Abstract
Adenosine, an endogenous signaling nucleoside that modulates many physiological processes has been implicated in playing an ever increasingly important role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). All cells contain adenosine and adenine nucleotides and the cellular production of adenosine is greatly enhanced under conditions of local hypoxia as may occur in inflammatory conditions such as asthma and COPD. In 1983, it was first reported that inhaled adenosine causes dose-related bronchoconstriction in patients with both allergic and non-allergic asthma but not in healthy volunteers. This hyperresponsiveness was also reported in patients with COPD, with those patients who smoked exhibiting a significantly greater response. This bronchoconstrictor effect of adenosine is orchestrated through the stimulation of specific cell membrane receptors and involves an important inflammatory cell, the mast cell.
There is substantial evidence which suggests that mast cell activation is central to this unique response to adenosine. Mast cell mediator release makes a significant contribution towards airflow obstruction and the consequent symptoms in patients with asthma. Over the last two decades, researchers have investigated the effect of mast cell inhibitors as well as mast cell mediator receptor antagonists and their role in attenuating the bronchoconstrictor response to inhaled adenosine 5′-monophosphate (AMP). Promising results have been shown using mast cell stabilizers, histamine H1 receptor antagonists, selective cysteinyl leukotriene-1 receptor antagonists and inhibitors of 5-lipoxygenase and cyclo-oxygenase. Through these findings, the mast cell has been recognized as being a critical inflammatory cell in the adenosine-induced response in patients with asthma and COPD.
To date, four subtypes (A1, A2A, A2B, A3) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. Activation of these receptors has pro- and anti-inflammatory consequences making the development of agonists and/or antagonists at these receptor sites a novel approach in the treatment of patients with asthma and COPD.
This review highlights the importance of adenosine in the pathophysiology of asthma and COPD, the critical role of the mast cell and the potential to target the adenosine receptor subtype in patients with asthma and COPD. The complete characterization of these adenosine receptor subtypes in terms of their distribution in humans and the development of selective agonists and antagonists, holds the key to our complete understanding of the role of this important mediator in asthma and COPD.
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References
Barnes PJ. A new approach to the treatment of asthma. N Engl J Med 1989; 321(22): 1517–27
Jacobsen MA, Bai TR. the role of adenosine in asthma. Danvers (MA): Wiley-Liss Inc., 1997
Oosterhoff Y, de Jong JW, Jansen MA, et al. Airway responsiveness to adenosine 5′-monophosphate in chronic obstructive pulmonary disease is determined by smoking. Am Rev Respir Dis 1993; 147(3): 553–8
Rutgers SR, Timens W, Tzanakis N, et al. Airway inflammation and hyperresponsiveness to adenosine 5′-monophosphate in chronic obstructive pulmonary disease. Clin Exp Allergy 2000; 30(5): 657–62
Feoktistov I, Polosa R, Holgate ST, et al. Adenosine A2B receptors: a novel therapeutic target in asthma? Trends Pharmacol Sci 1998; 19(4): 148–53
Bodansky O, Schwartz MK. 5′-Nucleotidase. Adv Clin Chem 1968; 11: 277–328
Mentzer RM, Rubio R, Berne RM. Release of adenosine by hypoxic canine lung tissue and its possible role in pulmonary circulation. Am J Physiol 1975; 229(6): 1625–31
Marquardt DL, Gruber HE, Wasserman SI. Adenosine release from stimulated mast cells. Proc Natl Acad Sci USA 1984; 81(19): 6192–6
Driver AG, Kukoly CA, Ali S, et al. Adenosine in bronchoalveolar lavage fluid in asthma. Am Rev Respir Dis 1993; 148(1): 91–7
Polosa R, Holgate ST. Adenosine bronchoprovocation: a promising marker of allergie inflammation in asthma? Thorax 1997; 52(10): 919–23
Madara JL, Patapoff TW, Gillece-Castro B, et al. 5′-adenosine monophosphate is the neutrophil-derived paracrine factor that elicits chloride secretion from T84 intestinal epithelial cell monolayers. J Clin Invest 1993; 91(5): 2320–5
Stafford A. Potentiation of adenosine and the adenine nucleotides by dipyridamole. Br J Pharmacol 1966; 28(2): 218–27
Cushley MJ, Tallant N, Holgate ST. The effect of dipyridamole on histamine- and adenosine-induced bronchoconstriction in normal and asthmatic subjects. Eur J Respir Dis 1985; 67(3): 185–92
Crimi N, Palermo F, Oliveri R, et al. Enhancing effect of dipyridamole inhalation on adenosine-induced bronchospasm in asthmatic patients. Allergy 1988; 43(3): 179–83
Cushley MJ, Tattersfield AE, Holgate ST. Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects. Br J Clin Pharmacol 1983; 15(2): 161–5
Mann JS, Holgate ST, Renwick AG, et al. Airway effects of purine nucleosides and nucleotides and release with bronchial provocation in asthma. J Appl Physiol 1986; 61(5): 1667–76
Finney MJ, Karlsson JA, Persson CG. Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation. Br J Pharmacol 1985; 85(1): 29–36
Blackburn MR, Volmer JB, Thrasher JL, et al. Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction. J Exp Med 2000; 192(2): 159–70
Shovlin CL, Hughes JM, Simmonds HA, et al. Adult presentation of adenosine deaminase deficiency. Lancet 1993; 341(8858): 1471
Hirschhorn R. Immunodeficiency disease due to deficiency of adenosine deaminase. In: Ochs HD, Smith CIE, Puck JM, editors. Primary immunodeficiency disease: a molecular and genetic approach. New York: Oxford University Press, 1999:121–38
Watt AH, Penny WJ, Singh H, et al. Adenosine causes transient dilatation of coronary arteries in man. Br J Clin Pharmacol 1987; 24(5): 665–8
Rose FR, Hirschhorn R, Weissmann G, et al. Adenosine promotes neutrophil chemotaxis. J Exp Med 1988; 167(3): 1186–94
Peachell PT, Columbo M, Kagey-Sobotka A, et al. Adenosine potentiates mediator release from human lung mast cells. Am Rev Respir Dis 1988; 138(5): 1143–51
Redington AE, Polosa R, Walls AF, et al. Role of mast cells and basophils in asthma. Chem Immunol 1995; 62: 22–59
Holgate ST, Church MK, Polosa R. Adenosine: a positive modulator of airway inflammation in asthma. Ann NY Acad Sci 1991; 629: 227–36
Forsythe P, McGarvey LPA, Heaney LG, et al. Adenosine stimulates human pulmonary mast cells. Thorax 1995; 50Suppl. 2: 132
Polosa R, Ng WH, Crimi N, et al. Release of mast-cell-derived mediators after endobronchial adenosine challenge in asthma. Am J Respir Crit Care Med 1995; 151 (3 Pt 1): 624–9
Phillips GD, Ng WH, Church MK, et al. The response of plasma histamine to bronchoprovocation with methacholine, adenosine 5′-monophosphate, and allergen in atopic nonasthmatic subjects. Am Rev Respir Dis 1990; 141(1): 9–13
Phillips GD, Scott VL, Richards R, et al. Effect of nedocromil sodium and sodium cromoglycate against bronchoconstriction induced by inhaled adenosine 5′-monophosphate. Eur Respir J 1989; 2(3): 210–7
Phillips GD, Finnerty JP, Holgate ST. Comparative protective effect of the inhaled beta 2-agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5′-monophosphate in asthma. J Allergy Clin Immunol 1990; 85(4): 755–62
Rutgers SR, Koeter GH, Van Der Mark TW, et al. Protective effect of oral terfenadine and not inhaled ipratropium on adenosine 5’-monophosphate-induced bronchoconstriction in patients with COPD. Clin Exp Allergy 1999; 29(9): 1287–92
Rafferty P, Beasley R, Holgate ST. The contribution of histamine to immediate bronchoconstriction provoked by inhaled allergen and adenosine 5′-monophosphate in atopic asthma. Am Rev Respir Dis 1987; 136(2): 369–73
Phillips GD, Rafferty P, Beasley R, et al. Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5′-monophosphate in non-atopic asthma. Thorax 1987; 42(12): 939–45
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(4): 405–9
Crimi E, Brusasco V, Brancatisano M, et al. Adenosine-induced bronchoconstriction: premedication with chlorpheniramine and nedocromil sodium. Eur J Respir Dis 1986; 69Suppl. 147: 255–7
Crimi N, Palermo F, Polosa R, et al. Effect of indomethacin on adenosine-induced bronchoconstriction. J Allergy Clinical Immunol 1989; 83(5): 921–5
Phillips GD, Holgate ST. The effect of oral terfenadine alone and in combination with flurbiprofen on the bronchoconstrictor response to inhaled adenosine 5’-monophosphate in nonatopic asthma. Am Rev Respir Dis 1989; 139(2): 463–9
Van-Schoor J, Joos GF, Kips JC, et al. The effect of ABT-761, a novel 5-lipoxygenase inhibitor, on exercise- and adenosine-induced bronchoconstriction in asthmatic subjects. Am J Respir Crit Care Med 1997; 155(3): 875–80
Rorke S, Jennison S, Jeffs JA, et al. The role of cysteinyl leukotrienes in adenosine 5′-monophosphate-induced bronchoconstriction in asthma. Thorax. In press
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): 1979–86
Moller A, Lippert U, Lessmann D, et al. Human mast cells produce IL-8. J Immunol 1993; 151(6): 3261–6
Ackerman V, Marini M, Vittori E, et al. Detection of cytokines and their cell sources in bronchial biopsy specimens from asthmatic patients. Relationship to atopic status, symptoms, and level of airway hyperresponsiveness. Chest 1994; 105(3): 687–96
Bradding P, Roberts JA, Britten KM, et al. Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 1994; 10(5): 471–80
Forsythe P, Ennis M. Adenosine, mast cells and asthma. Inflamm Res 1999; 48(6): 301–7
Nyce JW. Insight into adenosine receptor function using antisense and gene-knockout approaches. Trends Pharmacol Sci 1999; 20(2): 79–83
Cronstein BN, Daguma L, Nichols D, et al. The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively. J Clin Invest 1990; 85(4): 1150–7
Cronstein BN, Levin RI, Philips M, et al. Neutrophil adherence to endothelium is enhanced via adenosine A1 receptors and inhibited via adenosine A2 receptors. J Immunol 1992; 148(7): 2201–6
Dixon AK, Gubitz AK, Sirinathsinghji DJ, et al. Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 1996; 118(6): 1461–8
Bouma MG, Jeunhomme TM, Boyle DL, et al. Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors. J Immunol 1997; 158(11): 5400–8
Wollner A, Wollner S, Smith JB. Acting via A2 receptors adenosine inhibits the upregulation of Mac-1 (CD11b/CD18) expression on fMLP stimulated neutrophils. Am J Respir Cell Mol Biol 1993; 9: 179–85
Hughes PJ, Holgate ST, Church MK. Adenosine inhibits and potentiates IgE-dependent histamine release from human lung mast cells by an A2-purinocep-tor mediated mechanism. Biochem Pharmacol 1984; 33(23): 3847–52
Peachell PT, Lichtenstein LM, Schleimer RP. Differential regulation of human basophil and lung mast cell function by adenosine. J Pharmacol Exp Ther 1991; 256(2): 717–26
Feoktistov I, Biaggioni I. Adenosine A2B receptors. Pharmacol Rev 1997; 49(4): 381–402
Marquardt DL. Adenosine. In: Barnes PJ, Grunstein MM, Leff AR, et al., editors. Asthma. Philadelphia: Lippincott-Raven, 1997: 585–91
Linden J. Cloned adenosine A3 receptors: pharmacological properties, species differences and receptor functions. Trends Pharmacol Sci 1994; 15(8): 298–306
Ramkumar V, Stiles GL, Beaven MA, et al. The A3 adenosine receptor is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. J Biol Chem 1993; 268(23): 16887–90
Kohno Y, Ji X, Mawhorter SD, et al. Activation of A3 adenosine receptors on human eosinophils elevates intracellular calcium. Blood 1996; 88(9): 3569–74
Knight D, Zheng X, Rocchini C, et al. Adenosine A3 receptor stimulation inhibits migration of human eosinophils. J Leukoc Biol 1997; 62(4): 465–8
Walker BA, Jacobson MA, Knight DA, et al. Adenosine A3 receptor expression and function in eosinophils. Am J Respir Cell Mol Biol 1997; 16(5): 531–7
Ali S, Mustafa SJ, Metzger WJ. Adenosine receptor-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbit model. Am J Physiol 1994; 266 (3 Pt 1): L271–7
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(3): 1328–34
Nyce JW, Metzger WJ. DNA antisense therapy for asthma in an animal model. Nature 1997; 385(6618): 721–5
Hakonarson H, Shanbaky I, Guerra FM, et al. Modulation of adenosine A1, bradykinin B1, and histamine H1 receptor expression and function in atopic asthmatic sensitised airway smooth muscle [abstract]. Proceedings from The American Thoracic Society International Congress; 1998; Chicago
Nie Z, Mei Y, Ford M, et al. Oxidative stress increases A1 adenosine receptor expression by activating nuclear factor kappa B. Mol Pharmacol 1998; 53(4): 663–9
Bouma MG, Stad RK, van den Wildenberg FA, et al. Differential regulatory effects of adenosine on cytokine release by activated human monocytes. J Immunol 1994; 153(9): 4159–68
Fozard JR, Hannon JP. Adenosine receptor ligands: potential as therapeutic agents in asthma and COPD. Pulm Pharmacol Ther 1999; 12(2): 111–4
Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996; 334(21): 1380–8
Klotz KN, Hessling J, Hegler J, et al. Comparative pharmacology of human adenosine receptor subtypes -characterization of stably transfected receptors in CHO cells. Naunyn Schmiedebergs Arch Pharmacol 1998; 357(1): 1–9
Mann JS, Holgate ST. Specific antagonism of adenosine-induced bronchoconstriction in asthma by oral theophylline. Br J Clin Pharmacol 1985; 19(5): 685–92
Clarke H, Cushley MJ, Persson CG, et al. The protective effects of intravenous theophylline and enprofylline against histamine- and adenosine 5′-monophos-phate-provoked bronchoconstriction: implications for the mechanisms of action of xanthine derivatives in asthma. J Respir Pharmacol 1989; 2: 147–54
Ji X, Kim Y, Ahern D, et al. [3H]MRS 1754, a selective antagonist radioligand for A(2B) adenosine receptors. Biochem Pharmacol 2001; 61: 657–63
Feoktistov I, Garland EM, Goldstein AE, et al. Inhibition of human mast cell activation with the novel selective adenosine A2B receptor antagonist 3-isobutyl-8-pyrrolidinoxanthine (IPDX). Biochem Pharmacol 2001; 62(9): 1163–73
Ezeamuzie CI, Philips E. Adenosine A3 receptors on human eosinophils mediate inhibition of degranulation and Superoxide anion release. Br J Pharmacol 1999; 127(1): 188–94
Ezeamuzie CI. Involvement of A(3) receptors in the potentiation by adenosine of the inhibitory effect of theophylline on human eosinophil degranulation: possible novel mechanism of the anti-inflammatory action of theophylline. Biochem Pharmacol 2001; 61(12): 1551–9
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Rorke, S., Holgate, S.T. Targeting Adenosine Receptors. Am J Respir Med 1, 99–105 (2002). https://doi.org/10.1007/BF03256599
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DOI: https://doi.org/10.1007/BF03256599