Adenosine-induced bronchoconstriction in asthma: Role of mast cell-mediator release

doi:10.1016/0091-6749(85)90057-0

Journal of Allergy and Clinical Immunology

Volume 75, Issue 2, February 1985, Pages 272-278

https://doi.org/10.1016/0091-6749(85)90057-0 Get rights and content

Abstract

Adenosine, when it is administered by inhalation to asthmatic subjects, is a potent bronchoconstrictor, although its mechanism of action is not known. Since adenosine has been demonstrated to potentiate IgE-dependent mediator release from mast cells, we have investigated the possible relationship between adenosine-induced bronchoconstriction and release of mast cell mediators in 14 asthmatic subjects. In the first study the effect of the putative mast cell-stabilizing drug cromolyn sodium (SCG) was observed on the dose-related changes in SG_aw and FEV₁ produced by inhaled adenosine and histamine in seven subjects. Inhaled SCG (20 mg) had no effect on the airway responses to histamine. In contrast SCG significantly protected against adenosine-induced bronchoconstriction in four of the seven subjects as reflected by a decrease in the airway response to the highest concentrations of adenosine, from 65 ± 8% to 12 ± 3% (mean ± SEM) for SG_aw and 31 ± 7% to 8 ± 3% for FEV,. Those three subjects whose adenosine response was unaffected by SCG had received regular SCG until 12 hr before the studies. In a separate study on eight subjects, a single inhalation of adenosine, causing a maximum 61 ± 4% fall in SG_aw at 10 min, had no significant effect on circulating levels of histamine, neutrophil chemotactic factor, or cyclic AMP. Together these two studies suggest that bronchoconstriction produced by adenosine is not a consequence of enhanced mast cell-mediator release and that the inhibitory effects of SCG occur by a mechanism other than through mast cell stabilization.

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Citation Excerpt :
Furthermore, asthmatic patients exhibit hypersensitivity to inhaled ATP compared with healthy individuals [11]. AMP, which acts via adenosine [12], causes bronchoconstriction in asthmatics but not healthy subjects [13]. We have previously shown that the pulmonary effects of ATP in asthmatic and COPD patients are not mediated by adenosine [11,14].
Adenosine 5’-triphosphate (ATP) stimulates pulmonary vagal slow conducting C-fibres and fast conducting Aδ-fibres with rapidly adapting receptors (RARs). Pulmonary C-fibres but not RARs are also sensitive to capsaicin, a potent tussigenic agent in humans. Thus, the aim of this study was to determine the effects of ATP and its metabolite adenosine (given as adenosine 5’-monophosphate, AMP) on capsaicin challenge in asthmatic patients.
Cough (quantified as visual analogue scale, VAS), dyspnoea (quantified as Borg score), and FEV₁ were quantified following bronchoprovocation using capsaicin, adenosine and ATP in healthy non-smokers (age 40±4y, 6 males), smokers (45±4y, 5 males) and asthmatic patients (37±3y, 5 males); n = 10 in each group.
None of the healthy non-smokers responded to either AMP or ATP. AMP induced bronchoconstriction in one smoker and eight asthmatics, and ATP in two smokers and all ten asthmatics. The geometric mean of capsaicin causing ≥5 coughs (C5) increased from 134 to 203 μM in non-smokers and from 117 to 287 μM in asthmatics after AMP, whereas it decreased from 203 to 165 μM and 125 to 88 μM, respectively after ATP. AMP decreased C5 from 58 to 29 μM and ATP increased from 33 to 47 μM in smokers. However, due to intergroup variability, these effects of ATP and AMP were not statistically significant (0.125 ≤ p ≤ 0.998). That notwithstanding, in healthy and asthmatic subjects the effects of the ATP showed a tendency to be greater than those of AMP (p < 0.053). Dyspnea, assessed by Borg score, increased after ATP (p < 0.001) and AMP (p < 0.001) only in asthmatic patients. Intensity of cough assessed by VAS increased (p < 0.05) after second capsaicin challenges performed after AMP in all groups, but not after ATP.
Asthmatic patients exhibit hypersensitivity to aerosolized AMP and ATP, but aerosolized AMP does not mimic the effects of ATP and the effects of ATP are not mediated by adenosine.
Effects of aerosolized adenosine 5'-triphosphate in smokers and patients with COPD
2015, Chest
Extracellular adenosine 5′-triphosphate (ATP) stimulates vagal C and Ad 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.
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).
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.
Smokers and patients with COPD manifest hypersensitivity to extracellular ATP, which may play a mechanistic role in COPD. CHEST 2015;148(2):430-435
Predictive value of adenosine 5′-monophosphate challenge in preschool children for the diagnosis of asthma 5 years later
2012, Journal of Pediatrics
We evaluated the predictive values of preschool bronchial challenge with nebulized adenosine 5′-monophosphate (AMP) using the auscultation method for having asthma 5 years later. Preschool AMP challenge had a high negative (90%) and a moderate positive (67%) predictive value for asthma 5 years later. Positive predictive value increased with the age at which the challenge was performed. The degree of preschool response to AMP was associated with the severity of asthma at school age.
Theophylline
2009, Asthma and COPD
Theophylline remains one of the most widely prescribed drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD) worldwide, since it is inexpensive and widely available. The frequency of side-effects at the previously recommended doses and the relatively low efficacy of theophylline have recently led to reduced usage, since inhaled β₂-agonists are far more effective as bronchodilators and inhaled corticosteroids have a greater anti-inflammatory effect. Despite the fact that theophylline has been used in asthma therapy for over 70 years, there is still considerable uncertainty about its molecular mode of action in asthma and its logical place in therapy. Theophylline is a methylxanthine similar in structure to the common dietary xanthines caffeine and theobromine. Many salts of theophylline have also been marketed, the most common being aminophylline, the ethylene diamine salt used to increase solubility at neutral pH, so that intravenous administration is possible. Theophylline has several cellular effects that may contribute to its clinical efficacy in the treatment of asthma. The primary effect of theophylline is assumed to be the relaxation of airway smooth muscle. It is suggested that theophylline may exert its effects in asthma via some action outside the airways. It may be relevant that theophylline is ineffective when given by inhalation until therapeutic plasma concentrations are achieved. The molecular mechanism of anti-inflammatory effects of theophylline is now becoming clearer, and it seems likely that there is a synergistic interaction with the anti-inflammatory mechanism of corticosteroids through restoration of HDAC activity. This interaction may underlie the beneficial effects of theophylline when added to inhaled corticosteroids. This may be particularly appropriate in patients with more severe asthma in whom corticosteroids are less effective as there may be a reduction in HDAC activity in these patients as well as in smoking asthmatics patients and patients with COPD.
Theophylline
2008, Asthma and COPD: Basic Mechanisms and Clinical Management
Theophylline remains one of the most widely prescribed drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD) worldwide, since it is inexpensive and widely available. The frequency of side-effects at the previously recommended doses and the relatively low efficacy of theophylline have recently led to reduced usage, since inhaled β₂-agonists are far more effective as bronchodilators and inhaled corticosteroids have a greater anti-inflammatory effect. Despite the fact that theophylline has been used in asthma therapy for over 70 years, there is still considerable uncertainty about its molecular mode of action in asthma and its logical place in therapy. Theophylline is a methylxanthine similar in structure to the common dietary xanthines caffeine and theobromine. Many salts of theophylline have also been marketed, the most common being aminophylline, the ethylene diamine salt used to increase solubility at neutral pH, so that intravenous administration is possible. Theophylline has several cellular effects that may contribute to its clinical efficacy in the treatment of asthma. The primary effect of theophylline is assumed to be the relaxation of airway smooth muscle. It is suggested that theophylline may exert its effects in asthma via some action outside the airways. It may be relevant that theophylline is ineffective when given by inhalation until therapeutic plasma concentrations are achieved. The molecular mechanism of anti-inflammatory effects of theophylline is now becoming clearer, and it seems likely that there is a synergistic interaction with the anti-inflammatory mechanism of corticosteroids through restoration of HDAC activity. This interaction may underlie the beneficial effects of theophylline when added to inhaled corticosteroids. This may be particularly appropriate in patients with more severe asthma in whom corticosteroids are less effective as there may be a reduction in HDAC activity in these patients as well as in smoking asthmatics patients and patients with COPD.
Effect of histamine and adenosine 5′-monophosphate provocation on sputum neutrophils and related mediators in atopic patients
2005, Annals of Allergy, Asthma and Immunology
Airway hyperresponsiveness and inflammation can be noninvasively studied by bronchial provocation using direct (histamine) or indirect (adenosine 5′-monophosphate [AMP]) stimuli and induced sputum.
To report on the immediate effects of histamine and AMP challenge on induced sputum neutrophil counts and related mediator levels.
We performed a single-masked, randomized, placebo-controlled, 3-way, crossover, methodological study in 14 atopic patients (median age, 25 years; 8 males; mean ± SD forced expiratory volume in 1 second, 99% ± 5%) without anti-inflammatory medication use. At baseline, sputum induction was performed. Bronchial challenges with AMP, histamine, or placebo were performed 48 hours later. Thirty minutes after challenge, sputum induction was performed again. Challenge periods in each patient were separated by more than 2 weeks. Sputum cells and the mediators leukotriene B₄, interleukin 8, myeloperoxidase, and albumin were quantified.
Comparing median challenge-induced relative changes in cells and mediators, neither histamine nor AMP challenge altered the induced sputum neutrophil counts (histamine, 2.7%; AMP, 2.95%; placebo, −2%; P > .07 for all), interleukin 8 levels (histamine, 2.4 ng/mL; AMP, −3.8 ng/mL; placebo, −0.2 ng/mL; P > .06), leukotriene B₄ levels (histamine, −4.8 pg/mL; AMP, 3 pg/mL; placebo, 6 pg/mL; P > .08), or myeloperoxidase levels (histamine, 0.16 μg/mL; AMP, 0 μg/mL; placebo, −0.03 μg/mL; P > .07). Sputum albumin levels were increased after histamine challenge compared with AMP and placebo challenge (P < .01 for both).
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Original articleAdenosine-induced bronchoconstriction in asthma: Role of mast cell-mediator release

Abstract

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

The control of the metabolism and the hormonal role of adenosine

Essays Biochem

Adenosine receptors and the regulation of adenylate cyclase

Adv Cyclic Nucleotide Res

Adenosine regulates via two different types of receptors the accumulation of cyclic AMP in cultured brain cells

J Neurochem

Evidence for an A2/Ra adenosine receptor in the guinea pig trachea

Br J Pharmacol

Effect on tracheal smooth muscle of adenosine and methylxanthines, and their interaction

J Pharm Pharmacol

Inhaled adenosine and guanosine on airway resistance in normal and asthmatic subjects

Br J Clin Pharmacol

Adenosine antagonism as an alternative mechanism of action of methylxanthines in asthma

Agents Actions

Adenosine-induced bronchoconstriction in asthma: antagonism by inhaled theophylline

Am Rev Respir Dis

Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4, and E4

Role of adenylate cyclase in immunologic release of mediators from rat mast cells and agonist and antagonist effects of purine- and ribose-modified adenosine analogs

Potentiation of mast cell-mediator release by adenosine

J Inununol

Inhibitory effect of traxanox sodium on IgE-mediated histamine release from passively sensitized mast cells of the rat in vitro

Int Arch Allergy Appl Immunol

A simple numerical analysis of whole body plethysmograph data

Clin Sci

Original article
Adenosine-induced bronchoconstriction in asthma: Role of mast cell-mediator release

Evidence for an A₂/Ra adenosine receptor in the guinea pig trachea

Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C₄, D₄, and E₄