Journal of Molecular Medicine

, Volume 91, Issue 2, pp 173–181 | Cite as

Adenosine signaling during acute and chronic disease states

  • Harry Karmouty-Quintana
  • Yang Xia
  • Michael R. Blackburn


Adenosine is a signaling nucleoside that is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs. There are four adenosine receptors that are widely distributed on immune, epithelial, endothelial, neuronal,and stromal cells throughout the body. Interestingly, these receptors are subject to altered regulation following injury. Studies in mouse models and human cells and tissues have identified that the production of adenosine and its subsequent signaling through its receptors plays largely beneficial roles in acute disease states, with the exception of brain injury. In contrast, if elevated adenosine levels are sustained beyond the acute injury phase, adenosine responses can become detrimental by activating pathways that promote tissue injury and fibrosis. Understanding when during the course of disease adenosine signaling is beneficial as opposed to detrimental and defining the mechanisms involved will be critical for the advancement of adenosine-based therapies for acute and chronic diseases. The purpose of this review is to discuss key observations that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes, such as inflammatory cell regulation, vascular barrier function, and tissue fibrosis.


Adenosine receptors Inflammation Fibrosis Vascular barrier function CD73 ADORA2B ADORA2A ADORA3 ADORA1 Acute lung injury Remodeling Anti-inflammatory 



We would like to thank Tingting Weng and Kelly Volcik for their assistance in preparing and reviewing this manuscript. We would also like to acknowledge the following grant support: National Institute of Health Grants HL070952 to M.R.B. and DK083559 to Y.X. and American Heart Association Grant 12IRG9150001 to Y.X..

Conflict of interest

The authors have declared no conflict of interest.


  1. 1.
    Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364:656–665PubMedCrossRefGoogle Scholar
  2. 2.
    Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF, Eltzschig HK (2008) A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 111:2024–2035PubMedCrossRefGoogle Scholar
  3. 3.
    Schingnitz U, Hartmann K, Macmanus CF, Eckle T, Zug S, Colgan SP, Eltzschig HK (2010) Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol 184:5271–5279PubMedCrossRefGoogle Scholar
  4. 4.
    Eckle T, Grenz A, Laucher S, Eltzschig HK (2008) A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J Clin Invest 118:3301–3315PubMedGoogle Scholar
  5. 5.
    Zhou Y, Schneider DJ, Morschl E, Song L, Pedroza M, Karmouty-Quintana H, Le T, Sun CX, Blackburn MR (2010) Distinct roles for the A2B adenosine receptor in acute and chronic stages of bleomycin-induced lung injury. J Immunol 186:1097–1106PubMedCrossRefGoogle Scholar
  6. 6.
    Sharma AK, Linden J, Kron IL, Laubach VE (2009) Protection from pulmonary ischemia–reperfusion injury by adenosine A2A receptor activation. Respir Res 10:58PubMedCrossRefGoogle Scholar
  7. 7.
    Okusa MD, Linden J, Macdonald T, Huang L (1999) Selective A2A adenosine receptor activation reduces ischemia–reperfusion injury in rat kidney. Am J Physiol 277:F404–F412PubMedGoogle Scholar
  8. 8.
    Grenz A, Osswald H, Eckle T, Yang D, Zhang H, Tran ZV, Klingel K, Ravid K, Eltzschig HK (2008) The reno-vascular A2B adenosine receptor protects the kidney from ischemia. PLoS Med 5:e137PubMedCrossRefGoogle Scholar
  9. 9.
    Day YJ, Huang L, McDuffie MJ, Rosin DL, Ye H, Chen JF, Schwarzschild MA, Fink JS, Linden J, Okusa MD (2003) Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived cells. J Clin Invest 112:883–891PubMedGoogle Scholar
  10. 10.
    Eckle T, Krahn T, Grenz A, Kohler D, Mittelbronn M, Ledent C, Jacobson MA, Osswald H, Thompson LF, Unertl K et al (2007) Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors. Circulation 115:1581–1590PubMedCrossRefGoogle Scholar
  11. 11.
    Yang Z, Day YJ, Toufektsian MC, Xu Y, Ramos SI, Marshall MA, French BA, Linden J (2006) Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation 114:2056–2064PubMedCrossRefGoogle Scholar
  12. 12.
    Eltzschig HK, Rivera-Nieves J, Colgan SP (2009) Targeting the A2B adenosine receptor during gastrointestinal ischemia and inflammation. Expert Opin Ther Targets 13:1267–1277PubMedCrossRefGoogle Scholar
  13. 13.
    Day YJ, Marshall MA, Huang L, McDuffie MJ, Okusa MD, Linden J (2004) Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. Am J Physiol Gastrointest Liver Physiol 286:G285–G293PubMedCrossRefGoogle Scholar
  14. 14.
    Zhou Y, Schneider DJ, Blackburn MR (2009) Adenosine signaling and the regulation of chronic lung disease. Pharmacol Ther 123:105–116PubMedCrossRefGoogle Scholar
  15. 15.
    Chunn JL, Molina JG, Mi T, Xia Y, Kellems RE, Blackburn MR (2005) Adenosine-dependent pulmonary fibrosis in adenosine deaminase-deficient mice. J Immunol 175:1937–1946PubMedGoogle Scholar
  16. 16.
    Sun CX, Zhong H, Mohsenin A, Morschl E, Chunn JL, Molina JG, Belardinelli L, Zeng D, Blackburn MR (2006) Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury. J Clin Invest 116:2173–2182PubMedCrossRefGoogle Scholar
  17. 17.
    Zaynagetdinov R, Ryzhov S, Goldstein AE, Yin H, Novitskiy SV, Goleniewska K, Polosukhin VV, Newcomb DC, Mitchell D, Morschl E et al (2010) Attenuation of chronic pulmonary inflammation in A2B adenosine receptor knockout mice. Am J Respir Cell Mol Biol 42:564–571PubMedCrossRefGoogle Scholar
  18. 18.
    Chunn JL, Mohsenin A, Young HW, Lee CG, Elias JA, Kellems RE, Blackburn MR (2006) Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am J Physiol Lung Cell Mol Physiol 290:L579–L587PubMedCrossRefGoogle Scholar
  19. 19.
    Peng Z, Borea PA, Varani K, Wilder T, Yee H, Chiriboga L, Blackburn MR, Azzena G, Resta G, Cronstein BN (2009) Adenosine signaling contributes to ethanol-induced fatty liver in mice. J Clin Invest 119:582–594PubMedCrossRefGoogle Scholar
  20. 20.
    Chan ES, Fernandez P, Merchant AA, Montesinos MC, Trzaska S, Desai A, Tung CF, Khoa DN, Pillinger MH, Reiss AB et al (2006) Adenosine A2A receptors in diffuse dermal fibrosis: pathogenic role in human dermal fibroblasts and in a murine model of scleroderma. Arthritis Rheum 54:2632–2642PubMedCrossRefGoogle Scholar
  21. 21.
    Dai Y, Zhang W, Wen J, Zhang Y, Kellems RE, Xia Y (2011) A2B adenosine receptor-mediated induction of IL-6 promotes CKD. J Am Soc Nephrol 22:890–901PubMedCrossRefGoogle Scholar
  22. 22.
    Wen J, Jiang X, Dai Y, Zhang Y, Tang Y, Sun H, Mi T, Phatarpekar PV, Kellems RE, Blackburn MR et al (2011) Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling. FASEB J 24:740–749CrossRefGoogle Scholar
  23. 23.
    Mi T, Abbasi S, Zhang H, Uray K, Chunn JL, Xia LW, Molina JG, Weisbrodt NW, Kellems RE, Blackburn MR et al (2008) Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling. J Clin Invest 118:1491–1501PubMedCrossRefGoogle Scholar
  24. 24.
    Zhao Y, LaPar DJ, Steidle J, Emaminia A, Kron IL, Ailawadi G, Linden J, Lau CL (2010) Adenosine signaling via the adenosine 2B receptor is involved in bronchiolitis obliterans development. J Heart Lung Transpl 29:1405–1414CrossRefGoogle Scholar
  25. 25.
    Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5:247–264PubMedCrossRefGoogle Scholar
  26. 26.
    Kalla RV, Zablocki J (2009) Progress in the discovery of selective, high affinity A(2B) adenosine receptor antagonists as clinical candidates. Purinergic Signal 5:21–29PubMedCrossRefGoogle Scholar
  27. 27.
    Armentero MT, Pinna A, Ferre S, Lanciego JL, Muller CE, Franco R (2011) Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson’s disease. Pharmacol Ther 132:280–299PubMedCrossRefGoogle Scholar
  28. 28.
    Colgan SP, Eltzschig HK, Eckle T, Thompson LF (2006) Physiological roles for ecto-5′-nucleotidase (CD73). Purinergic Signal 2:351–360PubMedCrossRefGoogle Scholar
  29. 29.
    Hart ML, Gorzolla IC, Schittenhelm J, Robson SC, Eltzschig HK (2010) SP1-dependent induction of CD39 facilitates hepatic ischemic preconditioning. J Immunol 184:4017–4024PubMedCrossRefGoogle Scholar
  30. 30.
    Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, Hansen KR, Thompson LF, Colgan SP (2002) Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest 110:993–1002PubMedGoogle Scholar
  31. 31.
    Jackson EK, Ren J, Mi Z (2009) Extracellular 2′,3′-cAMP is a source of adenosine. J Biol Chem 284:33097–33106PubMedCrossRefGoogle Scholar
  32. 32.
    Volmer JB, Thompson LF, Blackburn MR (2006) Ecto-5′-nucleotidase (CD73)-mediated adenosine production is tissue protective in a model of bleomycin-induced lung injury. J Immunol 176:4449–4458PubMedGoogle Scholar
  33. 33.
    Ohta A, Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414:916–920PubMedCrossRefGoogle Scholar
  34. 34.
    Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Muller CE (2011) International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receptors–an update. Pharmacol Rev 63:1–34PubMedCrossRefGoogle Scholar
  35. 35.
    Friedman DJ, Kunzli BM, Yi AR, Sevigny J, Berberat PO, Enjyoji K, Csizmadia E, Friess H, Robson SC (2009) From the cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc Natl Acad Sci U S A 106:16788–16793PubMedCrossRefGoogle Scholar
  36. 36.
    Thompson LF, Eltzschig HK, Ibla JC, Van De Wiele CJ, Resta R, Morote-Garcia JC, Colgan SP (2004) Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med 200:1395–1405PubMedCrossRefGoogle Scholar
  37. 37.
    Hart ML, Grenz A, Gorzolla IC, Schittenhelm J, Dalton JH, Eltzschig HK (2011) Hypoxia-inducible factor-1alpha-dependent protection from intestinal ischemia/reperfusion injury involves ecto-5′-nucleotidase (CD73) and the A2B adenosine receptor. J Immunol 186:4367–4374PubMedCrossRefGoogle Scholar
  38. 38.
    Eckle T, Fullbier L, Wehrmann M, Khoury J, Mittelbronn M, Ibla J, Rosenberger P, Eltzschig HK (2007) Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury. J Immunol 178:8127–8137PubMedGoogle Scholar
  39. 39.
    Loffler M, Morote-Garcia JC, Eltzschig SA, Coe IR, Eltzschig HK (2007) Physiological roles of vascular nucleoside transporters. Arterioscler Thromb Vasc Biol 27:1004–1013PubMedCrossRefGoogle Scholar
  40. 40.
    Grenz A, Bauerle JD, Dalton JH, Ridyard D, Badulak A, Tak E, McNamee EN, Clambey E, Moldovan R, Reyes G et al (2012) Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. J Clin Invest 122:693–710PubMedCrossRefGoogle Scholar
  41. 41.
    Sitkovsky MV, Ohta A (2005) The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends Immunol 26:299–304PubMedCrossRefGoogle Scholar
  42. 42.
    Hasko G, Cronstein BN (2004) Adenosine: an endogenous regulator of innate immunity. Trends Immunol 25:33–39PubMedCrossRefGoogle Scholar
  43. 43.
    Blackburn MR, Vance CO, Morschl E, Wilson CN (2009) Adenosine receptors and inflammation. Handb Exp Pharmacol 215–269Google Scholar
  44. 44.
    Lappas CM, Rieger JM, Linden J (2005) A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 174:1073–1080PubMedGoogle Scholar
  45. 45.
    Raskovalova T, Lokshin A, Huang X, Jackson EK, Gorelik E (2006) Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I). Immunol Res 36:91–99PubMedCrossRefGoogle Scholar
  46. 46.
    Wallace KL, Linden J (2010) Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease. Blood 116:5010–5020PubMedCrossRefGoogle Scholar
  47. 47.
    Hasko G, Kuhel DG, Chen JF, Schwarzschild MA, Deitch EA, Mabley JG, Marton A, Szabo C (2000) Adenosine inhibits IL-12 and TNF-[alpha] production via adenosine A2a receptor-dependent and independent mechanisms. FASEB J 14:2065–2074PubMedCrossRefGoogle Scholar
  48. 48.
    Cronstein BN, Kramer SB, Weissmann G, Hirschhorn R (1983) Adenosine: a physiological modulator of superoxide anion generation by human neutrophils. J Exp Med 158:1160–1177PubMedCrossRefGoogle Scholar
  49. 49.
    Panther E, Corinti S, Idzko M, Herouy Y, Napp M, la Sala A, Girolomoni G, Norgauer J (2003) Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood 101:3985–3990PubMedCrossRefGoogle Scholar
  50. 50.
    Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M et al (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265PubMedCrossRefGoogle Scholar
  51. 51.
    Collins SL, Black KE, Chan-Li Y, Ahn YH, Cole PA, Powell JD, Horton MR (2011) Hyaluronan fragments promote inflammation by down-regulating the anti-inflammatory A2a receptor. Am J Respir Cell Mol Biol 45:675–683PubMedCrossRefGoogle Scholar
  52. 52.
    Fozard JR, Ellis KM, Villela Dantas MF, Tigani B, Mazzoni L (2002) Effects of CGS 21680, a selective adenosine A2A receptor agonist, on allergic airways inflammation in the rat. Eur J Pharmacol 438:183–188PubMedCrossRefGoogle Scholar
  53. 53.
    Nadeem A, Ponnoth DS, Ansari HR, Batchelor TP, Dey RD, Ledent C, Mustafa SJ (2009) A2A adenosine receptor deficiency leads to impaired tracheal relaxation via NADPH oxidase pathway in allergic mice. J Pharmacol Exp Ther 330:99–108PubMedCrossRefGoogle Scholar
  54. 54.
    Lau CL, Zhao Y, Kron IL, Stoler MH, Laubach VE, Ailawadi G, Linden J (2009) The role of adenosine A2A receptor signaling in bronchiolitis obliterans. Ann Thorac Surg 88:1071–1078PubMedCrossRefGoogle Scholar
  55. 55.
    Allen-Gipson DS, Wong J, Spurzem JR, Sisson JH, Wyatt TA (2006) Adenosine A2A receptors promote adenosine-stimulated wound healing in bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 290:L849–L855PubMedCrossRefGoogle Scholar
  56. 56.
    Montesinos MC, Desai A, Chen JF, Yee H, Schwarzschild MA, Fink JS, Cronstein BN (2002) Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A(2A) receptors. Am J Pathol 160:2009–2018PubMedCrossRefGoogle Scholar
  57. 57.
    Mohsenin A, Mi T, Xia Y, Kellems RE, Chen JF, Blackburn MR (2007) Genetic removal of the A2A adenosine receptor enhances pulmonary inflammation, mucin production, and angiogenesis in adenosine deaminase-deficient mice. Am J Physiol Lung Cell Mol Physiol 293:L753–L761PubMedCrossRefGoogle Scholar
  58. 58.
    Yang D, Zhang Y, Nguyen HG, Koupenova M, Chauhan AK, Makitalo M, Jones MR, St Hilaire C, Seldin DC, Toselli P et al (2006) The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest 116:1913–1923PubMedCrossRefGoogle Scholar
  59. 59.
    Eckle T, Hartmann K, Bonney S, Reithel S, Mittelbronn M, Walker LA, Lowes BD, Han J, Borchers CH, Buttrick PM et al (2012) Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia. Nat Med 18:774–782PubMedCrossRefGoogle Scholar
  60. 60.
    Sun CX, Zhong H, Mohsenin A, Morschl E, Chunn JL, Molina JG, Belardinelli L, Zeng D, Blackburn MR (2006) Role of A2B receptor signaling in adenosine-dependent pulmonary inflammation and injury. J Clin Invest 116:1–10CrossRefGoogle Scholar
  61. 61.
    Fernandez P, Trzaska S, Wilder T, Chiriboga L, Blackburn MR, Cronstein BN, Chan ES (2008) Pharmacological blockade of A2A receptors prevents dermal fibrosis in a model of elevated tissue adenosine. Am J Pathol 172:1675–1682PubMedCrossRefGoogle Scholar
  62. 62.
    Toldo S, Zhong H, Mezzaroma E, Van Tassell B, Kannan H, Zeng D, Belardinelli L, Voelkel N, Abbate A (2012) GS-6201, a selective blocker of the A2B adenosine receptor, attenuates cardiac remodeling following acute myocardial infarction in the mouse. J Pharmacol Exp Ther 343:587–595PubMedCrossRefGoogle Scholar
  63. 63.
    Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, Reiss AB, Pillinger MH, Chen JF, Schwarzschild MA et al (2006) Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 148:1144–1155PubMedCrossRefGoogle Scholar
  64. 64.
    Awad AS, Huang L, Ye H, Duong ET, Bolton WK, Linden J, Okusa MD (2006) Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy. Am J Physiol Ren Physiol 290:F828–F837CrossRefGoogle Scholar
  65. 65.
    Figler RA, Wang G, Srinivasan S, Jung DY, Zhang Z, Pankow JS, Ravid K, Fredholm B, Hedrick CC, Rich SS et al (2011) Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans. Diabetes 60:669–679PubMedCrossRefGoogle Scholar
  66. 66.
    Zhang Y, Dai Y, Wen J, Zhang W, Grenz A, Sun H, Tao L, Lu G, Alexander DC, Milburn MV et al (2011) Detrimental effects of adenosine signaling in sickle cell disease. Nat Med 17:79–86PubMedCrossRefGoogle Scholar
  67. 67.
    Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M (2006) Targeting adenosine A2A receptors in Parkinson’s disease. Trends Neurosci 29:647–654PubMedCrossRefGoogle Scholar
  68. 68.
    Cronstein BN (2005) Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 57:163–172PubMedCrossRefGoogle Scholar
  69. 69.
    Cushley MJ, Tattersfield AE, Holgate ST (1983) Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 15:161–165PubMedCrossRefGoogle Scholar
  70. 70.
    Hannon JP, Tigani B, Williams I, Mazzoni L, Fozard JR (2001) Mechanism of airway hyperresponsiveness to adenosine induced by allergen challenge in actively sensitized Brown Norway rats. Br J Pharmacol 132:1509–1523PubMedCrossRefGoogle Scholar
  71. 71.
    Driver AG, Kukoly CA, Ali S, Mustafa SJ (1993) Adenosine in bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis 148:91–97PubMedGoogle Scholar
  72. 72.
    Huszar E, Vass G, Vizi E, Csoma Z, Barat E, Molnar VG, Herjavecz I, Horvath I (2002) Adenosine in exhaled breath condensate in healthy volunteers and in patients with asthma. Eur Respir J 20:1393–1398PubMedCrossRefGoogle Scholar
  73. 73.
    Li Y, Wang W, Parker W, Clancy JP (2006) Adenosine regulation of cystic fibrosis transmembrane conductance regulator through prostenoids in airway epithelia. Am J Respir Cell Mol Biol 34:600–608PubMedCrossRefGoogle Scholar
  74. 74.
    Esther CR Jr, Lazaar AL, Bordonali E, Qaqish B, Boucher RC (2011) Elevated airway purines in COPD. Chest 140:954–960PubMedCrossRefGoogle Scholar
  75. 75.
    Goodarzi MT, Abdi M, Tavilani H, Nadi E, Rashidi M (2010) Adenosine deaminase activity in COPD patients and healthy subjects. Iran J Allergy Asthma Immunol 9:7–12PubMedGoogle Scholar
  76. 76.
    Zhou Y, Murthy JN, Zeng D, Belardinelli L, Blackburn MR (2010) Alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. PloS one 5:e9224PubMedCrossRefGoogle Scholar
  77. 77.
    Nagy LE, Diamond I, Casso DJ, Franklin C, Gordon AS (1990) Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the nucleoside transporter. J Biol Chem 265:1946–1951PubMedGoogle Scholar
  78. 78.
    Puig JG, Fox IH (1984) Ethanol-induced activation of adenine nucleotide turnover. Evidence for a role of acetate. J Clin Invest 74:936–941PubMedCrossRefGoogle Scholar
  79. 79.
    Chan ES, Cronstein BN (2002) Molecular action of methotrexate in inflammatory diseases. Arthritis Res 4:266–273PubMedCrossRefGoogle Scholar
  80. 80.
    Stamp LK, Hazlett J, Roberts RL, Frampton C, Highton J, Hessian PA (2012) Adenosine receptor expression in rheumatoid synovium: a basis for methotrexate action. Arthritis Res Ther 14:R138PubMedCrossRefGoogle Scholar
  81. 81.
    Bjorkman DJ, Boschert M, Tolman KG, Clegg DO, Ward JR (1993) The effect of long-term methotrexate therapy on hepatic fibrosis in rheumatoid arthritis. Arthritis Rheum 36:1697–1701PubMedCrossRefGoogle Scholar
  82. 82.
    Duell EA (1980) Adenosine-induced alterations in the adenosine 3′:5′-monophosphate levels in mammalian epidermis. Mol Pharmacol 18:49–52PubMedGoogle Scholar
  83. 83.
    Vali A, Asilian A, Khalesi E, Khoddami L, Shahtalebi M, Mohammady M (2005) Evaluation of the efficacy of topical caffeine in the treatment of psoriasis vulgaris. J Dermatolog Treat 16:234–237PubMedCrossRefGoogle Scholar
  84. 84.
    Lo Monaco A, Gulinelli S, Castellino G, Solini A, Ferrari D, La Corte R, Trotta F, Di Virgilio F (2007) Increased sensitivity to extracellular ATP of fibroblasts from patients affected by systemic sclerosis. Ann Rheum Dis 66:1124–1125PubMedCrossRefGoogle Scholar
  85. 85.
    Lazzerini PE, Natale M, Gianchecchi E, Capecchi PL, Montilli C, Zimbone S, Castrichini M, Balistreri E, Ricci G, Selvi E et al (2012) Adenosine A2A receptor activation stimulates collagen production in sclerodermic dermal fibroblasts either directly and through a cross-talk with the cannabinoid system. J Mol Med (Berl) 90:331–342CrossRefGoogle Scholar
  86. 86.
    Varani K, Laghi-Pasini F, Camurri A, Capecchi PL, Maccherini M, Diciolla F, Ceccatelli L, Lazzerini PE, Ulouglu C, Cattabeni F et al (2003) Changes of peripheral A2A adenosine receptors in chronic heart failure and cardiac transplantation. FASEB J 17:280–282PubMedGoogle Scholar
  87. 87.
    Desai AA, Zhou T, Ahmad H, Zhang W, Mu W, Trevino S, Wade MS, Raghavachari N, Kato GJ, Peters-Lawrence MH et al (2012) A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease. Am J Respir Crit Care Med 186:359–368PubMedCrossRefGoogle Scholar
  88. 88.
    Blackburn MR, Volmer JB, Thrasher JL, Zhong H, Crosby JR, Lee JJ, Kellems RE (2000) Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction. J Exp Med 192:159–170PubMedCrossRefGoogle Scholar
  89. 89.
    Karmouty-Quintana H, Zhong H, Acero L, Weng T, Melicoff E, West JD, Hemnes A, Grenz A, Eltzschig HK, Blackwell TS et al (2012) The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease. FASEB J 26:2546–2557PubMedCrossRefGoogle Scholar
  90. 90.
    Zhou Y, Schneider DJ, Morschl E, Song L, Pedroza M, Karmouty-Quintana H, Le T, Sun CX, Blackburn MR (2011) Distinct roles for the A2B adenosine receptor in acute and chronic stages of bleomycin-induced lung injury. J Immunol 186:1097–1106PubMedCrossRefGoogle Scholar
  91. 91.
    Farkas L, Gauldie J, Voelkel NF, Kolb M (2011) Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors. Am J Respir Cell Mol Biol 45:1–15PubMedCrossRefGoogle Scholar
  92. 92.
    Mustafa SJ, Nadeem A, Fan M, Zhong H, Belardinelli L, Zeng D (2007) Effect of a specific and selective A(2B) adenosine receptor antagonist on adenosine agonist AMP and allergen-induced airway responsiveness and cellular influx in a mouse model of asthma. J Pharmacol Exp Ther 320:1246–1251PubMedCrossRefGoogle Scholar
  93. 93.
    Ryzhov S, Novitskiy SV, Goldstein AE, Biktasova A, Blackburn MR, Biaggioni I, Dikov MM, Feoktistov I (2011) Adenosinergic regulation of the expansion and immunosuppressive activity of CD11b+Gr1+ cells. J Immunol 187:6120–6129PubMedCrossRefGoogle Scholar
  94. 94.
    Csoka B, Selmeczy Z, Koscso B, Nemeth ZH, Pacher P, Murray PJ, Kepka-Lenhart D, Morris SM Jr, Gause WC, Leibovich SJ et al (2012) Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J 26:376–386PubMedCrossRefGoogle Scholar
  95. 95.
    Wen J, Jiang X, Dai Y, Zhang Y, Tang Y, Sun H, Mi T, Phatarpekar PV, Kellems RE, Blackburn MR et al (2010) Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling. FASEB J 24:740–749PubMedCrossRefGoogle Scholar
  96. 96.
    Pedroza M, Schneider DJ, Karmouty-Quintana H, Coote J, Shaw S, Corrigan R, Molina JG, Alcorn JL, Galas D, Gelinas R et al (2011) Interleukin-6 contributes to inflammation and remodeling in a model of adenosine mediated lung injury. PLoS One 6:e22667PubMedCrossRefGoogle Scholar
  97. 97.
    Schneider DJ, Lindsay JC, Zhou Y, Molina JG, Blackburn MR (2010) Adenosine and osteopontin contribute to the development of chronic obstructive pulmonary disease. FASEB J 24:70–80PubMedCrossRefGoogle Scholar
  98. 98.
    Zhang Y, Dai Y, Wen J, Zhang W, Grenz A, Sun H, Tao L, Lu G, Alexander DC, Milburn MV et al (2011) Detrimental effects of adenosine signaling in sickle cell disease. Nat Med 17:79–86PubMedCrossRefGoogle Scholar
  99. 99.
    Katebi M, Fernandez P, Chan ES, Cronstein BN (2008) Adenosine A2A receptor blockade or deletion diminishes fibrocyte accumulation in the skin in a murine model of scleroderma, bleomycin-induced fibrosis. Inflammation 31:299–303PubMedCrossRefGoogle Scholar
  100. 100.
    Azdad K, Gall D, Woods AS, Ledent C, Ferre S, Schiffmann SN (2009) Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A–D2 receptor heteromerization. Neuropsychopharmacology 34:972–986PubMedCrossRefGoogle Scholar
  101. 101.
    Ross GW, Abbott RD, Petrovitch H, White LR, Tanner CM (2000) Relationship between caffeine intake and parkinson disease. JAMA 284:1378–1379PubMedCrossRefGoogle Scholar
  102. 102.
    Varani K, Padovan M, Vincenzi F, Targa M, Trotta F, Govoni M, Borea PA (2011) A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release. Arthritis Res Ther 13:R197PubMedCrossRefGoogle Scholar
  103. 103.
    Fishman P, Bar-Yehuda S, Liang BT, Jacobson KA (2012) Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today 17:359–366PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Harry Karmouty-Quintana
    • 1
  • Yang Xia
    • 1
  • Michael R. Blackburn
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyThe University of Texas Medical School at HoustonHoustonUSA

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