Protection from asthma in a high-risk birth cohort by attenuated P2X7 function

Abstract

Background Viral illnesses are important factors in both asthma inception and exacerbations, and allergic sensitization in early life further enhances asthma risk through unclear mechanisms. Cellular damage due to infection or allergen inhalation increases ATP in the airways with subsequent purinergic receptor activation. The purinergic receptor P2X7 may enhance airway leukocyte recruitment to the airways and P2X7 knockout mice display a reduced asthma-like phenotype. Objective Based upon the P2X7 knockout mouse, we hypothesized that children with low functioning P2X7 would have decreased rates of asthma. Methods We utilized a functional assay to determine P2X7 pore-producing capacity in whole blood samples in a birth cohort study at high risk for asthma development. The P2X7 assay was validated with known loss-of-function alleles in humans. P2X7 pore status categorization was used to assess asthma and allergy status in the cohort. Results Attenuated P2X7 function was associated with lower asthma rates at ages 6 and 8 and the greatest effects were observed in boys. Children with asthma at age 11 who had low P2X7 capacity had less severe disease in the previous year. Attenuated P2X7 function was also associated with sensitization to fewer aeroallergens. Conclusion P2X7 functional capacity is associated with asthma risk or disease severity and these relationships appear to be age-related.

Purinergic Receptors in Thrombosis and Inflammation

“…71,73 In addition, low-functioning P2X 7 receptor variants have been shown to be associated with reduced risks of childhood asthma and allergic sensitization in a birth cohort at high risk for the development of asthma. 76 Overall, these results suggest that the P2Y 2 , P2Y 6 , and P2X 7 receptor subtypes could represent new therapeutic targets to treat allergic lung inflammation.…”

Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

“…Although more in vivo studies are welcome to confirm the observations made on the models of asthmatic inflammation, targeting P2 receptor function might indeed represent a promising approach to develop new therapeutics for asthma as evidenced by a recent study in a birth cohort at high risk for development of asthma that reported an attenuated P2X7 function to be associated with lower asthma rates [143] (Table 1).…”

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.…”