0
Original Research: COPD |

Effects of Aerosolized Adenosine 5′-Triphosphate in Smokers and Patients With COPDAdenosine 52032-Triphosphate in COPD FREE TO VIEW

Ozen K. Basoglu, MD; Peter J. Barnes, DM, DSc, Master FCCP; Sergei A. Kharitonov, MD; Amir Pelleg, PhD
Author and Funding Information

From the Department of Chest Diseases (Dr Basoglu), Ege University School of Medicine, Izmir, Turkey; the Airway Disease Section (Drs Barnes and Kharitonov), National Heart & Lung Institute, Imperial College, London, England; and the Department of Medicine (Dr Pelleg), Drexel University College of Medicine, Philadelphia, PA.

CORRESPONDENCE TO: Amir Pelleg, PhD, Drexel University College of Medicine, Department of Medicine, NCB Mail Box 470, 245 N 15th St, Philadelphia, PA 19102-1192; e-mail: apelleg@drexelmed.edu


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):430-435. doi:10.1378/chest.14-2285
Text Size: A A A
Published online

BACKGROUND:  Extracellular adenosine 5′-triphosphate (ATP) stimulates vagal C and Aδ fibers in the lung, resulting in pronounced bronchoconstriction and cough mediated by P2X2/3 receptors located on vagal sensory nerve terminals. We investigated the effects of nebulized ATP on cough and symptoms in control subjects, healthy smokers, and patients with COPD and compared these responses to the effects of inhaled adenosine, the metabolite of ATP.

METHODS:  We studied the effects of inhaled ATP and adenosine monophosphate (AMP) on airway caliber, perception of dyspnea assessed by the Borg score, cough sensitivity, and ATP in exhaled breath condensate in healthy nonsmokers (n = 10), healthy smokers (n = 14), and patients with COPD (n = 7).

RESULTS:  In comparison with healthy subjects, ATP induced more dyspnea, cough, and throat irritation in smokers and patients with COPD, and the effects of ATP were more pronounced than those of AMP. The concentration of ATP in the exhaled breath condensate of patients with COPD was elevated compared with that of healthy subjects.

CONCLUSIONS:  Smokers and patients with COPD manifest hypersensitivity to extracellular ATP, which may play a mechanistic role in COPD.

Figures in this Article

The ubiquitous adenine nucleotide adenosine 5′-triphosphate (ATP) is released from cells under physiologic and pathophysiologic conditions.1 Extracellular ATP exerts multiple effects on various cell types that are mediated by purinergic 2 cell-surface receptors (P2Rs). These receptors are divided into two families: seven-transmembrane domain G protein-coupled receptors, P2YR, and trans-cell membrane cationic channels, P2XR. The binding of ATP to P2YR results in the activation of intracellular signaling cascades, whereas its binding to P2XR results in the opening of cationic channels.2 Both types of receptor are abundant in the lung.3 Extracellular ATP is rapidly degraded to adenosine monophosphate (AMP) and adenosine by ectoenzymes, mainly CD39 and CD73.4 Adenosine is deaminated and rapidly transported into cells and, therefore, is also rapidly eliminated from the extracellular space. Thus, ATP can mimic all the actions of adenosine but not vice versa.

It has been previously shown that aerosolized ATP is a potent bronchoconstrictor in healthy humans, and this action is more pronounced in patients with asthma with airway hyperresponsiveness,5,6 whereas aerosolized AMP causes bronchoconstriction only in patients with asthma,7 and this action is mediated by histamine release from airway mast cells.8 We have previously shown that the bronchoconstriction induced by ATP in healthy human subjects and patients with asthma is not mediated by adenosine.6 In a canine model, ATP induces bronchoconstriction via a pulmonary central vagal reflex as a result of the activation of P2XR located on vagal C fiber terminals in the lung.9 We have also shown that the heterodimer receptor P2X2/3 mediates the action of ATP on the guinea pig pulmonary C and Aδ fibers.10 Both of these fiber types are believed to play a major mechanistic role in cough.11,12

The effects of ATP inhalation in smokers and patients with COPD are unknown, and comparison of ATP and AMP (ie, adenosine13) challenges in these patients has not been reported. The present study was aimed at testing the following hypotheses: (1) smokers and patients with COPD manifest hypersensitivity to aerosolized ATP, (2) aerosolized ATP is a potent tussigenic agent, and (3) the actions of ATP in patients with COPD are not mediated by adenosine. To test these hypotheses, we have challenged healthy subjects, healthy smokers, and patients with COPD with aerosolized ATP and AMP.

Subjects

Thirty-one subjects (47 ± 8 years old) were studied; they were divided into three groups as follows: healthy nonsmokers (41 ± 3 years old, n = 10), healthy smokers (45 ± 3 years old, n = 14), and patients with COPD (58 ± 4 years old, n = 7) (Table 1). The latter were with FEV1/FVC of < 0.7 and FEV1 down to 50% predicted (GOLD [Global Initiative for Obstructive Lung Disease] I and II). Patients with COPD were clinically stable and free from respiratory tract infection or use of oral or inhaled corticosteroids in the preceding 4 weeks. The study was approved by the Ethics Committee of the Royal Brompton Hospital (study ID DHTABPT0336)

Table Graphic Jump Location
TABLE 1 ]  Characteristics of the Study Populations

Values are expressed as No. or mean ± SEM.

a 

Significant difference from normal smokers, P < .05.

Study Design

The study was a randomized, double-blind, crossover design. Each subject attended the laboratory on three occasions. Procedures on the screening visit included medical history and spirometry. At visits 2 and 3, separated by 2 to 7 days, the subjects were randomly given either an ATP or AMP challenge in random order. Before, immediately after, and 30 min after the challenge, spirometry and Borg dyspnea score were measured, and symptoms other than dyspnea were recorded. In addition, exhaled breath condensate (EBC) was collected.

Lung Function

To assess lung function, spirometric and reversibility tests14 were used. Both tests were performed using a dry spirometer (Vitalograph).

Borg Score

The modified Borg scale was a category scale in which words describing degrees of breathlessness were anchored to numbers between 0 and 10. The subjects were asked to select a number whose words most appropriately described their perception of breathlessness. The change in dyspnea was also expressed as ΔBorg, which was the difference in Borg score before and after the challenge.15,16

Inhalation Challenge

ATP and AMP (Sigma-Aldrich Corporation) were freshly dissolved in normal saline solution to produce a range of doubling concentrations from 0.227 to 929 μmol/mL for ATP and from 0.138 to 1,152 μmol/mL for AMP and were administrated by a breath-activated dosimeter (Markos Mefar SpA) with an output of 10 μL per inhalation.17 The subjects, while wearing a nose clip, inhaled five breaths of normal saline, followed by sequential doubling concentrations of either ATP or AMP. FEV1 was measured 2 min after the fifth inhalation until there was a fall in FEV1 of ≥ 20% from its value recorded after saline inhalation or until maximal concentration of either ATP or AMP was inhaled. The provocative dose causing a 20% decrease in FEV1 (PD20) was calculated by interpolation of the logarithmic dose-response curve.

Exhaled Breath Condensate

EBC was collected (EcoScreen; Jaeger) for 10 min with normal tidal breathing. The samples were stored at −80°C until used for determination of ATP concentration. A standard curve was set up with ATP concentrations ranging between 0.1 nM to 10 μM. The assay was run on a 96-well plate. ATP assay mix was automatically injected and luminescence detected (FLUOSTAR Optima; BMG Labtech GmbH).

Statistical Methods

All analyses were performed with a software package (GraphPad Software, Inc). The significance of differences among groups was assessed by Student t test, and analysis of categorical variables was examined by χ2 test. Pearson correlation coefficient and linear regression analysis were used to analyze the relationship between the percentage falls in FEV1 and Borg score. The PD20 values for ATP and AMP were logarithmically transformed to normalize their distribution and presented as geometric means. All other numerical variables were expressed as the mean ± SEM, and significance was defined as P < .05.

Airway Responsiveness to ATP and AMP

None of the healthy nonsmoking subjects responded to either AMP or ATP, with a ≥ 20% fall in FEV1 up to the maximal challenging dose. Of the remaining 21 smokers and patients with COPD, five (24%) responded to AMP and 10 (48%) to ATP, with a ≥ 20% fall in FEV1. The geometric mean PD20 for AMP and ATP were 207.3 and 210.6 μmol/mL and 151.4 and 178.5 μmol/mL, in smokers and patients with COPD, respectively (Fig 1).

Figure Jump LinkFigure 1 –  A, B, Individual PD20 values of ATP (A) and AMP (B) challenge tests. Horizontal bars represent geometric mean values, and dashed lines indicate the highest concentration administrated (929 μmol/mL for ATP and 1,152 μmol/mL for AMP). Geometric mean was calculated by excluding the patients not responding to the highest concentration of AMP or ATP. AMP = adenosine 5′-monophosphate; ATP = adenosine 5′-triphosphate; PD20 = provocative dose causing a 20% decrease in FEV1 (μmol/mL).Grahic Jump Location
Effect of ATP and AMP Challenge on Dyspnea

The perception of dyspnea assessed by the Borg score increased significantly after ATP challenge in smokers (from 0.04 to 1.57, P = .0002) and patients with COPD (from 0.14 to 2.71, P = .003). In contrast, after AMP challenge, there was a significant increase in Borg score only in smokers (from 0.04 to 1.04, P = .01). Comparison of the change in Borg score (ΔBorg) after ATP and AMP challenge revealed that ΔBorg was higher after ATP in all groups, and this increase was significant after ATP challenge in patients with COPD (ΔBorgATP = 2.6 vs ΔBorgAMP = 0.6, P = .005) (Fig 2). There was no correlation between the PD20 for bronchoconstriction and Borg score after AMP challenge (r = −0.2846, P > .05), whereas a significant negative correlation was observed between the PD20 and Borg score after ATP challenge (r = −0.5297, P = .002).

Figure Jump LinkFigure 2 –  A, B, ΔBorg after ATP (A) and AMP (B) challenge tests. *ΔBorg was higher after ATP in all groups, and this increase was significant after ATP challenge in patients with COPD (ΔBorgATP = 2.6 vs ΔBorgAMP = 0.6, P = .005). ΔBorg = difference between Borg score before and after the challenge test. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Effect of ATP and AMP Challenge on Symptoms

Twenty-eight subjects (90%) coughed after ATP challenge, whereas AMP challenge caused cough in only 13 (42%) subjects (P < .0001). ATP triggered cough in 70% of the healthy subjects, whereas AMP triggered cough in only 20%. The percentage of subjects who had throat irritation (81% and 52%, respectively; P < .0001) and sputum production (29% and 3%, respectively; P = .001) were also significantly higher after ATP compared with AMP challenge (Table 2). Thus, ATP was more potent than AMP in inducing symptoms all three groups.

Table Graphic Jump Location
TABLE 2 ]  Frequency of Symptoms After AMP and ATP Challenge

AMP = adenosine 5′-monophosphate; ATP = adenosine 5′-triphosphate.

ATP Concentrations in EBC

ATP levels in EBC of healthy subjects were greater than those of patients with COPD, but because of the small number of patients with COPD and marked intergroup and intragroup variability in the levels of ATP in the EBC, this difference did not reach significance (P = .222) (Table 3).

Table Graphic Jump Location
TABLE 3 ]  ATP Concentrations (nM) in Exhaled Breath Condensate

See Table 2 legend for expansion of abbreviation.

The present study provides new evidence for a potential mechanistic role for ATP in COPD and cough. We have found that smokers and patients with COPD manifest hypersensitivity to ATP and AMP, but the effects of ATP were significantly more pronounced than those of AMP, strongly suggesting that the effects of ATP are not mediated via adenosine, which is the product of the rapid degradation of ATP. Moreover, inhaled ATP triggered cough in healthy subjects and more so in smokers and patients with COPD.

More than a decade ago we proposed for the first time, to our knowledge, that extracellular ATP may play a mechanistic role in pulmonary disorders in general and asthma, COPD, and chronic cough in particular.17 Since then, data obtained by us and others have provided strong support for this hypothesis. As part of the inflammatory process in the lung, significant amounts of ATP are released into the extracellular space from various cells, including leukocytes, RBCs, epithelial and smooth muscle cells, platelets, vascular endothelium, nerve endings, and neuroepithelial bodies.18 Indeed, in subjects with asthma and mice sensitized to allergen, ATP concentrations are markedly elevated in the BAL fluid following allergen challenge compared with saline control subjects.19

ATP released into the extracellular space under inflammatory conditions may exert pronounced modulatory effects on inflammatory cells, thereby playing an important mechanistic role in inflammation.20 We have found that the concentration of ATP in EBC of patients with COPD is greater than that of healthy subjects; however, this difference was not statistically significant, probably due to the high variability of measurements in EBC and small number of patients with COPD. Indeed, this observation is in agreement with the finding that the concentration of ATP in RBCs of patients with COPD is three times greater than that that of healthy subjects.21 RBCs store large amounts of ATP, which is released into the extracellular space under physiologic and pathophysiologic conditions.22

In an earlier study,5 ATP was found to cause bronchoconstriction in healthy subjects and more so in patients with asthma. In this and our previous study,6 healthy subjects did not respond to ATP. ATP can act via a central pulmonary-pulmonary vagal reflex as well as adenosine the product of its rapid degradation by ectoenzymes. However, adenosine does not cause bronchoconstriction in healthy subjects7; thus, further studies are required to determine the cause of this discrepancy.

The present observation of aerosolized ATP as a potent tussigenic agent is in agreement with previously reported data. We have shown that extracellular ATP stimulates vagal afferent terminals of C- and Aδ-fibers in the lung,9,10 both of which are considered to mediate the cough reflex.11 This action of ATP is the result of the activation of P2X2/3R localized to these nerve fibers.10 Indeed, a study in human subjects has shown that a selective antagonist at P2X3R markedly and significantly reduced cough vs placebo (−75%, P < .001) in patients with chronic cough.23 Moreover, extracellular ATP induces airway smooth muscle hyperresponsiveness to methacholine mediated by Ca2+ sensitization via P2X receptors.24

Since ATP is rapidly degraded to adenosine diphosphate, AMP, and adenosine by ectoenzymes,4 an analysis of extracellular actions of ATP should aim to also assess a potential role of adenosine. In the present study, we compared the effects of aerosolized ATP to AMP, since the effects of the latter are known to be mediated by adenosine.13 We have previously shown that aerosolized ATP is more potent bronchoconstrictor than AMP in patients with asthma.6 In agreement with our previous study, the present results indicate that the effects of aerosolized ATP are more pronounced than those of AMP also in healthy subjects, smokers, and patients with COPD. The differential potency of ATP and adenosine in the lungs is similar to that observed in the heart25 and can be explained to a large extent by the ability of extracellular ATP to directly stimulate vagal sensory afferent fibers in both organs, whereas adenosine is devoid of this action.25,26

Taken together, the present data give further support to our original hypothesis that endogenous extracellular ATP plays a mechanistic role in COPD and chronic cough. In addition, it strongly suggests that the inhibition of specific ATP signal transduction pathways in the lungs, for example with P2X3R antagonists, constitutes an attractive target for the development of new therapeutic modalities in these settings.

Author contributions: P. J. B. was the director of the project; he was responsible for the study’s compliance with all institutional administrative, ethical, and clinical requirements. P. J. B. and A. P. conceptualized the study and outlined its original design; O. K. B. and S. A. K. executed the study; O. K. B. complied and analyzed the data; A. P. was in charge of all basic scientific aspects of the study; and O. K. B. and A. P. wrote the original draft of the manuscript. All authors reviewed and edited the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

AMP

adenosine 5′-monophosphate

ATP

adenosine 5′-triphosphate

ΔBorg

change in Borg dyspnea score

EBC

exhaled breath condensate

P2R

purinergic 2 receptor

PD20

provocative dose causing a 20% decrease in FEV1

Lazarowski ER, Boucher RC, Harden TK. Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol. 2003;64(4):785-795. [CrossRef] [PubMed]
 
Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci. 2007;64(12):1471-1483. [CrossRef] [PubMed]
 
Burnstock G, Brouns I, Adriaensen D, Timmermans JP. Purinergic signaling in the airways. Pharmacol Rev. 2012;64(4):834-868. [CrossRef] [PubMed]
 
Zimmermann H. Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol. 2000;362(4-5):299-309. [CrossRef] [PubMed]
 
Pellegrino R, Wilson O, Jenouri G, Rodarte JR. Lung mechanics during induced bronchoconstriction. J Appl Physiol (1985). 1996;81(2):964-975. [PubMed]
 
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):1905-1909. [CrossRef] [PubMed]
 
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):161-165. [CrossRef] [PubMed]
 
Cushley MJ, Holgate ST. Adenosine-induced bronchoconstriction in asthma: role of mast cell-mediator release. J Allergy Clin Immunol. 1985;75(2):272-278. [CrossRef] [PubMed]
 
Pelleg A, Hurt CM. Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. J Physiol. 1996;490(pt 1):265-275. [CrossRef] [PubMed]
 
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-S60.
 
Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J. 1995;8(7):1193-1202. [CrossRef] [PubMed]
 
Widdicombe J. Sensory mechanisms. Pulm Pharmacol. 1996;9(5-6):383-387. [CrossRef] [PubMed]
 
Mann JS, Holgate ST, Renwick AG, Cushley MJ. Airway effects of purine nucleosides and nucleotides and release with bronchial provocation in asthma. J Appl Physiol (1985). 1986;61(5):1667-1676. [PubMed]
 
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163(5):1256-1276. [CrossRef] [PubMed]
 
Rutgers SR, ten Hacken NH, Koeter GH, Postma DS. Borg scores before and after challenge with adenosine 5′-monophosphate and methacholine in subjects with COPD and asthma. Eur Respir J. 2000;16(3):486-490. [CrossRef] [PubMed]
 
Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Campbell EJ. The perception of breathlessness in asthma. Am Rev Respir Dis. 1982;126(5):825-828. [PubMed]
 
Pelleg A, Schulman ES. Adenosine 5′-triphosphate axis in obstructive airway diseases. Am J Ther. 2002;9(5):454-464. [CrossRef] [PubMed]
 
Adriaensen D, Timmermans JP. Purinergic signalling in the lung: important in asthma and COPD? Curr Opin Pharmacol. 2004;4(3):207-214. [CrossRef] [PubMed]
 
Idzko M, Hammad H, van Nimwegen M, et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med. 2007;13(8):913-919. [CrossRef] [PubMed]
 
Jacob F, Pérez Novo C, Bachert C, Van Crombruggen K. Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal. 2013;9(3):285-306. [CrossRef] [PubMed]
 
Sprague RS, Ellsworth ML, Stephenson AH, Kleinhenz ME, Lonigro AJ. Deformation-induced ATP release from red blood cells requires CFTR activity. Am J Physiol. 1998;275(5 pt 2):H1726-H1732. [PubMed]
 
Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The erythrocyte as a regulator of vascular tone. Am J Physiol. 1995;269(6 pt 2):H2155-H2161. [PubMed]
 
Abdulqawi R, Dockry R, Holt K, et al. Inhibition of ATP-gated P2X3 channels by AF-219: an effective anti-tussive mechanism in chronic cough. Eur Respir J. 2013;42(suppl 57):386s.
 
Oguma T, Ito S, Kondo M, et al. Roles of P2X receptors and Ca2+sensitization in extracellular adenosine triphosphate-induced hyperresponsiveness in airway smooth muscle. Clin Exp Allergy. 2007;37(6):893-900. [CrossRef] [PubMed]
 
Xu J, Kussmaul W, Kurnik PB, Al-Ahdav M, Pelleg A. Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. V. Role of purinergic receptors. Am J Physiol Regul Integr Comp Physiol. 2005;288(3):R651-R655. [CrossRef] [PubMed]
 
Katchanov G, Xu J, Schulman ES, Pelleg A. ATP causes neurogenic bronchoconstriction in the dog. Drug Dev Res. 1998;45(3-4):342-349. [CrossRef]
 

Figures

Figure Jump LinkFigure 1 –  A, B, Individual PD20 values of ATP (A) and AMP (B) challenge tests. Horizontal bars represent geometric mean values, and dashed lines indicate the highest concentration administrated (929 μmol/mL for ATP and 1,152 μmol/mL for AMP). Geometric mean was calculated by excluding the patients not responding to the highest concentration of AMP or ATP. AMP = adenosine 5′-monophosphate; ATP = adenosine 5′-triphosphate; PD20 = provocative dose causing a 20% decrease in FEV1 (μmol/mL).Grahic Jump Location
Figure Jump LinkFigure 2 –  A, B, ΔBorg after ATP (A) and AMP (B) challenge tests. *ΔBorg was higher after ATP in all groups, and this increase was significant after ATP challenge in patients with COPD (ΔBorgATP = 2.6 vs ΔBorgAMP = 0.6, P = .005). ΔBorg = difference between Borg score before and after the challenge test. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Characteristics of the Study Populations

Values are expressed as No. or mean ± SEM.

a 

Significant difference from normal smokers, P < .05.

Table Graphic Jump Location
TABLE 2 ]  Frequency of Symptoms After AMP and ATP Challenge

AMP = adenosine 5′-monophosphate; ATP = adenosine 5′-triphosphate.

Table Graphic Jump Location
TABLE 3 ]  ATP Concentrations (nM) in Exhaled Breath Condensate

See Table 2 legend for expansion of abbreviation.

References

Lazarowski ER, Boucher RC, Harden TK. Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol. 2003;64(4):785-795. [CrossRef] [PubMed]
 
Burnstock G. Purine and pyrimidine receptors. Cell Mol Life Sci. 2007;64(12):1471-1483. [CrossRef] [PubMed]
 
Burnstock G, Brouns I, Adriaensen D, Timmermans JP. Purinergic signaling in the airways. Pharmacol Rev. 2012;64(4):834-868. [CrossRef] [PubMed]
 
Zimmermann H. Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol. 2000;362(4-5):299-309. [CrossRef] [PubMed]
 
Pellegrino R, Wilson O, Jenouri G, Rodarte JR. Lung mechanics during induced bronchoconstriction. J Appl Physiol (1985). 1996;81(2):964-975. [PubMed]
 
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):1905-1909. [CrossRef] [PubMed]
 
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):161-165. [CrossRef] [PubMed]
 
Cushley MJ, Holgate ST. Adenosine-induced bronchoconstriction in asthma: role of mast cell-mediator release. J Allergy Clin Immunol. 1985;75(2):272-278. [CrossRef] [PubMed]
 
Pelleg A, Hurt CM. Mechanism of action of ATP on canine pulmonary vagal C fibre nerve terminals. J Physiol. 1996;490(pt 1):265-275. [CrossRef] [PubMed]
 
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-S60.
 
Widdicombe JG. Neurophysiology of the cough reflex. Eur Respir J. 1995;8(7):1193-1202. [CrossRef] [PubMed]
 
Widdicombe J. Sensory mechanisms. Pulm Pharmacol. 1996;9(5-6):383-387. [CrossRef] [PubMed]
 
Mann JS, Holgate ST, Renwick AG, Cushley MJ. Airway effects of purine nucleosides and nucleotides and release with bronchial provocation in asthma. J Appl Physiol (1985). 1986;61(5):1667-1676. [PubMed]
 
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163(5):1256-1276. [CrossRef] [PubMed]
 
Rutgers SR, ten Hacken NH, Koeter GH, Postma DS. Borg scores before and after challenge with adenosine 5′-monophosphate and methacholine in subjects with COPD and asthma. Eur Respir J. 2000;16(3):486-490. [CrossRef] [PubMed]
 
Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Campbell EJ. The perception of breathlessness in asthma. Am Rev Respir Dis. 1982;126(5):825-828. [PubMed]
 
Pelleg A, Schulman ES. Adenosine 5′-triphosphate axis in obstructive airway diseases. Am J Ther. 2002;9(5):454-464. [CrossRef] [PubMed]
 
Adriaensen D, Timmermans JP. Purinergic signalling in the lung: important in asthma and COPD? Curr Opin Pharmacol. 2004;4(3):207-214. [CrossRef] [PubMed]
 
Idzko M, Hammad H, van Nimwegen M, et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med. 2007;13(8):913-919. [CrossRef] [PubMed]
 
Jacob F, Pérez Novo C, Bachert C, Van Crombruggen K. Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal. 2013;9(3):285-306. [CrossRef] [PubMed]
 
Sprague RS, Ellsworth ML, Stephenson AH, Kleinhenz ME, Lonigro AJ. Deformation-induced ATP release from red blood cells requires CFTR activity. Am J Physiol. 1998;275(5 pt 2):H1726-H1732. [PubMed]
 
Ellsworth ML, Forrester T, Ellis CG, Dietrich HH. The erythrocyte as a regulator of vascular tone. Am J Physiol. 1995;269(6 pt 2):H2155-H2161. [PubMed]
 
Abdulqawi R, Dockry R, Holt K, et al. Inhibition of ATP-gated P2X3 channels by AF-219: an effective anti-tussive mechanism in chronic cough. Eur Respir J. 2013;42(suppl 57):386s.
 
Oguma T, Ito S, Kondo M, et al. Roles of P2X receptors and Ca2+sensitization in extracellular adenosine triphosphate-induced hyperresponsiveness in airway smooth muscle. Clin Exp Allergy. 2007;37(6):893-900. [CrossRef] [PubMed]
 
Xu J, Kussmaul W, Kurnik PB, Al-Ahdav M, Pelleg A. Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. V. Role of purinergic receptors. Am J Physiol Regul Integr Comp Physiol. 2005;288(3):R651-R655. [CrossRef] [PubMed]
 
Katchanov G, Xu J, Schulman ES, Pelleg A. ATP causes neurogenic bronchoconstriction in the dog. Drug Dev Res. 1998;45(3-4):342-349. [CrossRef]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543