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: 15 may 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.
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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.
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