Effects of Aerosolized Adenosine 5′-Triphosphate vs Adenosine 5′-Monophosphate on Dyspnea and Airway Caliber in Healthy Nonsmokers and Patients With Asthma

Başoğlu, Özen K.; Pelleg, Amir; Essilfie-Quaye, Sarah; Brindicci, Caterina; Barnes, Peter J.; Kharitonov, Sergei A.

doi:10.1378/chest.128.4.1905

Cited by 82 publications

(63 citation statements)

References 13 publications

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“…Therapies inhibiting these ectoenzymes could potentially accentuate airway epithelial apoptosis (65,66) and inflammatory responses (45) because of increased ATP-mediated activation of P2X 7 receptors, which are up-regulated in lung diseases (67). In addition, these enzymes are likely responsible for the rapid elimination of aerosolized nucleotides (1-100 M) used to diagnose asthma and chronic obstructive pulmonary disease (ATP and AMP) (47,48), for the treatment of CF and primary ciliary dyskinesia (UTP) (49 -52) and in animal studies (48,68,69).…”

Section: Discussionmentioning

confidence: 99%

“…Several airway ectonucleotidases have been shown to hydrolyze ATP, ADP, and/or AMP as follows: NTPDase 1, NTPDase 3, NSAP, E-NPPs, and ecto-AK (14,15,28). Based on their kinetic properties, we hypothesized that specific enzymes regulate ASL nucleotide levels encountered under physiological conditions (Ͻ0.1 M) (8,12,20), whereas others regulate higher ASL concentrations reached during tissue injury (0.1-1 M) (43-46) or aerosolization (1-100 M) for diagnostic (47,48) or therapeutic (49 -52) purposes. The biochemical network was first simplified by classifying the enzymes into the following two groups: 1) low affinity high capacity (K M Ն 50 M; NTPDase 3, lowNSAP), and 2) high affinity low capacity (K M Ͻ 50 M; NTPDase 1, E-NPPs, highNSAP, and ecto-AK).…”

Section: Reactionsmentioning

confidence: 99%

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Mathematical Model of Nucleotide Regulation on Airway Epithelia

Zuo¹,

Picher²,

Okada³

et al. 2008

Journal of Biological Chemistry

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In the airways, adenine nucleotides support a complex signaling network mediating host defenses. Released by the epithelium into the airway surface liquid (ASL) layer, they regulate mucus clearance through P2 (ATP) receptors, and following surface metabolism through P1 (adenosine; Ado) receptors. The complexity of ASL nucleotide regulation provides an ideal subject for biochemical network modeling. A mathematical model was developed to integrate nucleotide release, the ectoenzymes supporting the dephosphorylation of ATP into Ado, Ado deamination into inosine (Ino), and nucleoside uptake. The model also includes ecto-adenylate kinase activity and feed-forward inhibition of Ado production by ATP and ADP. The parameters were optimized by fitting the model to experimental data for the steady-state and transient concentration profiles generated by adding ATP to polarized primary cultures of human bronchial epithelial (HBE) cells. The model captures major aspects of ATP and Ado regulation, including their >4-fold increase in concentration induced by mechanical stress mimicking normal breathing. The model also confirmed the independence of steady-state nucleotide concentrations on the ASL volume, an important regulator of airway clearance. An interactive approach between simulations and assays revealed that feedforward inhibition is mediated by selective inhibition of ecto-5-nucleotidase. Importantly, the model identifies ecto-adenylate kinase as a key regulator of ASL ATP and proposes novel strategies for the treatment of airway diseases characterized by impaired nucleotide-mediated clearance. These new insights into the biochemical processes supporting ASL nucleotide regulation illustrate the potential of this mathematical model for fundamental and clinical research. Mucociliary clearance (MCC)4 constitutes the first line of defense against airway infection (1). Inhaled pathogens are trapped by a mucus layer, positioned above ciliated epithelia by a periciliary (PCL) layer. Together, mucus and PCL form the ASL layer, which is continuously transported cephalad by coordinated ciliary beating. Through their interactions with P2 receptors, adenine nucleotides regulate all major epithelial functions supporting MCC, including Cl Ϫ /liquid secretion via the Ca 2ϩ -activated Cl Ϫ channel and the cystic fibrosis transmembrane regulator (CFTR) (2), mucin secretion (3, 4), and ciliary beat activity (5, 6). Nucleotides are released by the epithelium into the ASL layer under basal conditions (7,8), and their release rate increases in response to mechanical stress imparted by tidal breathing (8 -12). Nucleotide-mediated epithelial responses are modified by surface enzymes (ectonucleotidases) that convert a fraction of the ATP into Ado (13-15). This nucleoside activates airway epithelial signaling pathways through P1 receptors, typically the A 2B receptor, which stimulates ciliary beat activity (16) and Cl Ϫ /liquid secretion by CFTR (17). In healthy airways, the purinergic regulation of MCC is mediated by both P1 and P2 receptor-m...

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Section: Discussionmentioning

confidence: 99%

Section: Reactionsmentioning

confidence: 99%

Mathematical Model of Nucleotide Regulation on Airway Epithelia

Zuo¹,

Picher²,

Okada³

et al. 2008

Journal of Biological Chemistry

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“…ATP enhances citric acidevoked and histamine-evoked cough in preclinical models, effects that can be attenuated by P2X3 selective antagonists (Kamei and Takahashi, 2006;Ford, 2012). In humans, local delivery of ATP initiates cough and bronchospasm (Basoglu et al, 2005). In addition to an involvement of P2X3 receptors in neurogenic cough, activation of P2X7 receptors may contribute to inflammation associated with airway dysfunction (Ford, 2012).…”

Section: Therapeutic Indicationsmentioning

confidence: 99%

P2X Receptors as Drug Targets

2012

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The study of P2X receptors has long been handicapped by a poverty of small-molecule tools that serve as selective agonists and antagonists. There has been progress, particularly in the past 10 years, as cell-based high-throughput screening methods were applied, together with large chemical libraries. This has delivered some drug-like molecules in several chemical classes that selectively target P2X1, P2X3, or P2X7 receptors. Some of these are, or have been, in clinical trials for rheumatoid arthritis, pain, and cough. Current preclinical research programs are studying P2X receptor involvement in pain, inflammation, osteoporosis, multiple sclerosis, spinal cord injury, and bladder dysfunction. The determination of the atomic structure of P2X receptors in closed and open (ATP-bound) states by X-ray crystallography is now allowing new approaches by molecular modeling. This is supported by a large body of previous work using mutagenesis and functional expression, and is now being supplemented by molecular dynamic simulations and in silico ligand docking. These approaches should lead to P2X receptors soon taking their place alongside other ion channel proteins as therapeutically important drug targets.

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“…For example, data were presented to suggest that ATP plays an important modulatory role in histamine release from human lung mast cells, and it was suggested that it may be involved in allergic/asthma reactions (Schulman et al, 1999). ATP was shown to be a more potent bronchoconstrictor and to have greater effects on dyspnea and other symptoms than AMP in patients with asthma (Basoglu et al, 2005). P2X7 receptor function is altered in asthma; P2X7 pore activity is associated with change in nasal lavage neutrophil counts during the development of asthma symptoms (Denlinger et al, 2009).…”

Section: A Asthmamentioning

confidence: 99%