Extracellular Adenosine Triphosphate and Chronic Obstructive Pulmonary Disease

Lommatzsch, Marek; Cicko, Sanja; Müller, Tobias; Lucattelli, Monica; Bratke, Kai; Stoll, Paul; Grimm, Melanie; Dürk, Thorsten; Zissel, Gernot; Ferrari, Davide; Virgilio, Francesco Di; Sorichter, Stephan; Lungarella, Giuseppe; Virchow, J. Christian; Idzko, Marco

doi:10.1164/rccm.200910-1506oc

Cited by 181 publications

(180 citation statements)

References 35 publications

(34 reference statements)

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“…30 Such issues may also affect purine measures in BAL. 4,26 Although EBC collection does not introduce chemical gradients or expose airway surfaces to mechanical forces, 16,22 we cannot exclude the possibility that patient selection, storage time, or the particular EBC collection device used in this study infl uenced measured concentrations. Furthermore, the very low and highly variable fraction of airway secretions within the condensate posed considerable analytic challenges.…”

Section: Airway Surface Concentrations and Dilution In Ebcmentioning

confidence: 98%

“…25 Differences in adenosine may have been masked by treatment effects, since use of inhaled corticosteroids (common within our COPD cohorts) has been associated with reduced EBC adenosine. 5 In addition, smoking has been shown to alter airway purines 4,26 and may have made it more diffi cult to distinguish COPD from healthy smokers, although the strong relationship between COPD and smoking limited our ability to directly assess the impact of smoking in this study. Indeed, our fi ndings support a model in which infl ammatory responses to smoking result in increased airway purines (adenosine and AMP), which intensify as chronic infl ammation develops and worsens in COPD.…”

Section: Airway Surface Concentrations and Dilution In Ebcmentioning

confidence: 99%

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Elevated Airway Purines in COPD

Esther

Lazaar

Bordonali

et al. 2011

Chest

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Purinergic signaling pathways regulate airways defense mechanisms, including mucociliary clearance and infl ammatory responses. These pathways are activated by extracellular purines, which include adenosine triphosphate (ATP) and its metabolites adenosine diphosphate, adenosine monophosphate (AMP), and adenosine. Adenosine, in particular, has been linked to infl ammatory airways diseases, 1 including twofold to fourfold elevations in blood 2,3 and BAL fl uid 4 of subjects with asthma. Similarly, adenosine concentrations in exhaled breath condensate (EBC) are elevated in subjects with stable asthma, 5,6 increased with asthma exacerbations, 7 and decreased with successful treatment. Findings from animal models, particularly the adenosine deaminase knockout mouse, 8,9 further support a link between airway infl ammation and lung adenosine.These data suggest that purinergic signaling pathways may be active in infl ammatory lung diseases such as COPD and may be targets for therapeutic intervention. 10 Indeed, elevated airway adenosine concentrations in COPD have been inferred from studies of human airway adenosine receptors, 11 and several reviews have touted potential benefi ts of pharmacologic blockade of adenosine receptors. 10,12 Although these benefi ts are a reasonable extrapolation from the animal 8,13 and human studies, 4,5 a recent investigation suggested that airway adenosine concentrations (as measured in sputum) may actually be lower in COPD. 14 However, adenosine concentrations in respiratory samples such as sputum or BAL can be altered unpredictably by extracellular metabolism during processing or by mechanical and osmotic forces that trigger purine release during collection.

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Section: Airway Surface Concentrations and Dilution In Ebcmentioning

confidence: 98%

Section: Airway Surface Concentrations and Dilution In Ebcmentioning

confidence: 99%

Elevated Airway Purines in COPD

Esther

Lazaar

Bordonali

et al. 2011

Chest

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“…Under inflammatory conditions, cells can release nucleotides into the extracellular environment (12,14,16,17,49), desensitizing neighboring P2 receptors and causing aberrant regulation of P2 receptor functions (50). In asthmatic eosinophils, P2X1 activity was rescued when the cells were treated with high concentrations of apyrase.…”

Section: Discussionmentioning

confidence: 99%

“…In human airways, nucleotides can be derived from damaged airway epithelium, airway smooth muscle, the accumulation and activation of diverse immune cells (e.g., mast cells, T lymphocytes, eosinophils, and neutrophils) (12), and activated platelets (13). Increased ATP concentrations in bronchoalveolar lavage fluids were reported from chronic smokers (14) and patients with asthma (15), chronic obstructive pulmonary disease (14), cystic fibrosis (16), and idiopathic pulmonary fibrosis (17).…”

mentioning

confidence: 99%

Impaired P2X1 Receptor–Mediated Adhesion in Eosinophils from Asthmatic Patients

Wright

Mahaut‐Smith

Symon

et al. 2016

The Journal of Immunology

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Eosinophils play an important role in the pathogenesis of asthma and can be activated by extracellular nucleotides released following cell damage or inflammation. For example, increased ATP concentrations were reported in bronchoalveolar lavage fluids of asthmatic patients. Although eosinophils are known to express several subtypes of P2 receptors for extracellular nucleotides, their function and contribution to asthma remain unclear. In this article, we show that transcripts for P2X1, P2X4, and P2X5 receptors were expressed in healthy and asthmatic eosinophils. The P2X receptor agonist α,β-methylene ATP (α,β-meATP; 10 μM) evoked rapidly activating and desensitizing inward currents (peak 18 ± 3 pA/pF at −60 mV) in healthy eosinophils, typical of P2X1 homomeric receptors, which were abolished by the selective P2X1 antagonist NF449 (1 μM) (3 ± 2 pA/pF). α,β-meATP–evoked currents were smaller in eosinophils from asthmatic patients (8 ± 2 versus 27 ± 5 pA/pF for healthy) but were enhanced following treatment with a high concentration of the nucleotidase apyrase (17 ± 5 pA/pF for 10 IU/ml and 11 ± 3 pA/pF for 0.32 IU/ml), indicating that the channels are partially desensitized by extracellular nucleotides. α,β-meATP (10 μM) increased the expression of CD11b activated form in eosinophils from healthy, but not asthmatic, donors (143 ± 21% and 108 ± 11% of control response, respectively). Furthermore, α,β-meATP increased healthy (18 ± 2% compared with control 10 ± 1%) but not asthmatic (13 ± 1% versus 10 ± 0% for control) eosinophil adhesion. Healthy human eosinophils express functional P2X1 receptors whose activation leads to eosinophil αMβ2 integrin–dependent adhesion. P2X1 responses are constitutively reduced in asthmatic compared with healthy eosinophils, probably as the result of an increase in extracellular nucleotide concentration.

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“…In contrast, it can also lead to uncontrolled inflammation, promotion of chronic inflammatory disease states and fibrotic remodelling (24). P2Y 2 antagonists could evolve as useful drugs for the treatment for chronic inflammatory diseases (25,26).…”

Section: Nucleotides and Their Receptors In Inflammationmentioning

confidence: 99%

The platelet P2 receptors in inflammation

Cattaneo¹

2015

Hamostaseologie

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SummaryIn addition to their well characterized and established role in haemostasis and thrombosis, platelets contribute to the pathogenesis of inflammation. Adenine nucleotides are signalling molecules that regulate the function of virtually every cell in the body, by interacting with P2 receptors. Their important role in inflammation is well established. In the last few years, the pro-inflammatory roles of adenine nucleotides interacting with their platelet P2 receptors has emerged. In particular, it was shown that the platelet P2Y 12 receptor for ADP significantly contributed to the proinflammatory effects of cysteinyl leukotrienes (CysLT) in experimental models of asthma in mice. More importantly, it was recently shown that P2Y 12 variants were associated with lung function in a large family-based asthma cohort and that the P2Y 12 antagonist prasugrel tended to decrease bronchial hyper-reactivity to mannitol in patients with allergic bronchial asthma in a randomized, placebo controlled trial. Conclusion: These data strongly suggest that P2Y 12 may represent an important pharmacological target for the treatment of patients with allergic bronchial asthma. Schlüsselwörter

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Extracellular Adenosine Triphosphate and Chronic Obstructive Pulmonary Disease

Abstract: COPD is characterized by a strong and persistent up-regulation of extracellular ATP in the airways. Extracellular ATP appears to contribute to the pathogenesis of COPD by promoting inflammation and tissue degradation.

Cited by 181 publications

References 35 publications

Elevated Airway Purines in COPD

Elevated Airway Purines in COPD

Impaired P2X1 Receptor–Mediated Adhesion in Eosinophils from Asthmatic Patients

The platelet P2 receptors in inflammation

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