Adenosine: Its Contribution to Our Understanding in Airway Inflammation

  • Riccardo Polosa
Part of the Allergy Frontiers book series (ALLERGY, volume 2)


Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as local regulator in airway inflammation and pulmonary diseases. The notion that increased adenosine concentrations are associated with lung inflammation indicates the importance of this signaling pathway, which involves the activation of a family of cell surface G-protein coupled receptor subtypes named as A1, A2A, A2B and A3. These can be identified on a large variety of inflammatory structural cell types with known relevance to the pathogenesis of chronic inflammatory disorders of the airways such as asthma and chronic obstructive pulmonary disease (COPD). As a consequence, new molecules with high affinity and high selectivity for the human adenosine receptors subtypes designed to control the airway inflammatory component of asthma have been launched and are currently tested in clinical trials as anti-asthma treatments. In addition, an important development is the use of adenosine (or AMP) as a diagnostic test for discriminating asthma from COPD, and as an accurate biomarker to monitor corticosteroid requirements in asthma. It is likely that therapies interfering with adenosine signalling in the airways and the availability of adenosine-based diagnostic tests will offer a considerable advance in the management of asthma and COPD.


Mast Cell Airway Inflammation Adenosine Receptor Allergy Clin Immunol Exhale Breath Condensate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ohta A., Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 2001;414:916–920.PubMedCrossRefGoogle Scholar
  2. 2.
    Arch JRS, Newsholme EA. The control of the metabolism and the hormonal role of adenos-ine. Essays Biochem 1978;14:82–123.PubMedGoogle Scholar
  3. 3.
    Blackburn MR, Volmer JB, Thrasher JL, Zhong H, Crosby JR, Lee JJ, Kellems RE. Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction. J Exp Med 2000;192: 159–170.PubMedCrossRefGoogle Scholar
  4. 4.
    Chunn JL, Molina JG, Mi T, Xia Y, Kellems RE, Blackburn MR. Adenosine-dependent pulmonary fibrosis in adenosine deaminase-deficient mice. J Immunol 2005;175:1937–1946.PubMedGoogle Scholar
  5. 5.
    Ma B, Blackburn MR, Lee CG, Homer RJ, Liu W, Flavell RA, Boyden L, Lifton RP, Sun CX, Young HW, Elias JA. Adenosine metabolism and murine strain-specific IL-4-induced inflammation, emphysema, and fibrosis. J Clin Invest 2006;116(5):1274–1283.PubMedCrossRefGoogle Scholar
  6. 6.
    Driver AG, Kukoly CA, Ali S, Mustafa SJ. Adenosine in bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis 1993;148:91–97.PubMedGoogle Scholar
  7. 7.
    Huszar E, Vass G, Vizi E, Csoma Z, Barat E, Molnar Vilagos G, Herjavecz I, Horvath I. Adenosine in exhaled breath condensate in healthy volunteers and in patients with asthma. Eur Respir J 2002;20:1393–1398.PubMedCrossRefGoogle Scholar
  8. 8.
    Cushley MJ, Tattersfield AE, Holgate ST: Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 1983;15:161–165.PubMedGoogle Scholar
  9. 9.
    Oosterhoff Y, de Jong JW, Jansen MA, Koeter GH, Postma DS. Airway responsiveness to adenosine 5′-monophosphate in chronic obstructive pulmonary disease is determined by smoking. Am Rev Respir Dis 1993;147:553–558.PubMedGoogle Scholar
  10. 10.
    Russo C, Arcidiacono G, Polosa R. Adenosine receptors: promising targets for the development of novel therapeutics and diagnostics for asthma. Fundam Clin Pharmacol 2006 Feb;20(1):9–19.PubMedCrossRefGoogle Scholar
  11. 11.
    Spicuzza L, Bonfiglio C, Polosa R. Research applications and implications of adenosine in diseased airways. Trends Pharmacol Sci 2003 Aug;24(8):409–413.PubMedCrossRefGoogle Scholar
  12. 12.
    Holgate ST, Lewis RA., Austen FK. Role of adenylate cyclase in immunologic release of mediators from rat mast cells: agonist and antagonist effects of purine- and ribose-modified adenosine analogs. Proc Natl Acad Sci USA 1980;77:6800–6804.PubMedCrossRefGoogle Scholar
  13. 13.
    Mann JS, Holgate ST, Renwick AG, Cushley MJ. Airway effects of purine nucle-osides and nucleotides and release with bronchial provocation in asthma. J Appl Physiol 1986;61:1667–1676.PubMedGoogle Scholar
  14. 14.
    Phillips GD, Ng WH, Church MK, Holgate ST. The response of plasma histamine to bron-choprovocation with methacholine, adenosine 5′-monophosphate, and allergen in atopic nonasthmatic subjects. Am Rev Respir Dis 1990;141:9–13.PubMedGoogle Scholar
  15. 15.
    Rafferty P, Beasley R, Holgate ST. The contribution of histamine to immediate bronchocon-striction provoked by inhaled allergen and adenosine 5′-monophosphate in atopic asthma. Am Rev Respir Dis 1987;136:369–373.PubMedGoogle Scholar
  16. 16.
    Phillips GD, Polosa R, Holgate ST. The effect of histamine H1 receptor antagonism with terfenadine on concentration-related AMP-induced bronchoconstriction in asthma. Clin Exp Allergy 1989;19:405–409.PubMedCrossRefGoogle Scholar
  17. 17.
    Rorke S, Jennison S, Jeffs JA, Sampson AP, Arshad H, Holgate ST. Role of cysteinyl leu-kotrienes in adenosine 5′-monophosphate induced bronchoconstriction in asthma. Thorax 2002;57:323–327.PubMedCrossRefGoogle Scholar
  18. 18.
    Phillips GD, Holgate ST. The effect of oral terfenadine alone and in combination with flurbi-profen on the bronchoconstrictor response to inhaled adenosine 5′-monophosphate in nonat-opic asthma. Am Rev Respir Dis 1989;139:463–469.PubMedGoogle Scholar
  19. 19.
    Crimi N, Palermo F, Polosa R, Oliveri R, Maccarrone C, Palermo B, Mistretta A. Effect of indomethacin on adenosine-induced bronchoconstriction. J Allergy Clin Immunol 1989;83:921–925.PubMedCrossRefGoogle Scholar
  20. 20.
    Crimi N, Polosa R, Magri S, et al. Inhaled lysine acetylsalicylate (L-ASA) attenuates the bronchoconstrictor response to adenosine 59-monophosphate (AMP) in asthmatic subjects. Eur Respir J 1995;8:905–912.PubMedGoogle Scholar
  21. 21.
    Phillips GD, Scott VL, Richards R, Holgate ST. Effect of nedocromil sodium and sodium cromoglycate against bronchoconstriction induced by inhaled adenosine 5′-monophosphate. Eur Respir J 1989;2:210–217.PubMedGoogle Scholar
  22. 22.
    Richards R, Phillips GD, Holgate ST. Nedocromil sodium is more potent than sodium cro-moglycate against AMP-induced bronchoconstriction in atopic asthmatic subjects. Clin Exp Allergy 1989;19:285–291.PubMedCrossRefGoogle Scholar
  23. 23.
    Persiani S, D'Amato M, Makovec F, Arshad H, Holgate ST, Rovati LC. Pharmacokinetics of andolast after administration of single escalating doses by inhalation in mild asthmatic patients. Biopharm Drug Dispos 2001;22:73–81.PubMedCrossRefGoogle Scholar
  24. 24.
    Polosa R, Lau LCK, Holgate ST. Inhibition of adenosine 5′-monophosphate and methacholine-induced bronchoconstriction in asthma by inhaled frusemide. Eur Respir J 1990;3:665–672.PubMedGoogle Scholar
  25. 25.
    Polosa R, Rajakulasingam K, Prosperini G, Church MK, Holgate ST. Relative potencies and time-courses of changes in AMP airway responsiveness with inhaled frusemide and bumeta-nide in asthma. J Allergy Clin Immunol 1993;92:288–297.PubMedCrossRefGoogle Scholar
  26. 26.
    Polosa R. Inhaled loop diuretics: How do we interpret their modulatory role in asthma? Allergy 1993;48:555–558.PubMedCrossRefGoogle Scholar
  27. 27.
    Polosa R, Ng WH, Crimi N, Vancheri C, Holgate ST, Church MK, Mistretta A. Release of mast cell-derived mediators after endobronchial adenosine challenge in asthma. Am J Respir Crit Care Med 1995;151:624–629.PubMedGoogle Scholar
  28. 28.
    Polosa R, Pagano C, Dokic D, Prosperini G, Church MK, Crimi N. Histamine release upon AMP nasal provocation in allergic subjects. Thorax 1999;54:230–233.PubMedCrossRefGoogle Scholar
  29. 29.
    Zeng D, Prosperini G, Russo C, Spicuzza L, Cacciola RR, Di Maria GU, Polosa R. Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation. J Allergy Clin Immunol 2004;114(2):316–320.PubMedCrossRefGoogle Scholar
  30. 30.
    Polosa R, Ciamarra I, Mangano G, Prosperini G, Pistorio MP, Vancheri C, Crimi N. Bronchial hyperresponsiveness and airway inflammation markers in nonasthmatics with allergic rhinitis. Eur Respir J 2000;15(1):30–35.PubMedCrossRefGoogle Scholar
  31. 31.
    van den Berge M, Meijer RJ, Kerstjens HA, et al. PC20 adenosine 5′-monophosphate is more closely associated with airway inflammation in asthma than PC20 methacholine. Am J Respir Crit Care Med 2001;163:1546–1550.Google Scholar
  32. 32.
    van Den Toorn LM, Prins JB, Overbeek SE, Hoogsteden HC, de Jongste JC. Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000;162(3 Pt 1):953–957.Google Scholar
  33. 33.
    Prieto L, Gutierrez V, Uixera S, Bruno L. Concentrations of exhaled nitric oxide in asthmatics and subjects with allergic rhinitis sensitized to the same pollen allergen. Clin Exp Allergy 2002;32(12):1728–1733.PubMedCrossRefGoogle Scholar
  34. 34.
    van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden HC, Prins JB. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001;164(11):2107–2113.PubMedGoogle Scholar
  35. 35.
    van Velzen E, van den Bos JW, Benckhuijsen JA, van Essel T, de Bruijn R, Aalbers R. Effect of allergen avoidance at high altitude on direct and indirect bronchial hyperresponsiveness and markers of inflammation in children with allergic asthma. Thorax 1996;51(6):582–584.PubMedCrossRefGoogle Scholar
  36. 36.
    Grootendorst DC, Dahlen SE, Van Den Bos JW, Duiverman EJ, Veselic-Charvat M, Vrijlandt EJ, O'Sullivan S, Kumlin M, Sterk PJ, Roldaan AC. Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids. Clin Exp Allergy 2001;31(3):400–408.PubMedCrossRefGoogle Scholar
  37. 37.
    Polosa R, Li Gotti F, Mangano G, Mastruzzo C, Pistorio MP, Crimi N. Monitoring of seasonal variability in bronchial hyper-responsiveness and sputum cell counts in non-asthmatic subjects with rhinitis and effect of specific immunotherapy. Clin Exp Allergy 2003;33(7):873–881.PubMedCrossRefGoogle Scholar
  38. 38.
    Currie GP, Lee DK, Haggart K, Bates CE, Lipworth BJ. Effects of montelukast on surrogate inflammatory markers in corticosteroid-treated patients with asthma. Am J Respir Crit Care Med 2003;167(9):1232–1238.PubMedCrossRefGoogle Scholar
  39. 39.
    Prieto L, Gutierrez V, Colas C, Tabar A, Perez-Frances C, Bruno L, Uixera S. Effect of oma-lizumab on adenosine 5′-monophosphate responsiveness in subjects with allergic asthma. Int Arch Allergy Immunol 2006;139(2):122–131.PubMedCrossRefGoogle Scholar
  40. 40.
    van den Berge M, Kerstjens HA, Meijer RJ, de Reus DM, Koeter GH, Kauffman HF, Postma DS. Corticosteroid-induced improvement in the PC20 of adenosine monophosphate is more closely associated with reduction in airway inflammation than improvement in the PC20 of methacholine. Am J Respir Crit Care Med 2001;164(7):1127–1132.PubMedGoogle Scholar
  41. 41.
    Prosperini G, Rajakulasingam K, Cacciola RR, Spicuzza L, Rorke S, Holgate ST, Di Maria GU, Polosa R. Changes in sputum counts and airway hyperresponsiveness after budesonide: monitoring anti-inflammatory response on the basis of surrogate markers of airway inflammation. J Allergy Clin Immunol 2002;110(6):855–861.PubMedCrossRefGoogle Scholar
  42. 42.
    Ketchell RI, Jensen MW, Lumley P, Wright AM, Allenby MI, O'connor BJ. Rapid effect of inhaled fluticasone propionate on airway responsiveness to adenosine 5′-monophosphate in mild asthma. J Allergy Clin Immunol 2002;110(4):603–606.PubMedCrossRefGoogle Scholar
  43. 43.
    Luijk B, Kempsford RD, Wright AM, Zanen P, Lammers JW. Duration of effect of single-dose inhaled fluticasone propionate on AMP-induced bronchoconstriction. Eur Respir J 2004;23(4):559–564.PubMedCrossRefGoogle Scholar
  44. 44.
    Scichilone N, Deykin A, Pizzichini E, Bellia V, Polosa R. Monitoring response to treatment in asthma management: food for thought. Clin Exp Allergy 2004;34(8):1168–1177.PubMedCrossRefGoogle Scholar
  45. 45.
    Prieto L, Bruno L, Gutierrez V, Uixera S, Perez-Frances C, Lanuza A, Ferrer A. Airway responsiveness to adenosine 5′-monophosphate and exhaled nitric oxide measurements: predictive value as markers for reducing the dose of inhaled corticosteroids in asthmatic subjects. Chest 2003;124(4):1325–1333.PubMedCrossRefGoogle Scholar
  46. 46.
    Volmer JB, Thompson LF, Blackburn MR. Ecto-5′-nucleotidase (CD73)-mediated adenosine production is tissue protective in a model of bleomycin-induced lung injury. J Immunol 2006 Apr 1;176(7):4449–4458.PubMedGoogle Scholar
  47. 47.
    Banerjee SK, Young HW, Volmer JB, Blackburn MR. Gene expression profiling in inflammatory airway disease associated with elevated adenosine. Am J Physiol Lung Cell Mol Physiol 2002 Feb;282(2):L169–82.PubMedGoogle Scholar
  48. 48.
    Polosa R. Adenosine-receptor subtypes: their relevance to adenosine-mediated responses in asthma and COPD. Eur Respir J 2002;20:488–496.PubMedCrossRefGoogle Scholar
  49. 49.
    Thiel M, Caldwell CC, Sitkovsky M V. The critical role of adenosine A2A receptors in down-regulation of inflammation and immunity in the pathogenesis of infectious diseases. Microbes Infect 2003;5(6):515–526.PubMedCrossRefGoogle Scholar
  50. 50.
    Fortin A, Harbour D, Fernandes M, Borgeat P, Bourgoin S. Differential expression of adenos-ine receptors in human neutrophils: up-regulation by specific Th1 cytokines and lipopolysac-charide. J Leukoc Biol 2006 Mar;79(3):574–585.PubMedCrossRefGoogle Scholar
  51. 51.
    Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma. J Allergy Clin Immunol 2003 Nov;112(5):819–827PubMedCrossRefGoogle Scholar
  52. 52.
    Ennis M. Neutrophils in asthma pathophysiology. Curr Allergy Asthma Rep 2003;3(2): 159–165.PubMedCrossRefGoogle Scholar
  53. 53.
    Cronstein BN, Levin RI, Philips M, Hirschhorn R, Abramson SB, Weissmann G. Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors. J Immunol 1992 Apr 1;148(7):2201–2206.PubMedGoogle Scholar
  54. 54.
    Felsch A, Stocker K, Borchard U. Phorbol ester-stimulated adherence of neutrophils to endothelial cells is reduced by adenosine A2 receptor agonists. J Immunol 1995 July 1;155(1):333–338.PubMedGoogle Scholar
  55. 55.
    Zhao Z.Q, Clark KL, Wang N-P, Velez DA, Guyton RA, Vinten-Johansen J. Comparison of AMP579 and adenosine in inhibition of cell-cell interaction between human neutrophil and vascular endothelial cell. Drug Dev Res 2000;49:266–272.CrossRefGoogle Scholar
  56. 56.
    Sullivan GW, Lee DD, Ross WG, DiVietro JA, Lappas CM, Lawrence MB, Linden J. Activation of A2A adenosine receptors inhibits expression of alpha 4/beta 1 integrin (very late antigen-4) on stimulated human neutrophils. J Leukoc Biol 2004 Jan;75(1):127–134.PubMedCrossRefGoogle Scholar
  57. 57.
    Eltzschig HK, Thompson LF, Karhausen J, Cotta RJ, Ibla JC, Robson SC, Colgan SP. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 2004 Dec 15;104(13):3986–92. Epub 2004 Aug 19.PubMedCrossRefGoogle Scholar
  58. 58.
    Cronstein BN, Daguma L, Nichols D, Hutchison AJ, Williams M. The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemo-taxis and inhibit O2 generation, respectively. J Clin Invest 1990 Apr;85(4):1150–1157PubMedCrossRefGoogle Scholar
  59. 59.
    McGarrity ST, Stephenson AH, Webster RO. Regulation of human neutrophil functions by adenine nucleotides. J Immunol 1989 Mar 15;142(6):1986–1994.PubMedGoogle Scholar
  60. 60.
    Cassatella MA. Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol 1999;73:369–509.PubMedCrossRefGoogle Scholar
  61. 61.
    Flamand N, Boudreault S, Picard S, Austin M, Surette ME, Plante H, Krump E, Vallee MJ, Gilbert C, Naccache P, Laviolette M, Borgeat P. Adenosine, a potent natural suppressor of arachidonic acid release and leukotriene biosynthesis in human neutrophils. Am J Respir Crit Care Med 2000 Feb;161(2 Pt 2):S88–94PubMedGoogle Scholar
  62. 62.
    Surette ME, Krump E, Picard S, Borgeat P. Activation of leukotriene synthesis in human neutrophils by exogenous arachidonic acid: inhibition by adenosine A(2a) receptor agonists and crucial role of autocrine activation by leukotriene B(4). Mol Pharmacol 1999 Nov;56(5):1055–1062PubMedGoogle Scholar
  63. 63.
    Thiel M, Chouker A. Acting via A2 receptors, adenosine inhibits the production of tumor necrosis factor-alpha of endotoxin-stimulated human polymorphonuclear leukocytes. J Lab Clin Med 1995 Sept;126(3):275–282PubMedGoogle Scholar
  64. 64.
    McColl SR, St-Onge M, Dussault AA, Laflamme C, Bouchard L, Boulanger J, Pouliot M. Immunomodulatory impact of the A2A adenosine receptor on the profile of chemokines produced by neutrophils. FASEB J 2006 Jan;20(1):187–189.PubMedGoogle Scholar
  65. 65.
    Kohno Y, Sei Y, Koshiba M, Kim HO, Jacobson KA. Induction of apoptosis in HL-60 human promyelocytic leukemia cells by adenosine A(3) receptor agonists. Biochem Biophys Res Commun 1996 Feb 27;219(3):904–910.PubMedCrossRefGoogle Scholar
  66. 66.
    Walker BA, Rocchini C, Boone RH, Ip S, Jacobson MA. Adenosine A2a receptor activation delays apoptosis in human neutrophils. J Immunol 1997 Mar 15;158(6):2926–2931.PubMedGoogle Scholar
  67. 67.
    Yasui K, Agematsu K, Shinozaki K, Hokibara S, Nagumo H, Nakazawa T, Komiyama A. Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J Leukoc Biol 2000 Apr;67(4):529–535.PubMedGoogle Scholar
  68. 68.
    Tetley TD. Macrophages and the pathogenesis of COPD. Chest 2002 May;121(5 Suppl):156S–159S.PubMedCrossRefGoogle Scholar
  69. 69.
    Khoa ND, Montesinos MC, Reiss AB, Delano D, Awadallah N, Cronstein BN. Inflammatory cytokines regulate function and expression of adenosine A(2A) receptors in human monocytic THP-1 cells. J Immunol 2001 Oct 1;167(7):4026–4032.PubMedGoogle Scholar
  70. 70.
    Murphree LJ, Sullivan GW, Marshall MA, Linden J. Lipopolysaccharide rapidly modifies adenosine receptor transcripts in murine and human macrophages: role of NF-kappaB in A(2A) adenosine receptor induction. Biochem J 2005 Nov 1;391(Pt 3):575–580.PubMedGoogle Scholar
  71. 71.
    Nemeth ZH, Lutz CS, Csoka B, Deitch EA, Leibovich SJ, Gause WC, Tone M, Pacher P, Vizi ES, Hasko G. Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism. J Immunol 2005 Dec 15;175(12): 8260–8270.PubMedGoogle Scholar
  72. 72.
    Pike MC, Snyderman R. Transmethylation reactions are required for initial morphologic and biochemical responses of human monocytes to chemoattractants. J Immunol 1981 Oct;127(4):1444–1449.PubMedGoogle Scholar
  73. 73.
    Szabo C, Scott GS, Virag L, Egnaczyk G, Salzman AL, Shanley TP, Hasko G. Suppression of macrophage inflammatory protein (MIP)-1alpha production and collagen-induced arthritis by adenosine receptor agonists. Br J Pharmacol 1998 Sept;125(2):379–387.PubMedCrossRefGoogle Scholar
  74. 74.
    Bouma MG, Stad RK, van den Wildenberg FA, Buurman WA. Differential regulatory effects of adenosine on cytokine release by activated human monocytes. J Immunol 1994 Nov 1;153(9):4159–4168.PubMedGoogle Scholar
  75. 75.
    Majumdar S, Aggarwal BB. Adenosine suppresses activation of nuclear factor-kappaB selectively induced by tumor necrosis factor in different cell types. Oncogene 2003 Feb 27;22(8):1206–1218.PubMedCrossRefGoogle Scholar
  76. 76.
    Nemeth ZH, Leibovich SJ, Deitch EA, Vizi ES, Szabo C, Hasko G. cDNA microarray analysis reveals a nuclear factor-kappaB-independent regulation of macrophage function by adenosine. J Pharmacol Exp Ther 2003 Sept;306(3):1042–1049.PubMedCrossRefGoogle Scholar
  77. 77.
    Sajjadi FG, Takabayashi K, Foster AC, Domingo RC, Firestein GS. Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors. J Immunol 1996 May 1;156(9):3435–3442.PubMedGoogle Scholar
  78. 78.
    Borcherding DR, Peet NP, Munson HR, Zhang H, Hoffman PF, Bowlin TL, Edwards CK 3rd. Carbocyclic nucleosides as inhibitors of human tumor necrosis factor-alpha production: effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996 June 21;39(13):2615–2620.PubMedCrossRefGoogle Scholar
  79. 79.
    Munro R, Ressner R, Stone M, Gessner G, Jarvis MF, Saltzman A. Differential expression of adenosine A2A and A2B receptor subtypes on myeloid U937 and THP-1 cells: Adenosine A2B receptor activation selectively stimulates cAMP formation and inhibition of TNF release in THP-1 cells. Drug Dev Res 1998;44(1):41–47.CrossRefGoogle Scholar
  80. 80.
    Hasko G, Nemeth ZH, Vizi ES, Salzman AL, Szabo C. An agonist of adenosine A3 receptors decreases interleukin-12 and interferon-gamma production and prevents lethality in endotox-emic mice. Eur J Pharmacol 1998 Oct 9;358(3):261–268.PubMedCrossRefGoogle Scholar
  81. 81.
    Bradshaw M, Rutherford MS, Hoeper BJ, McWhinney CD, Borcherding DR, Schook LB, Edwards CK 3rd. Specific transcriptional inhibition of bone marrow-derived macrophage tumor necrosis factor-alpha gene expression and protein production using novel enantiomeric carbocyclic nucleoside analogues. J Pharmacol Exp Ther 1995 June;273(3):1506–1518PubMedGoogle Scholar
  82. 82.
    Sipka S, Kovacs I, Szanto S, Szegedi G, Brugos L, Bruckner G, Jozsef Szentmiklosi A. Adenosine inhibits the release of interleukin-1beta in activated human peripheral mononu-clear cells. Cytokine 2005 Aug 21;31(4):258–263.PubMedCrossRefGoogle Scholar
  83. 83.
    Le Moine O, Stordeur P, Schandene L, Marchant A, de Groote D, Goldman M, Deviere J. Adenosine enhances IL-10 secretion by human monocytes. J Immunol 1996 June 1;156(11):4408–4414.PubMedGoogle Scholar
  84. 84.
    Larche M, Robinson DS, Kay AB. The role of T lymphocytes in the pathogenesis of asthma. J Allergy Clin Immunol 2003 Mar;111(3):450–463.PubMedCrossRefGoogle Scholar
  85. 85.
    Jeffery PK. Lymphocytes, chronic bronchitis and chronic obstructive pulmonary disease. Novartis Found Symp 2001;234:149–61; discussion 161–168.PubMedCrossRefGoogle Scholar
  86. 86.
    Antonysamy MA, Moticka EJ, Ramkumar V. Adenosine acts as an endogenous modulator of IL-2-dependent proliferation of cytotoxic T lymphocytes. J Immunol 1995 Sept 15;155(6):2813–2821.PubMedGoogle Scholar
  87. 87.
    Gessi S, Varani K, Merighi S, Morelli A, Ferrari D, Leung E, Baraldi PG, Spalluto G, Borea PA. Pharmacological and biochemical characterization of A3 adenosine receptors in Jurkat T cells. Br J Pharmacol 2001 Sept;134(1):116–126.PubMedCrossRefGoogle Scholar
  88. 88.
    Mirabet M, Herrera C, Cordero OJ, Mallol J, Lluis C, Franco R. Expression of A2B adeno-sine receptors in human lymphocytes: their role in T cell activation. J Cell Sci 1999 Feb;112 (Pt 4):491–502.PubMedGoogle Scholar
  89. 89.
    Dong RP, Kameoka J, Hegen M, Tanaka T, Xu Y, Schlossman SF, Morimoto C. Characterization of adenosine deaminase binding to human CD26 on T cells and its biologic role in immune response. J Immunol 1996 Feb 15;156(4):1349–1355.PubMedGoogle Scholar
  90. 90.
    Zhang H, Conrad DM, Butler JJ, Zhao C, Blay J, Hoskin DW. Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3′,5′-monophosphate and phosphatases. J Immunol 2004 July 15;173(2):932–944.PubMedGoogle Scholar
  91. 91.
    Majumdar S, Aggarwal BB. Methotrexate suppresses NF-kappaB activation through inhibition of IkappaBalpha phosphorylation and degradation. J Immunol 2001 Sept 1;167(5):2911–2920.PubMedGoogle Scholar
  92. 92.
    Lappas CM, Rieger JM, Linden J. A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4 + T cells. J Immunol 2005 Jan 15;174(2):1073–1080.PubMedGoogle Scholar
  93. 93.
    Erdmann AA, Gao ZG, Jung U, Foley J, Borenstein T, Jacobson KA, Fowler DH. Activation of Th1 and Tc1 cell adenosine A2A receptors directly inhibits IL-2 secretion in vitro and IL-2-driven expansion in vivo. Blood 2005 June 15;105(12):4707–4714.PubMedCrossRefGoogle Scholar
  94. 94.
    Redington AE, Polosa R, Walls AF, Howarth PH, Holgate ST. Role of mast cells and basophils in asthma. Chem Immunol 1995;62:22–59.PubMedCrossRefGoogle Scholar
  95. 95.
    Kay AB. The role of eosinophils in the pathogenesis of asthma. Trends Mol Med 2005 Apr;11(4):148–152.PubMedCrossRefGoogle Scholar
  96. 96.
    Marquardt DL, Parker CE, Sullivan TJ. Potentiation of mast cell mediator release by adeno-sine. J Immunol 1978;120:871–876.PubMedGoogle Scholar
  97. 97.
    Church MK, Pao GJ-K, Holgate ST. Characterisation of histamine secretion from mechanically dispersed human lung mast cells: effects of anti-IgE, calcium ionophore A23187, compound 48/80 and basic polypeptides. J Immunol 1982;129:2116–2121.PubMedGoogle Scholar
  98. 98.
    Peachell PT, Columbo M, Kagey-Sabotka A, Lichtenstein LM, Marone G. Adenosine potentiates mediator release from human lung mast cells. Am Rev Respir Dis 1988;138:1143–1151.PubMedGoogle Scholar
  99. 99.
    Forsythe P, McGarvey LPA, Heaney LG, MacMahon J, Ennis M. Adenosine induces hista-mine release from human BAL mast cells. Clin Sci 1999;96:349–355.PubMedCrossRefGoogle Scholar
  100. 100.
    Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 2001;53:527–552.PubMedGoogle Scholar
  101. 101.
    Ali S, Mustafa SJ, Metzger WJ. Adenosine-induced bronchoconstriction and contraction of airway smooth muscle from allergic rabbits with late-phase airway obstruction: evidence for an inducible adenosine A1 receptor. J Pharmacol Exp Ther 1994;268:1328–1334.PubMedGoogle Scholar
  102. 102.
    El-Hashim A, D'Agostino B, Matera MG, Page C. Characterization of adenosine receptors involved in adenosine-induced bronchoconstriction in allergic rabbits. Br J Pharmacol 1996;119:1262–1268.PubMedGoogle Scholar
  103. 103.
    Nyce JW, Metzger WJ. DNA antisense therapy for asthma in an animal model. Nature 1997;385:721–725.PubMedCrossRefGoogle Scholar
  104. 104.
    Fozard JR, Hannon JP. Species differences in adenosine receptor-mediated bronchoconstric-tor responses. Clin Exp Allergy 2000;30;1213–1220.PubMedCrossRefGoogle Scholar
  105. 105.
    Zhong H, Belardinelli L, Maa T, Feoktistov I, Biaggioni I, Zeng D. A(2B) adenosine receptors increase cytokine release by bronchial smooth muscle cells. Am J Respir Cell Mol Biol 2004;30(1):118–125.PubMedCrossRefGoogle Scholar
  106. 106.
    Sun CX, Young HW, Molina JG, Volmer JB, Schnermann J, Blackburn MR. A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury. J Clin Invest 2005;115(1):35–43.PubMedGoogle Scholar
  107. 107.
    Neely CF, Keith IM. A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung. Am J Physiol 1995;268(6 Pt 1):L1036–46.PubMedGoogle Scholar
  108. 108.
    Neely CF, Jin J, Keith IM. A1-adenosine receptor antagonists block endotoxin-induced lung injury. Am J Physiol 1997;272(2 Pt 1):L353–61.PubMedGoogle Scholar
  109. 109.
    Zhong H, Belardinelli L, Maa T, Zeng D. Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts. Am J Respir Cell Mol Biol 2005;32(1):2–8.PubMedCrossRefGoogle Scholar
  110. 110.
    Wollner A, Wollner S, Smith JB. Acting via A2 receptors, adenosine inhibits the upregula-tion of Mac-1 (Cd11b/CD18) expression on FMLP-stimulated neutrophils. Am J Respir Cell Mol Biol 1993;9:179–185.PubMedGoogle Scholar
  111. 111.
    Fredholm BB, Zhang Y, Van Der Ploeg L. Adenosine A2A receptors mediate the inhibitory effect of adenosine on formyl-Met-Leu-Phe-stimulated respiratory burst in neutrophil leucocytes. Naunyn Schmiedebergs Arch Pharmacol 1996;354:262–267.PubMedCrossRefGoogle Scholar
  112. 112.
    Hannon JP, Bray-French KM, Phillips RM, Fozard JR. Further pharmacological characterization of the adenosine receptor subtype mediating inhibition of oxidative burst in human isolated neutrophils. Drug Dev Res 1998;43(4):214–224.CrossRefGoogle Scholar
  113. 113.
    Koshiba M, Rosin DL, Hatashi N, Linden J, Sitkovsky MV. Patterns of A2A extracellular adenosine receptor expression in different functional subsets of human peripheral T cells. Flow cytometry studies with anti-A2A receptor monoclonal antibodies. Mol Pharmacol 1999;55:614–624.PubMedGoogle Scholar
  114. 114.
    Fozard JR, Ellis KM, Villela Dantas MF, Tigani B, Mazzoni L. Effects of CGS 21680, a selective adenosine A2A receptor agonist, on allergic airways inflammation in the rat. Eur J Pharmacol 2002;438:55–60.CrossRefGoogle Scholar
  115. 115.
    Grant MB, Tarnuzzer RW, Caballero S, Ozeck MJ, Davis MI, Spoerri PE, Feoktistov I, Biaggion I, Shryock JC, Belardinelli L. Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. Circ Res 1999;85(8):699–706.PubMedGoogle Scholar
  116. 116.
    Feoktistov I, Goldstein AE, Ryzhov S, Zeng D, Belardinelli L, Voyno-Yasenetskaya T, Biaggioni I. Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ Res 2002;90(5):531–538.PubMedCrossRefGoogle Scholar
  117. 117.
    Clancy JP, Ruiz FE, Sorscher EJ. Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway. Am J Physiol 1999;276(2 Part 1):C361–C369.PubMedGoogle Scholar
  118. 118.
    Feoktistov I, Biaggioni, I. Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. J Clin Invest 1995;96(4):1979–1986.PubMedCrossRefGoogle Scholar
  119. 119.
    Feoktistov I, Garland EM, Goldstein AE, Zeng D, Belardinelli L, Wells JN, Biaggioni I. Inhibition of human mast cell activation with the novel selective adenosine A(2B) receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX)(2). Biochem Pharmacol 2001;62:1163–1173.PubMedCrossRefGoogle Scholar
  120. 120.
    Feoktistov I, Polosa R, Holgate ST, Biaggioni I. Adenosine A2B receptors: a novel therapeutic target in asthma? Trends Pharmacol Sci 1998;19:148–153.PubMedCrossRefGoogle Scholar
  121. 121.
    Ryzhov S, Goldstein AE, Matafonov A, Zeng D, Biaggioni I, Feoktistov I. Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma. J Immunol 2004;172(12):7726–7733.PubMedGoogle Scholar
  122. 122.
    Dent G, Rabe KF. Theophylline and airway inflammation. Clin Exp Allergy 1998;28(Suppl 3):35–41.PubMedGoogle Scholar
  123. 123.
    Sun C-X, Zhong H, Mohsenin A, Morschl E, Chunn JL, Molina JG, Belardinelli L, Zeng D, Blackburn MR. Role of the A2B adenosine receptor signaling in adenosine dependent pulmonary inflammation and injury. J Clin Invest 2006;116(8):2173–2182.PubMedCrossRefGoogle Scholar
  124. 124.
    Salvatore CA, Tilley SL, Latour AM, Fletcher DS, Koller BH, Jacobson MA. Disruption of the A(3) adenosine receptor gene in mice and its effect on stimulated inflammatory cells. J Biol Chem 2000;275(6):4429–4434.PubMedCrossRefGoogle Scholar
  125. 125.
    Zhong H, Shlykov SG, Molina JG, Sanborn BM, Jacobson MA, Tilley SL, Blackburn MR. Activation of murine lung mast cells by the adenosine A3 receptor. J Immunol 2003;171(1):338–345.PubMedGoogle Scholar
  126. 126.
    Kohno Y, Ji X, Mawhorter SD, Koshiba M, Jacobson KA. Activation of A3 adenosine receptors on human eosinophils elevates intracellular calcium. Blood 1996;88:3569–3574.PubMedGoogle Scholar
  127. 127.
    Walker BA, Jacobson MA, Knight DA, Salvatore CA, Weir T, Zhou D, Bai TR. Adenosine A3 receptor expression and function in eosinophils. Am J Respir Cell Mol Biol 1997;16:531–537.PubMedGoogle Scholar
  128. 128.
    Knight K, Zheng X, Rocchini C, Jacobson M, Bai T, Walker BA. Adenosine A3 receptor stimulation inhibits migration of human eosinophils. J Leukoc Biol 1997;62:465–468.PubMedGoogle Scholar
  129. 129.
    Ezeamuzie CI, Philips E. Adenosine A3 receptors on human eosinophils mediate inhibition of degranulation and superoxide anion release. Br J Pharmacol 1999;127:188–194.PubMedCrossRefGoogle Scholar
  130. 130.
    Reeves JJ, Harris CA, Hayes BP, Butchers PR, Sheehan MJ. Studies on the effects of adeno-sine A3 receptor stimulation on human eosinophils isolated from non-asthmatic or asthmatic donors. Inflamm Res 2000;49:666–672.PubMedCrossRefGoogle Scholar
  131. 131.
    Kay AB, Phipps S, Robinson DS. A role for eosinophils in airway remodelling in asthma. Trends Immunol 2004;25(9):477–482.PubMedCrossRefGoogle Scholar
  132. 132.
    Young HW, Molina JG, Dimina D, Zhong H, Jacobson M, Chan LN, Chan TS, Lee JJ, Blackburn MR. A3 adenosine receptor signaling contributes to airway inflammation and mucus production in adenosine deaminase-deficient mice. J Immunol 2004;173(2):1380–1389.PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Riccardo Polosa
    • 1
  1. 1.Director, Institute of Internal Medicine and Clinical Immunology, S. Marta HospitalUniversity of CataniaCataniaItaly

Personalised recommendations