Targeting the ATP-Axis in Lungs as a New Therapheutic Modality for COPD
Main Article Content
Abstract
Adenosine 5’-triphosphate (ATP) is found in every cell of the body where it plays a critical role in cellular metabolism and energetics. ATP is released from cells under physiologic and pathophysiologic conditions; extracellular ATP acts as an autocrine and paracrine agent. Its effects on targeted cells are mediated by subtypes of purinergic receptors (P2R). In the lungs, relatively large amounts of ATP are released under inflammatory conditions. Extracellular ATP triggers a central vagal reflex by activating purinergic receptor P2XR localized on pulmonary vagal sensory nerve terminals. This results in cough, bronchoconstriction and the release of pro-inflammatory neuropeptides via axon reflex. COPD patients manifest higher sensetivity to aerosolized ATP than healthy subjects, and the levels of ATP in COPD patients’ lungs are 3x that found in healthy subjects. This review succinctly details (i) the sources amd mechanisms of ATP’s release into the extracellular space, (ii) the ways extracellular ATP is eliminated, (iii) the deleterious effects of ATP in the lungs in general and in COPD in particular, and (iv) the rationale for the blockade of these actions of ATP in the lungs as a novel therapeutic approach in the management of COPD patients.
Article Details
How to Cite
PELLEG, PH.D, Amir; BARNES, FRS, Peter J.; SCHULMAN, M.D, Edward S.
Targeting the ATP-Axis in Lungs as a New Therapheutic Modality for COPD.
Medical Research Archives, [S.l.], v. 11, n. 10, oct. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4487>. Date accessed: 23 nov. 2024.
doi: https://doi.org/10.18103/mra.v11i10.4487.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007; 81(1): 1-5.
2. Meyers KM, Holmsen H, Seachord CL. Comparative study of platelet dense granule constituents. The American journal of physiology 1982; 243(3): R454-61.
3. Nirody JA, Budin I, Rangamani P. ATP synthase: Evolution, energetics, and membrane interactions. J Gen Physiol 2020; 152(11).
4. Bonora M, Patergnani S, Rimessi A, et al. ATP synthesis and storage. Purinergic Signal 2012; 8(3): 343-57.
5. Corriden R, Insel PA. Basal release of ATP: an autocrine-paracrine mechanism for cell regulation. Sci Signal 2010; 3(104): re1.
6. Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci 2007; 64(12): 1471-83.
7. Jacobson KA, Delicado EG, Gachet C, et al. Update of P2Y receptor pharmacology: IUPHAR Review 27. Br J Pharmacol 2020; 177(11): 2413-33.
8. Illes P, Muller CE, Jacobson KA, et al. Update of P2X receptor properties and their pharmacology: IUPHAR Review 30. Br J Pharmacol 2021; 178(3): 489-514.
9. Burnstock G. Purine and purinergic receptors. Brain Neurosci Adv 2018; 2: 2398212818817494.
10. Jacobson KA, Muller CE. Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology 2016; 104: 31-49.
11. Burnstock G, Brouns I, Adriaensen D, Timmermans JP. Purinergic signaling in the airways. Pharmacol Rev 2012; 64(4): 834-68.
12. Lazarowski ER, Boucher RC. Purinergic receptors in airway epithelia. Curr Opin Pharmacol 2009; 9(3): 262-7.
13. Wirsching E, Fauler M, Fois G, Frick M. P2 Purinergic Signaling in the Distal Lung in Health and Disease. Int J Mol Sci 2020; 21(14).
14. Pelleg A. Extracellular adenosine 5'-triphosphate in pulmonary disorders. Biochem Pharmacol 2021; 187: 114319.
15. Pelleg A, Schulman ES, Barnes PJ. Extracellular Adenosine 5'-Triphosphate in Obstructive Airway Diseases. Chest 2016; 150(4): 908-15.
16. Taruno A. ATP Release Channels. Int J Mol Sci 2018; 19(3).
17. Penuela S, Gehi R, Laird DW. The biochemistry and function of pannexin channels. Biochim Biophys Acta 2013; 1828(1): 15-22.
18. Chekeni FB, Elliott MR, Sandilos JK, et al. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. Nature 2010; 467(7317): 863-7.
19. Adamson SE, Leitinger N. The role of pannexin1 in the induction and resolution of inflammation. FEBS Lett 2014; 588(8): 1416-22.
20. Bodin P, Burnstock G. Purinergic signalling: ATP release. Neurochem Res 2001; 26(8-9): 959-69.
21. Mills DCB, Robb I.A., Roberts, G.C.K. The release of nucleotides, 5-hydroxytryptamine and enzymes from human blood platelets during aggregation. J Physiol (Lond) 1968; 195(3): 715-29.
22. Day HJ, Holmsen, H. Concepts of the blood platelet release reaction. Semin Hematol 1971; 4(1): 3-27.
23. Holmsen H. Platelet metabolism and activation. Semin Hematol 1985; 22(3): 219-40.
24. Dean BM, Perrett D. Studies on adenine and adenosine metabolism by intact human erythrocytes using high performance liquid chromatography. Biochim Biophys Acta 1976; 437(1): 1-5.
25. Bergfeld GR, Forrester T. Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res 1992; 26(1): 40-7.
26. Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The erythrocyte as a regulator of vascular tone. The American journal of physiology 1995; 269(6 Pt 2): H2155-61.
27. Pearson JD, Gordon JL. Vascular endothelial and smooth muscle cells in culture selectively release adenine nucleotides. Nature 1979; 281(5730): 384-6.
28. Bodin P, Bailey D, Burnstock G. Increased flow-induced ATP release from isolated vascular endothelial cells but not smooth muscle cells. Br J Pharmacol 1991; 103(1): 1203-5.
29. Ralevic V, Milner P, Kirkpatrick KA, Burnstock G. Flow-induced release of adenosine 5'-triphosphate from endothelial cells of the rat mesenteric arterial bed. Experientia 1992; 48(1): 31-4.
30. Yang S, Cheek DJ, Westfall DP, Buxton IL. Purinergic axis in cardiac blood vessels. Agonist-mediated release of ATP from cardiac endothelial cells. Circ Res 1994; 74(3): 401-7.
31. Bodin P, Burnstock G. ATP-stimulated release of ATP by human endothelial cells. J Cardiovasc Pharmacol 1996; 27(6): 872-5.
32. Katsuragi T, Tamesue S, Sato C, Sato Y, Furukawa T. ATP release by angiotensin II from segments and cultured smooth muscle cells of guinea-pig taenia coli. Naunyn Schmiedebergs Arch Pharmacol 1996; 354(6): 796-9.
33. Katsuragi T, Soejima O, Tokunaga T, Furukawa T. Evidence for postjunctional release of ATP evoked by stimulation of muscarinic receptors in ileal longitudinal muscles of guinea pig. J Pharmacol Exp Ther 1992; 260(3): 1309-13.
34. Begandt D, Good ME, Keller AS, et al. Pannexin channel and connexin hemichannel expression in vascular function and inflammation. BMC Cell Biol 2017; 18(Suppl 1): 2.
35. Lundberg JM. Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev 1996; 48(1): 113-78.
36. Forrester T. An estimate of adenosine triphosphate release into the venous effluent from exercising human forearm muscle. The Journal of physiology 1972; 224(3): 611-28.
37. Fredholm BB, Hedqvist P, Lindstrom K, Wennmalm M. Release of nucleosides and nucleotides from the rabbit heart by sympathetic nerve stimulation. Acta Physiol Scand 1982; 116(3): 285-95.
38. Darius H, Stahl GL, Lefer AM. Pharmacologic modulation of ATP release from isolated rat hearts in response to vasoconstrictor stimuli using a continuous flow technique. J Pharmacol Exp Ther 1987; 240(2): 542-7.
39. Katsuragi T, Tokunaga T, Ohba M, Sato C, Furukawa T. Implication of ATP released from atrial, but not papillary, muscle segments of guinea pig by isoproterenol and forskolin. Life Sci 1993; 53(11): 961-7.
40. Tokunaga T, Katsuragi T, Sato C, Furukawa T. ATP release evoked by isoprenaline from adrenergic nerves of guinea pig atrium. Neurosci Lett 1995; 186(2-3): 95-8.
41. Paddle BM, Burnstock G. Release of ATP from perfused heart during coronary vasodilatation. Blood Vessels 1974; 11(3): 110-9.
42. Forrester T, Williams CA. Release of adenosine triphosphate from isolated adult heart cells in response to hypoxia. The Journal of physiology 1977; 268(2): 371-90.
43. Williams CA, Forrester T. Possible source of adenosine triphosphate released from rat myocytes in response to hypoxia and acidosis. Cardiovasc Res 1983; 17(5): 301-12.
44. Dosch M, Gerber J, Jebbawi F, Beldi G. Mechanisms of ATP Release by Inflammatory Cells. Int J Mol Sci 2018; 19(4).
45. Baxter M, Eltom S, Dekkak B, et al. Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung. Thorax 2014; 69(12): 1080-9.
46. Tsai Shihn H, Kinoshita M, Kusu T, et al. The Ectoenzyme E-NPP3 Negatively Regulates ATP-Dependent Chronic Allergic Responses by Basophils and Mast Cells. Immunity 2015; 42(2): 279-93.
47. Bucchioni E CZ, Polkey M, Collins JV, Cramer D, Allegra L, Barnes PJ, Kharitonov SA. Adenosine 5'-triphosphate (ATP) is increased in exhaled breath condensate in COPD. Am J Respir Crit Care Med 2002; 165: A599.
48. Basoglu OK, Barnes PJ, Kharitonov SA, Pelleg A. Effects of Aerosolized Adenosine 5'-Triphosphate in Smokers and Patients With COPD. Chest 2015; 148(2): 430-5.
49. Hlapčić I, Hulina-Tomašković A, Somborac-Bačura A, Rajković MG, Dugac AV, Popović-Grle S, Rumora L. Extracellular adenosine triphosphate is associated with airflow limitation severity and symptoms burden in patients with chronic obstructive pulmonary disease. Scientific Reports 2019; 9:15349. https://doi.org/10.1038/s41598-019-51855
50. Mortaz E, Braber S, Nazary M, Givi ME, Nijkamp FP, Folkerts G. ATP in the pathogenesis of lung emphysema. Eur J Pharmacol 2009; 619(1-3): 92-6.
51. Cicko S, Lucattelli M, Muller T, et al. Purinergic Receptor Inhibition Prevents the Development of Smoke-Induced Lung Injury and Emphysema. J Immunol 2010; 185(1): 688-97.
52. Lommatzsch M, Cicko S, Müller T, et al. Extracellular Adenosine Triphosphate and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2010; 181(9): 928-34.
53. Colgan SP, Eltzschig HK, Eckle T, Thompson LF. Physiological roles for ecto-5'-nucleotidase (CD73). Purinergic Signal 2006; 2(2): 351-60.
54. Knapp K, Zebisch M, Pippel J, El-Tayeb A, Müller CE, Sträter N. Crystal structure of the human ecto-5'-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure 2012; 20(12): 2161-73.
55. Schetinger MR, Morsch VM, Bonan CD, Wyse AT. NTPDase and 5'-nucleotidase activities in physiological and disease conditions: new perspectives for human health. Biofactors 2007; 31(2): 77-98.
56. Zhao H, Bo C, Kang Y, Li H. What Else Can CD39 Tell Us? Frontiers in Immunology 2017; 8.
57. Antonioli L, Pacher P, Vizi ES, Hasko G. CD39 and CD73 in immunity and inflammation. Trends Mol Med 2013; 19(6): 355-67.
58. Timperi E, Barnaba V. CD39 Regulation and Functions in T Cells. Int J Mol Sci 2021; 22(15).
59. Jacobson KA, Pradhan B, Wen Z, Pramanik A. New paradigms in purinergic receptor ligand discovery. Neuropharmacology 2023; 230: 109503.
60. Pasquini S, Contri C, Borea PA, Vincenzi F, Varani K. Adenosine and Inflammation: Here, There and Everywhere. Int J Mol Sci 2021; 22(14).
61. Polosa R. Adenosine-receptor subtypes: their relevance to adenosine-mediated responses in asthma and chronic obstructive pulmonary disease. Eur Respir J 2002; 20(2): 488-96.
62. Liu TT, Wang YL, Zhang Z, et al. Abnormal adenosine metabolism of neutrophils inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus. BMC Pulm Med 2023; 23(1): 258.
63. Eckle T, Fullbier L, Wehrmann M, et al. Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury. Journal of immunology 2007; 178(12): 8127-37.
64. Li J, Wang L, Chen X, et al. CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-beta-mTOR-HIF-1 signaling in patients with non-small cell lung cancer. Oncoimmunology 2017; 6(6): e1320011.
65. Hu XM, Shi NR, Zhang JZ, et al. CD73: Friend or Foe in Lung Injury. Int J Mol Sci 2023; 24(6).
66. Pelleg A, Hurt CM. Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. The Journal of physiology 1996; 490 ( Pt 1): 265-75.
67. Pellegrino R, Wilson O, Jenouri G, Rodarte JR. Lung mechanics during induced bronchoconstriction. J Appl Physiol 1996; 81(2): 964-75.
68. Katchanov G, Xu J, Schulman ES, Pelleg A. ATP causes neurogenic bronchoconstriction in the dog. Drug Dev Res 1998; 45(3-4): 342-9.
69. Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB, McGarvey L. Anatomy and Neurophysiology of Cough. Chest 2014; 146(6): 1633-48.
70. Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J 1995; 8(7): 1193-202.
71. Kamei J, Takahashi Y, Yoshikawa Y, Saitoh A. Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity. Eur J Pharmacol 2005; 528(1-3): 158-61.
72. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. The Lancet 2015; 385(9974): 1198-205.
73. Garceau D, Chauret N. BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther 2019; 56: 56-62.
74. Pelleg A, Xu F, Zhuang J, Undem B, Burnstock G. DT-0111: a novel drug-candidate for the treatment of COPD and chronic cough. Ther Adv Respir Dis 2019; 13: 1753466619877960.
75. Burgoyne DS. Managed care considerations for the treatment of chronic cough. Am J Manag Care 2022; 28(9 Suppl): S166-S74.
76. Sykes DL, Zhang M, Morice AH. Treatment of chronic cough: P2X3 receptor antagonists and beyond. Pharmacol Ther 2022; 237: 108166.
77. Basoglu OK, Pelleg A, Essilfie-Quaye S, Brindicci C, Barnes PJ, Kharitonov SA. Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma. Chest 2005; 128(4): 1905-9.
78. Barnes PJ. Asthma as an axon reflex. The Lancet 1986; 327(8475): 242-5.
79. Barnes PJ. Neurogenic Inflammation in Airways. Int Arch Allergy Immunol 1991; 94(1-4): 303-9.
80. Barnes PJ, Baraniuk JN, Belvisi MG. Neuropeptides in the Respiratory Tract: Part I. Am Rev Respir Dis 1991; 144(5): 1187-98.
81. Schulman ES, Glaum MC, Post T, et al. ATP Modulates Anti-IgE–Induced Release of Histamine from Human Lung Mast Cells. Am J Respir Cell Mol Biol 1999; 20(3): 530-7.
82. Pelleg A, Schulman ES. Adenosine 5'-Triphosphate Axis in Obstructive Airway Diseases. Am J Therap 2002; 9(5): 454-64.
83. Mortaz E, Folkerts G, Nijkamp FP, Henricks PA. ATP and the pathogenesis of COPD. Eur J Pharmacol 2010; 638(1-3): 1-4.
84. Pelleg A, Undem BJ. A-317491 Inhibits the activation of guinea-pig pulmonary vagal sensory nerve terminals by α,β methylene_ATP. Clin Immunol 2005; 115(Suppl 1): S59-60.
85. Weigand LA, Ford AP, Undem BJ. A role for ATP in bronchoconstriction-induced activation of guinea pig vagal intrapulmonary C-fibres. The Journal of physiology 2012; 590(16): 4109-20.
86. Ford AP, Undem BJ. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders. Front Cell Neurosci 2013; 7: 267.
87. Winkelmann VE, Thompson KE, Neuland K, et al. Inflammation-induced upregulation of P2X(4) expression augments mucin secretion in airway epithelia. Am J Physiol Lung Cell Mol Physiol 2019; 316(1): L58-L70.
88. Obara K, Inaba R, Kawakita M, Murata A, Yoshioka K, Tanaka Y. Effects of NP-1815-PX, a P2X4 Receptor Antagonist, on Contractions in Guinea Pig Tracheal and Bronchial Smooth Muscles. Biol Pharm Bull 2022; 45(8): 1158-65.
89. Nagaoka M, Nara M, Tamada T, et al. Regulation of adenosine 5'-triphosphate (ATP)-gated P2X(4) receptors on tracheal smooth muscle cells. Respir Physiol Neurobiol 2009; 166(1): 61-7.
90. Wang L, Feng X, Hu B, Xia Q, Ni X, Song Y. P2X4R promotes airway remodeling by acting on the phenotype switching of bronchial smooth muscle cells in rats. Purinergic Signal 2018; 14(4): 433-42.
91. Yoshida K, Ito MA, Sato N, et al. Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation. Journal of immunology 2020; 204(12): 3077-85.
92. Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med 2014; 35(1): 71-86.
93. Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2016; 138(1): 16-27.
94. Kuprash DV, Nedospasov SA. Molecular and Cellular Mechanisms of Inflammation. Biochemistry (Mosc) 2016; 81(11): 1237-9.
95. Liu JP, Liu SC, Hu SQ, et al. ATP ion channel P2X purinergic receptors in inflammation response. Biomed Pharmacother 2023; 158: 114205.
96. Linden J, Koch-Nolte F, Dahl G. Purine Release, Metabolism, and Signaling in the Inflammatory Response. Annu Rev Immunol 2019; 37: 325-47.
97. Adriaensen D. Purinergic signalling in the lung: important in asthma and COPD? Curr Opin Pharmacol 2004; 4(3): 207-14.
98. Idzko M, Hammad H, van Nimwegen M, et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nature Med 2007; 13(8): 913-9.
99. Vieira RP, Müller T, Grimm M, et al. Purinergic Receptor Type 6 Contributes to Airway Inflammation and Remodeling in Experimental Allergic Airway Inflammation. Am J Respir Crit Care Med 2011; 184(2): 215-23.
100. Birring SS, Dicpinigaitis PV, Smith JA, et al. Efficacy and Safety of Gefapixant for Refractory or Unexplained Chronic Cough over 52 Weeks. Am J Respir Crit Care Med 2023; 207(11): 1539-42.
101. McGarvey L, Sher M, Shvarts YG, et al. The Efficacy and Safety of Gefapixant in a Phase 3b Trial of Patients with Recent-Onset Chronic Cough. Lung 2023; 201(2): 111-8.
102. Morice A, Smith JA, McGarvey L, et al. Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study. Eur Respir J 2021; 58(5).
103. McGarvey L, Smith JA, Morice A, et al. A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 2b Trial of P2X3 Receptor Antagonist Sivopixant for Refractory or Unexplained Chronic Cough. Lung 2023; 201(1): 25-35.
104. Barjaktarevic IZ, Milstone AP. Nebulized Therapies in COPD: Past, Present, and the Future. Int J Chron Obstruct Pulmon Dis 2020; 15: 1665-77.
105. Labaki WW, Rosenberg SR. Chronic Obstructive Pulmonary Disease. Ann Intern Med 2020; 173(3): ITC17-ITC32.
106. Pelleg A, Sirtori E, Rolland JF, Mahadevan A. DT-0111: a novel P2X3 receptor antagonist. Purinergic Signal 2023.
2. Meyers KM, Holmsen H, Seachord CL. Comparative study of platelet dense granule constituents. The American journal of physiology 1982; 243(3): R454-61.
3. Nirody JA, Budin I, Rangamani P. ATP synthase: Evolution, energetics, and membrane interactions. J Gen Physiol 2020; 152(11).
4. Bonora M, Patergnani S, Rimessi A, et al. ATP synthesis and storage. Purinergic Signal 2012; 8(3): 343-57.
5. Corriden R, Insel PA. Basal release of ATP: an autocrine-paracrine mechanism for cell regulation. Sci Signal 2010; 3(104): re1.
6. Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci 2007; 64(12): 1471-83.
7. Jacobson KA, Delicado EG, Gachet C, et al. Update of P2Y receptor pharmacology: IUPHAR Review 27. Br J Pharmacol 2020; 177(11): 2413-33.
8. Illes P, Muller CE, Jacobson KA, et al. Update of P2X receptor properties and their pharmacology: IUPHAR Review 30. Br J Pharmacol 2021; 178(3): 489-514.
9. Burnstock G. Purine and purinergic receptors. Brain Neurosci Adv 2018; 2: 2398212818817494.
10. Jacobson KA, Muller CE. Medicinal chemistry of adenosine, P2Y and P2X receptors. Neuropharmacology 2016; 104: 31-49.
11. Burnstock G, Brouns I, Adriaensen D, Timmermans JP. Purinergic signaling in the airways. Pharmacol Rev 2012; 64(4): 834-68.
12. Lazarowski ER, Boucher RC. Purinergic receptors in airway epithelia. Curr Opin Pharmacol 2009; 9(3): 262-7.
13. Wirsching E, Fauler M, Fois G, Frick M. P2 Purinergic Signaling in the Distal Lung in Health and Disease. Int J Mol Sci 2020; 21(14).
14. Pelleg A. Extracellular adenosine 5'-triphosphate in pulmonary disorders. Biochem Pharmacol 2021; 187: 114319.
15. Pelleg A, Schulman ES, Barnes PJ. Extracellular Adenosine 5'-Triphosphate in Obstructive Airway Diseases. Chest 2016; 150(4): 908-15.
16. Taruno A. ATP Release Channels. Int J Mol Sci 2018; 19(3).
17. Penuela S, Gehi R, Laird DW. The biochemistry and function of pannexin channels. Biochim Biophys Acta 2013; 1828(1): 15-22.
18. Chekeni FB, Elliott MR, Sandilos JK, et al. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. Nature 2010; 467(7317): 863-7.
19. Adamson SE, Leitinger N. The role of pannexin1 in the induction and resolution of inflammation. FEBS Lett 2014; 588(8): 1416-22.
20. Bodin P, Burnstock G. Purinergic signalling: ATP release. Neurochem Res 2001; 26(8-9): 959-69.
21. Mills DCB, Robb I.A., Roberts, G.C.K. The release of nucleotides, 5-hydroxytryptamine and enzymes from human blood platelets during aggregation. J Physiol (Lond) 1968; 195(3): 715-29.
22. Day HJ, Holmsen, H. Concepts of the blood platelet release reaction. Semin Hematol 1971; 4(1): 3-27.
23. Holmsen H. Platelet metabolism and activation. Semin Hematol 1985; 22(3): 219-40.
24. Dean BM, Perrett D. Studies on adenine and adenosine metabolism by intact human erythrocytes using high performance liquid chromatography. Biochim Biophys Acta 1976; 437(1): 1-5.
25. Bergfeld GR, Forrester T. Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res 1992; 26(1): 40-7.
26. Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The erythrocyte as a regulator of vascular tone. The American journal of physiology 1995; 269(6 Pt 2): H2155-61.
27. Pearson JD, Gordon JL. Vascular endothelial and smooth muscle cells in culture selectively release adenine nucleotides. Nature 1979; 281(5730): 384-6.
28. Bodin P, Bailey D, Burnstock G. Increased flow-induced ATP release from isolated vascular endothelial cells but not smooth muscle cells. Br J Pharmacol 1991; 103(1): 1203-5.
29. Ralevic V, Milner P, Kirkpatrick KA, Burnstock G. Flow-induced release of adenosine 5'-triphosphate from endothelial cells of the rat mesenteric arterial bed. Experientia 1992; 48(1): 31-4.
30. Yang S, Cheek DJ, Westfall DP, Buxton IL. Purinergic axis in cardiac blood vessels. Agonist-mediated release of ATP from cardiac endothelial cells. Circ Res 1994; 74(3): 401-7.
31. Bodin P, Burnstock G. ATP-stimulated release of ATP by human endothelial cells. J Cardiovasc Pharmacol 1996; 27(6): 872-5.
32. Katsuragi T, Tamesue S, Sato C, Sato Y, Furukawa T. ATP release by angiotensin II from segments and cultured smooth muscle cells of guinea-pig taenia coli. Naunyn Schmiedebergs Arch Pharmacol 1996; 354(6): 796-9.
33. Katsuragi T, Soejima O, Tokunaga T, Furukawa T. Evidence for postjunctional release of ATP evoked by stimulation of muscarinic receptors in ileal longitudinal muscles of guinea pig. J Pharmacol Exp Ther 1992; 260(3): 1309-13.
34. Begandt D, Good ME, Keller AS, et al. Pannexin channel and connexin hemichannel expression in vascular function and inflammation. BMC Cell Biol 2017; 18(Suppl 1): 2.
35. Lundberg JM. Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev 1996; 48(1): 113-78.
36. Forrester T. An estimate of adenosine triphosphate release into the venous effluent from exercising human forearm muscle. The Journal of physiology 1972; 224(3): 611-28.
37. Fredholm BB, Hedqvist P, Lindstrom K, Wennmalm M. Release of nucleosides and nucleotides from the rabbit heart by sympathetic nerve stimulation. Acta Physiol Scand 1982; 116(3): 285-95.
38. Darius H, Stahl GL, Lefer AM. Pharmacologic modulation of ATP release from isolated rat hearts in response to vasoconstrictor stimuli using a continuous flow technique. J Pharmacol Exp Ther 1987; 240(2): 542-7.
39. Katsuragi T, Tokunaga T, Ohba M, Sato C, Furukawa T. Implication of ATP released from atrial, but not papillary, muscle segments of guinea pig by isoproterenol and forskolin. Life Sci 1993; 53(11): 961-7.
40. Tokunaga T, Katsuragi T, Sato C, Furukawa T. ATP release evoked by isoprenaline from adrenergic nerves of guinea pig atrium. Neurosci Lett 1995; 186(2-3): 95-8.
41. Paddle BM, Burnstock G. Release of ATP from perfused heart during coronary vasodilatation. Blood Vessels 1974; 11(3): 110-9.
42. Forrester T, Williams CA. Release of adenosine triphosphate from isolated adult heart cells in response to hypoxia. The Journal of physiology 1977; 268(2): 371-90.
43. Williams CA, Forrester T. Possible source of adenosine triphosphate released from rat myocytes in response to hypoxia and acidosis. Cardiovasc Res 1983; 17(5): 301-12.
44. Dosch M, Gerber J, Jebbawi F, Beldi G. Mechanisms of ATP Release by Inflammatory Cells. Int J Mol Sci 2018; 19(4).
45. Baxter M, Eltom S, Dekkak B, et al. Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung. Thorax 2014; 69(12): 1080-9.
46. Tsai Shihn H, Kinoshita M, Kusu T, et al. The Ectoenzyme E-NPP3 Negatively Regulates ATP-Dependent Chronic Allergic Responses by Basophils and Mast Cells. Immunity 2015; 42(2): 279-93.
47. Bucchioni E CZ, Polkey M, Collins JV, Cramer D, Allegra L, Barnes PJ, Kharitonov SA. Adenosine 5'-triphosphate (ATP) is increased in exhaled breath condensate in COPD. Am J Respir Crit Care Med 2002; 165: A599.
48. Basoglu OK, Barnes PJ, Kharitonov SA, Pelleg A. Effects of Aerosolized Adenosine 5'-Triphosphate in Smokers and Patients With COPD. Chest 2015; 148(2): 430-5.
49. Hlapčić I, Hulina-Tomašković A, Somborac-Bačura A, Rajković MG, Dugac AV, Popović-Grle S, Rumora L. Extracellular adenosine triphosphate is associated with airflow limitation severity and symptoms burden in patients with chronic obstructive pulmonary disease. Scientific Reports 2019; 9:15349. https://doi.org/10.1038/s41598-019-51855
50. Mortaz E, Braber S, Nazary M, Givi ME, Nijkamp FP, Folkerts G. ATP in the pathogenesis of lung emphysema. Eur J Pharmacol 2009; 619(1-3): 92-6.
51. Cicko S, Lucattelli M, Muller T, et al. Purinergic Receptor Inhibition Prevents the Development of Smoke-Induced Lung Injury and Emphysema. J Immunol 2010; 185(1): 688-97.
52. Lommatzsch M, Cicko S, Müller T, et al. Extracellular Adenosine Triphosphate and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2010; 181(9): 928-34.
53. Colgan SP, Eltzschig HK, Eckle T, Thompson LF. Physiological roles for ecto-5'-nucleotidase (CD73). Purinergic Signal 2006; 2(2): 351-60.
54. Knapp K, Zebisch M, Pippel J, El-Tayeb A, Müller CE, Sträter N. Crystal structure of the human ecto-5'-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure 2012; 20(12): 2161-73.
55. Schetinger MR, Morsch VM, Bonan CD, Wyse AT. NTPDase and 5'-nucleotidase activities in physiological and disease conditions: new perspectives for human health. Biofactors 2007; 31(2): 77-98.
56. Zhao H, Bo C, Kang Y, Li H. What Else Can CD39 Tell Us? Frontiers in Immunology 2017; 8.
57. Antonioli L, Pacher P, Vizi ES, Hasko G. CD39 and CD73 in immunity and inflammation. Trends Mol Med 2013; 19(6): 355-67.
58. Timperi E, Barnaba V. CD39 Regulation and Functions in T Cells. Int J Mol Sci 2021; 22(15).
59. Jacobson KA, Pradhan B, Wen Z, Pramanik A. New paradigms in purinergic receptor ligand discovery. Neuropharmacology 2023; 230: 109503.
60. Pasquini S, Contri C, Borea PA, Vincenzi F, Varani K. Adenosine and Inflammation: Here, There and Everywhere. Int J Mol Sci 2021; 22(14).
61. Polosa R. Adenosine-receptor subtypes: their relevance to adenosine-mediated responses in asthma and chronic obstructive pulmonary disease. Eur Respir J 2002; 20(2): 488-96.
62. Liu TT, Wang YL, Zhang Z, et al. Abnormal adenosine metabolism of neutrophils inhibits airway inflammation and remodeling in asthma model induced by Aspergillus fumigatus. BMC Pulm Med 2023; 23(1): 258.
63. Eckle T, Fullbier L, Wehrmann M, et al. Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury. Journal of immunology 2007; 178(12): 8127-37.
64. Li J, Wang L, Chen X, et al. CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-beta-mTOR-HIF-1 signaling in patients with non-small cell lung cancer. Oncoimmunology 2017; 6(6): e1320011.
65. Hu XM, Shi NR, Zhang JZ, et al. CD73: Friend or Foe in Lung Injury. Int J Mol Sci 2023; 24(6).
66. Pelleg A, Hurt CM. Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. The Journal of physiology 1996; 490 ( Pt 1): 265-75.
67. Pellegrino R, Wilson O, Jenouri G, Rodarte JR. Lung mechanics during induced bronchoconstriction. J Appl Physiol 1996; 81(2): 964-75.
68. Katchanov G, Xu J, Schulman ES, Pelleg A. ATP causes neurogenic bronchoconstriction in the dog. Drug Dev Res 1998; 45(3-4): 342-9.
69. Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB, McGarvey L. Anatomy and Neurophysiology of Cough. Chest 2014; 146(6): 1633-48.
70. Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J 1995; 8(7): 1193-202.
71. Kamei J, Takahashi Y, Yoshikawa Y, Saitoh A. Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity. Eur J Pharmacol 2005; 528(1-3): 158-61.
72. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. The Lancet 2015; 385(9974): 1198-205.
73. Garceau D, Chauret N. BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration. Pulm Pharmacol Ther 2019; 56: 56-62.
74. Pelleg A, Xu F, Zhuang J, Undem B, Burnstock G. DT-0111: a novel drug-candidate for the treatment of COPD and chronic cough. Ther Adv Respir Dis 2019; 13: 1753466619877960.
75. Burgoyne DS. Managed care considerations for the treatment of chronic cough. Am J Manag Care 2022; 28(9 Suppl): S166-S74.
76. Sykes DL, Zhang M, Morice AH. Treatment of chronic cough: P2X3 receptor antagonists and beyond. Pharmacol Ther 2022; 237: 108166.
77. Basoglu OK, Pelleg A, Essilfie-Quaye S, Brindicci C, Barnes PJ, Kharitonov SA. Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma. Chest 2005; 128(4): 1905-9.
78. Barnes PJ. Asthma as an axon reflex. The Lancet 1986; 327(8475): 242-5.
79. Barnes PJ. Neurogenic Inflammation in Airways. Int Arch Allergy Immunol 1991; 94(1-4): 303-9.
80. Barnes PJ, Baraniuk JN, Belvisi MG. Neuropeptides in the Respiratory Tract: Part I. Am Rev Respir Dis 1991; 144(5): 1187-98.
81. Schulman ES, Glaum MC, Post T, et al. ATP Modulates Anti-IgE–Induced Release of Histamine from Human Lung Mast Cells. Am J Respir Cell Mol Biol 1999; 20(3): 530-7.
82. Pelleg A, Schulman ES. Adenosine 5'-Triphosphate Axis in Obstructive Airway Diseases. Am J Therap 2002; 9(5): 454-64.
83. Mortaz E, Folkerts G, Nijkamp FP, Henricks PA. ATP and the pathogenesis of COPD. Eur J Pharmacol 2010; 638(1-3): 1-4.
84. Pelleg A, Undem BJ. A-317491 Inhibits the activation of guinea-pig pulmonary vagal sensory nerve terminals by α,β methylene_ATP. Clin Immunol 2005; 115(Suppl 1): S59-60.
85. Weigand LA, Ford AP, Undem BJ. A role for ATP in bronchoconstriction-induced activation of guinea pig vagal intrapulmonary C-fibres. The Journal of physiology 2012; 590(16): 4109-20.
86. Ford AP, Undem BJ. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders. Front Cell Neurosci 2013; 7: 267.
87. Winkelmann VE, Thompson KE, Neuland K, et al. Inflammation-induced upregulation of P2X(4) expression augments mucin secretion in airway epithelia. Am J Physiol Lung Cell Mol Physiol 2019; 316(1): L58-L70.
88. Obara K, Inaba R, Kawakita M, Murata A, Yoshioka K, Tanaka Y. Effects of NP-1815-PX, a P2X4 Receptor Antagonist, on Contractions in Guinea Pig Tracheal and Bronchial Smooth Muscles. Biol Pharm Bull 2022; 45(8): 1158-65.
89. Nagaoka M, Nara M, Tamada T, et al. Regulation of adenosine 5'-triphosphate (ATP)-gated P2X(4) receptors on tracheal smooth muscle cells. Respir Physiol Neurobiol 2009; 166(1): 61-7.
90. Wang L, Feng X, Hu B, Xia Q, Ni X, Song Y. P2X4R promotes airway remodeling by acting on the phenotype switching of bronchial smooth muscle cells in rats. Purinergic Signal 2018; 14(4): 433-42.
91. Yoshida K, Ito MA, Sato N, et al. Extracellular ATP Augments Antigen-Induced Murine Mast Cell Degranulation and Allergic Responses via P2X4 Receptor Activation. Journal of immunology 2020; 204(12): 3077-85.
92. Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med 2014; 35(1): 71-86.
93. Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2016; 138(1): 16-27.
94. Kuprash DV, Nedospasov SA. Molecular and Cellular Mechanisms of Inflammation. Biochemistry (Mosc) 2016; 81(11): 1237-9.
95. Liu JP, Liu SC, Hu SQ, et al. ATP ion channel P2X purinergic receptors in inflammation response. Biomed Pharmacother 2023; 158: 114205.
96. Linden J, Koch-Nolte F, Dahl G. Purine Release, Metabolism, and Signaling in the Inflammatory Response. Annu Rev Immunol 2019; 37: 325-47.
97. Adriaensen D. Purinergic signalling in the lung: important in asthma and COPD? Curr Opin Pharmacol 2004; 4(3): 207-14.
98. Idzko M, Hammad H, van Nimwegen M, et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nature Med 2007; 13(8): 913-9.
99. Vieira RP, Müller T, Grimm M, et al. Purinergic Receptor Type 6 Contributes to Airway Inflammation and Remodeling in Experimental Allergic Airway Inflammation. Am J Respir Crit Care Med 2011; 184(2): 215-23.
100. Birring SS, Dicpinigaitis PV, Smith JA, et al. Efficacy and Safety of Gefapixant for Refractory or Unexplained Chronic Cough over 52 Weeks. Am J Respir Crit Care Med 2023; 207(11): 1539-42.
101. McGarvey L, Sher M, Shvarts YG, et al. The Efficacy and Safety of Gefapixant in a Phase 3b Trial of Patients with Recent-Onset Chronic Cough. Lung 2023; 201(2): 111-8.
102. Morice A, Smith JA, McGarvey L, et al. Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study. Eur Respir J 2021; 58(5).
103. McGarvey L, Smith JA, Morice A, et al. A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 2b Trial of P2X3 Receptor Antagonist Sivopixant for Refractory or Unexplained Chronic Cough. Lung 2023; 201(1): 25-35.
104. Barjaktarevic IZ, Milstone AP. Nebulized Therapies in COPD: Past, Present, and the Future. Int J Chron Obstruct Pulmon Dis 2020; 15: 1665-77.
105. Labaki WW, Rosenberg SR. Chronic Obstructive Pulmonary Disease. Ann Intern Med 2020; 173(3): ITC17-ITC32.
106. Pelleg A, Sirtori E, Rolland JF, Mahadevan A. DT-0111: a novel P2X3 receptor antagonist. Purinergic Signal 2023.