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Attenuated P2X₇ Pore Function as a Risk Factor for Virus-induced Loss of Asthma Control

¹ Section of Allergy, Pulmonary, and Critical Care, Department of Medicine, ² Department of Biomolecular Chemistry, ³ Paul P. Carbone Comprehensive Cancer Center, ⁴ Department of Anesthesiology, and ⁵ Section of Allergy and Immunology, Department of Pediatrics, University of Wisconsin, Madison, Wisconsin

Correspondence and requests for reprints should be addressed to Loren C. Denlinger, M.D., Ph.D., Section of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, P.O. Box 9988, Madison, WI 53792. E-mail: ldenling{at}wisc.edu

Rationale: Upper respiratory tract infection is a guideline accepted risk domain for the loss of asthma control. The ionotrophic nucleotide receptor P2X₇ regulates compartmentalized acute inflammation and the immune response to airway pathogens.

Objectives: We hypothesized that variability in P2X₇ function contributes to neutrophilic airway inflammation during a cold and thereby is linked to acute asthma.

Methods: Research volunteers with asthma were enrolled at the onset of a naturally occurring cold and monitored through convalescence, assessing symptoms, lung function, and airway inflammation. P2X₇ pore activity in whole blood samples was measured using a genomically validated flow cytometric assay.

Measurements and Main Results: Thirty-five participants with mild to moderate allergic asthma were enrolled and 31 completed all visits. P2X₇ pore function correlated with the change in nasal lavage neutrophil counts during the cold (R_s = 0.514, P = 0.004) and was inversely related to the change in asthma symptoms (R_s = –0.486, P = 0.009). The change in peak expiratory flow recordings, precold use of inhaled corticosteroids, and P2X₇ pore function were multivariate predictors of asthma symptoms (P = 0.001, < 0.001 and = 0.003 respectively). Attenuated P2X₇ activity was associated with the risk of losing asthma control (crude odds ratio, 11.0; 95% confidence interval, 1.1–106.4) even after adjustment for inhaled corticosteroids and rhinovirus (odds ratio, 15.0).

Conclusions: A whole blood P2X₇ pore assay robustly identifies participants with loss-of-function genotypes. Using this assay as an epidemiologic tool, attenuated P2X₇ pore activity may be a novel biomarker of virus-induced loss of asthma control.

Key Words: asthma • virus • neutrophils • P2X₇

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject P2X7 is a cation channel expressed by leukocytes and airway epithelial cells that is important to pathogen control and concomitant cellular inflammation. Its contribution to asthma pathophysiology has previously not been demonstrated. What This Study Adds to the Field Attenuated P2X7 function is common in mild to moderate asthma, and is associated with decreased virus-induced nasal inflammation as well as an increased risk of an acute loss of symptom control.