fibrosis via the Sdf-1/Cxcr4 Axis-related pathway. Am J Transl Res 9:4125–4136PubMedPubMedCentralGoogle Scholar
  11. Church MK, Holgate ST (1993) Adenosine-induced bronchoconstriction and its inhibition by Nedocromil sodium. J Allergy Clin Immunol 92:190–194CrossRefPubMedGoogle Scholar
  12. Cushley MJ, Tattersfield AE, Holgate ST (1983) Inhaled adenosine and Guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 15:161–165CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dada L, Gonzalez AR, Urich D et al (2012) Alcohol worsens acute lung injury by inhibiting alveolar sodium transport through the adenosine A1 receptor. PLoS One 7:E30448CrossRefPubMedPubMedCentralGoogle Scholar
  14. Dai Y, Zhang W, Wen J et al (2011) A2b adenosine receptor-mediated induction of Il-6 promotes Ckd. J Am Soc Nephrol 22:890–901CrossRefPubMedPubMedCentralGoogle Scholar
  15. Davies J, Karmouty-Quintana H, Le TT et al (2014) Adenosine promotes vascular barrier function in Hyperoxic lung injury. Physiol Rep 2:e12155CrossRefPubMedPubMedCentralGoogle Scholar
  16. Della Latta V, Cabiati M, Rocchiccioli S et al (2013) The role of the Adenosinergic system in lung fibrosis. Pharmacol Res 76:182–189CrossRefPubMedGoogle Scholar
  17. Della Latta V, Cecchettini A, Del Ry S et al (2015) Bleomycin in the setting of lung fibrosis induction: from biological mechanisms to counteractions. Pharmacol Res 97:122–130CrossRefPubMedGoogle Scholar
  18. Eckle T, Grenz A, Laucher S et al (2008) A2b adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J Clin Invest 118:3301–3315PubMedPubMedCentralGoogle Scholar
  19. Eckle T, Koeppen M, Eltzschig HK (2009) Role of extracellular adenosine in acute lung injury. Physiology (Bethesda) 24:298–306Google Scholar
  20. Factor P, Mutlu GM, Chen et al (2007) Adenosine regulation of alveolar fluid clearance. Proc Natl Acad Sci U S A 104:4083–4088CrossRefPubMedPubMedCentralGoogle Scholar
  21. Fan R, Huang XY, Du KY et al (2016) The regulative Effcets of A2a adenosine receptor on expression of Socs-3 in rats of hypoxic pulmonary hypertension. Zhonghua Jie He He Hu Xi Za Zhi 39:469–473PubMedGoogle Scholar
  22. Fernandez LG, Sharma AK, Lapar DJ et al (2013a) Adenosine A1 receptor activation attenuates lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 145:1654–1659CrossRefPubMedPubMedCentralGoogle Scholar
  23. Fernandez P, Perez-Aso M, Smith G et al (2013b) Extracellular generation of adenosine by the Ectonucleotidases Cd39 and Cd73 promotes dermal fibrosis. Am J Pathol 183:1740–1746CrossRefPubMedPubMedCentralGoogle Scholar
  24. Franco R, Casado V, Ciruela F et al (1997) Cell surface adenosine Deaminase: much more than an Ectoenzyme. Prog Neurobiol 52:283–294CrossRefPubMedGoogle Scholar
  25. Fredholm BB, Ap IJ, Jacobson KA et al (2001) International union of pharmacology xxv nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552PubMedGoogle Scholar
  26. Gazoni LM, Walters DM, Unger EB et al (2010) Activation of A1-A2a or A3 adenosine receptors attenuates lung ischemia-reperfusion injury. J Thorac Cardiovasc Surg 140:440–446CrossRefPubMedPubMedCentralGoogle Scholar
  27. Gomez G, Zhao W, Schwartz LB (2011) Disparity in Fcepsilonri-induced degranulation of primary human lung and skin mast cells exposed to adenosine. J Clin Immunol 31:479–487CrossRefPubMedPubMedCentralGoogle Scholar
  28. Gonzales JN, Gorshkov B, Varn MN et al (2014) Protective effect of adenosine receptors against lipopolysaccharide-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 306:L497–L507CrossRefPubMedPubMedCentralGoogle Scholar
  29. Gottlieb SS, Ticho B, Deykin A et al (2011) Effects of Bg9928-an adenosine a(1) receptor antagonist in patients with congestive heart failure. J Clin Pharmacol 51:899–907CrossRefPubMedGoogle Scholar
  30. Haeusler D, Grassinger L, Fuchshuber F et al (2015) Hide and seek: a comparative autoradiographic in vitro investigation of the adenosine A3 receptor. Eur J Nucl Med Mol Imaging 42:928–939CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hasko G, Pacher P (2008) A2a receptors in inflammation and injury: lessons learned from transgenic animals. J Leukoc Biol 83:447–455CrossRefPubMedGoogle Scholar
  32. Hoegl S, Brodsky KS, Blackburn MR et al (2015) Alveolar epithelial A2b adenosine receptors in pulmonary protection during acute lung injury. J Immunol 195:1815–1824CrossRefPubMedPubMedCentralGoogle Scholar
  33. Huang X, Wu P, Huang F et al (2017) Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2a receptor-induced Sdf-1/Cxcr4/Pi3k/Akt signaling. J Biomed Sci 24:52CrossRefPubMedPubMedCentralGoogle Scholar
  34. Karmouty-Quintana H, Xia Y, Blackburn MR (2013) Adenosine signaling during acute and chronic disease states. J Mol Med (Berl) 91:173–181CrossRefGoogle Scholar
  35. Konrad FM, Meichssner N, Bury A et al (2017) Inhibition of Sdf-1 receptors Cxcr4 and Cxcr7 attenuates acute pulmonary inflammation via the adenosine A2b-receptor on blood cells. Cell Death Dis 8:E2832CrossRefPubMedPubMedCentralGoogle Scholar
  36. Liu H, Zhang Y, Wu et al (2016) Beneficial role of erythrocyte adenosine A2b receptor-mediated amp-activated protein kinase activation in high-altitude hypoxia. Circulation 134:405–421CrossRefPubMedGoogle Scholar
  37. Mann JS, Cushley MJ, Holgate ST (1985) Adenosine-induced bronchoconstriction in asthma role of parasympathetic stimulation and adrenergic inhibition. Am Rev Respir Dis 132:1–6PubMedGoogle Scholar
  38. Mediavilla-Varela M, Castro J, Chiappori A et al (2017) A novel antagonist of the immune checkpoint protein adenosine A2a receptor restores tumor-infiltrating lymphocyte activity in the context of the tumor microenvironment. Neoplasia 19:530–536CrossRefPubMedPubMedCentralGoogle Scholar
  39. Metsola J, Maksimow M, Ojaniemi M et al (2014) Postnatal development and Lps responsiveness of pulmonary adenosine receptor expression and of adenosine-metabolizing enzymes in mice. Pediatr Res 76:515–521CrossRefPubMedGoogle Scholar
  40. Mulloy DP, Sharma AK, Fernandez LG et al (2013) Adenosine A3 receptor activation attenuates lung ischemia-reperfusion injury. Ann Thorac Surg 95:1762–1767CrossRefPubMedPubMedCentralGoogle Scholar
  41. Nadeem A, Fan M, Ansari HR et al (2007) Enhanced airway reactivity and inflammation in A2a adenosine receptor-deficient allergic mice. Am J Physiol Lung Cell Mol Physiol 292:L1335–L1344CrossRefPubMedGoogle Scholar
  42. Neely CF, Haile DM, Cahill BE et al (1991) Adenosine and Atp produce vasoconstriction in the feline pulmonary vascular bed by different mechanisms. J Pharmacol Exp Ther 258:753–761PubMedGoogle Scholar
  43. Neely CF, Keith IM (1995) A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung. Am J Phys 268:L1036–L1046Google Scholar
  44. Ngamsri KC, Wagner R, Vollmer I et al (2010) Adenosine receptor A1 regulates Polymorphonuclear cell trafficking and microvascular permeability in lipopolysaccharide-induced lung injury. J Immunol 185:4374–4384CrossRefPubMedGoogle Scholar
  45. Nishi H, Pelleg A, Schulman ES (2016) Ige receptor-mediated histamine release in human lung mast cells: modulation by Purinergic receptor ligands. Ann Clin Lab Sci 46:463–469PubMedGoogle Scholar
  46. Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in Downregulation of inflammation and protection from tissue damage. Nature 414:916–920CrossRefPubMedGoogle Scholar
  47. Ongini E, Fredholm BB (1996) Pharmacology of adenosine A2a receptors. Trends Pharmacol Sci 17:364–372CrossRefPubMedGoogle Scholar
  48. Pelleg A, Hurt CM, Hewlett EL (1996) Atp shortens atrial action potential duration in the dog: role of adenosine the Vagus nerve and G protein. Can J Physiol Pharmacol 74:15–22CrossRefPubMedGoogle Scholar
  49. Pelleg A, Schulman ES (2002) Adenosine 5′-triphosphate Axis in obstructive airway diseases. Am J Ther 9:454–464CrossRefPubMedGoogle Scholar
  50. Petty JM, Sueblinvong V, Lenox CC et al (2007) Pulmonary stromal-derived Factor-1 expression and effect on neutrophil recruitment during acute lung injury. J Immunol 178:8148–8157CrossRefPubMedGoogle Scholar
  51. Philip K, Mills TW, Davies J et al (2017) Hif1a up-regulates the Adora2b receptor on alternatively activated macrophages and contributes to pulmonary fibrosis. FASEB J 31:4745–4758CrossRefPubMedGoogle Scholar
  52. Polosa R, Blackburn MR (2009) Adenosine receptors as targets for therapeutic intervention in asthma and chronic obstructive pulmonary disease. Trends Pharmacol Sci 30:528–535CrossRefPubMedPubMedCentralGoogle Scholar
  53. Polosa R, Ng WH, Crimi N et al (1995) Release of mast-cell-derived mediators after Endobronchial adenosine challenge in asthma. Am J Respir Crit Care Med 151:624–629PubMedGoogle Scholar
  54. Qian G, Cao J, Chen C et al (2013) Paeoniflorin inhibits pulmonary artery smooth muscle cells proliferation via Upregulating A2b adenosine receptor in rat. PLoS One 8:E69141CrossRefPubMedPubMedCentralGoogle Scholar
  55. Rath D, Chatterjee M, Borst O et al (2014) Expression of stromal cell-derived Factor-1 receptors Cxcr4 and Cxcr7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. Eur Heart J 35:386–394CrossRefPubMedGoogle Scholar
  56. Rudich N, Dekel O, Sagi-Eisenberg R (2015) Down-regulation of the A3 adenosine receptor in human mast cells Upregulates mediators of angiogenesis and remodeling. Mol Immunol 65:25–33CrossRefPubMedGoogle Scholar
  57. Sands WA, Woolson HD, Milne GR et al (2006) Exchange protein activated by cyclic amp (Epac)-mediated induction of suppressor of cytokine signaling 3 (Socs-3) in vascular endothelial cells. Mol Cell Biol 26:6333–6346CrossRefPubMedPubMedCentralGoogle Scholar
  58. Schepp CP, Reutershan J (2008) Bench-to-bedside review: adenosine receptors--promising targets in acute lung injury? Crit Care 12:226CrossRefPubMedPubMedCentralGoogle Scholar
  59. Schingnitz U, Hartmann K, Macmanus CF et al (2010) Signaling through the A2b adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol 184:5271–5279CrossRefPubMedPubMedCentralGoogle Scholar
  60. Smail H, Baste JM, Gay A et al (2016) Role of inflammatory cells and adenosine in lung ischemia Reoxygenation injury using a model of lung donation after cardiac death. Exp Lung Res 42:131–141CrossRefPubMedGoogle Scholar
  61. Sun CX, Young HW, Molina JG et al (2005) A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury. J Clin Invest 115:35–43CrossRefPubMedPubMedCentralGoogle Scholar
  62. Thiel M, Chouker A, Ohta A et al (2005) Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol 3:E174CrossRefPubMedPubMedCentralGoogle Scholar
  63. Thorn JA, Jarvis SM (1996) Adenosine Transporters. Gen Pharmacol 27:613–620CrossRefPubMedGoogle Scholar
  64. Wilson CN, Nadeem A, Spina D et al (2009) Adenosine receptors and asthma. Handb Exp Pharmacol 329:362Google Scholar
  65. Zhou Y, Schneider DJ, Blackburn MR (2009) Adenosine signaling and the regulation of chronic lung disease. Pharmacol Ther 123:105–116CrossRefPubMedPubMedCentralGoogle Scholar
  66. Zimmermann H (2000) Extracellular metabolism of Atp and other nucleotides. Naunyn Schmiedeberg's Arch Pharmacol 362:299–309CrossRefGoogle Scholar
  67. Zimmermann H, Zebisch M, Strater N (2012) Cellular function and molecular structure of Ecto-Nucleotidases. Purinergic Signal 8:437–502CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of MedicineDrexel University College of Medicine PhiladelphiaPhiladelphiaUSA
  2. 2.Department of Clinical and Sperimental MedicineUniversity of CataniaCataniaItaly

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