P2X₇-Regulated Protection from Exacerbations and Loss of Control Is Independent of Asthma Maintenance Therapy

Abstract

Rationale: The function of the P2X 7 nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied. Objectives: To evaluate the association between P2X 7 , asthma exacerbations, and incomplete symptom control in a more diverse population. Methods: A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X 7 pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently. Measurements and Main Results: A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting b 2 -agonists use (odds ratio, 2.7; 95% confidence interval, 1.2-6.2; P ¼ 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1-9.3; P ¼ 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV 1 reversal (P , 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase. Conclusions: P2X 7 pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.Keywords: asthma; P2X 7 ; exacerbation; Asthma Clinical Research Network; corticosteroidsThe release of ATP during cell injury is a danger signal to the airway inflammatory response (1). Levels of ATP in the airway are elevated after allergen challenge in humans and mice, contributing to production of dendritic cell-derived cytokines important to efficient recruitment of eosinophils and lymphocytes and the subsequent development of airway hyperresponsiveness to methacholine (2). In addition, airway ATP levels are likely elevated during virus-induced asthma exacerbations in humans (3) and serve as an airway biomarker of neutrophilic inflammation during infection (4). The nucleotide receptor P2X 7 regulates this process. This receptor is a trimeric, nonselective cation channel expressed by leukocytes and epithelial cells that opens a larger pore on full activation (size restriction 900 Da) (5, 6). Data by Müller and coworkers (7) in the ovalbumin-sensitized mouse model suggest that inhibition of P2X 7 partially attenuates dendritic cell-dependent influx of eosinophils and lymphocytes and the development of airway hyperresponsiveness and remodeling. Consistent with a role for this receptor in compartmental recruitment of granulocytes, w...

The Ectoenzyme E-NPP3 Negatively Regulates ATP-Dependent Chronic Allergic Responses by Basophils and Mast Cells

“…Indeed, several previous studies indicated that P2X7 is implicated in the pathogenesis of airway allergic inflammation in mice and humans (Denlinger et al, 2013;Idzko et al, 2007;Manthei et al, 2012;Mü ller et al, 2011) as well as contact hypersensitivity in a mouse model (Weber et al, 2010). However, all of these studies focused on dendritic cells as a target of ATP.…”

The Roles of Mitochondrial Damage-Associated Molecular Patterns in Diseases

“…In addition, blood neutrophils harvested from the patients with COPD show a stronger chemotaxis and an elastase release in response to ATP treatment compared with the control subjects (92). In patients with asthma, in addition to increased levels of ATP in BALF, the functional activity or Single Nucleotide Polymorphism of P2X7R is also associated with the exacerbation or severity of asthma (33,96). While the pathogenesis of these lung diseases differs from each other, inflammatory responses are commonly involved in the development and acute exacerbation of these diseases.…”

Personalized management of asthma exacerbations: lessons from genetic studies

“…Attenuated whole blood monocyte P2X 7 pore activity in mild-intermittent asthmatics is associated with 11 times odds of developing an asthma exacerbation and 15 times odds of developing an asthma exacerbation in the presence of rhinovirus and use of ICS[61]. In a case-control study, the rs2230911:C>G SNP in P2RX7 was significantly associated with a history of prednisone use in African American asthmatics adjusted for ICS and long-acting beta-agonist use[62]. In a multi-ethnic population of moderate severe asthmatics, individuals with attenuated P2X 7 pore function were found to have a higher rate of asthma exacerbations despite medium-dose ICS use[62].…”

“…In a case-control study, the rs2230911:C>G SNP in P2RX7 was significantly associated with a history of prednisone use in African American asthmatics adjusted for ICS and long-acting beta-agonist use[62]. In a multi-ethnic population of moderate severe asthmatics, individuals with attenuated P2X 7 pore function were found to have a higher rate of asthma exacerbations despite medium-dose ICS use[62]. …”