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Identification of an ATP/P2X7/mast cell pathway mediating ozone-induced bronchial hyperresponsiveness
Xiaomei Kong, … , Samir N.P. Kelada, Stephen L. Tilley
Xiaomei Kong, … , Samir N.P. Kelada, Stephen L. Tilley
Published September 21, 2021
Citation Information: JCI Insight. 2021;6(21):e140207. https://doi.org/10.1172/jci.insight.140207.
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Research Article Cell biology Immunology

Identification of an ATP/P2X7/mast cell pathway mediating ozone-induced bronchial hyperresponsiveness

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Abstract

Ozone is a highly reactive environmental pollutant with well-recognized adverse effects on lung health. Bronchial hyperresponsiveness (BHR) is one consequence of ozone exposure, particularly for individuals with underlying lung disease. Our data demonstrated that ozone induced substantial ATP release from human airway epithelia in vitro and into the airways of mice in vivo and that ATP served as a potent inducer of mast cell degranulation and BHR, acting through P2X7 receptors on mast cells. Both mast cell–deficient and P2X7 receptor–deficient (P2X7–/–) mice demonstrated markedly attenuated BHR to ozone. Reconstitution of mast cell–deficient mice with WT mast cells and P2X7–/– mast cells restored ozone-induced BHR. Despite equal numbers of mast cells in reconstituted mouse lungs, mice reconstituted with P2X7–/– mast cells demonstrated significantly less robust BHR than mice reconstituted with WT mast cells. These results support a model where P2X7 on mast cells and other cell types contribute to ozone-induced BHR.

Authors

Xiaomei Kong, William C. Bennett, Corey M. Jania, Kelly D. Chason, Zachary German, Jennifer Adouli, Samuel D. Budney, Brandon T. Oby, Catharina van Heusden, Eduardo R. Lazarowski, Ilona Jaspers, Scott H. Randell, Barry A. Hedgespeth, Glenn Cruse, Xiaoyang Hua, Stephen A. Schworer, Gregory J. Smith, Samir N.P. Kelada, Stephen L. Tilley

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Figure 5

ATP induces mast cell activation via the P2X7 receptor.

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ATP induces mast cell activation via the P2X7 receptor.
(A and B) ATP-in...
(A and B) ATP-induced mast cell degranulation and lipid mediator production is P2X7 dependent. WT and P2X7–/– BMMCs were incubated with 0 μM or 300 μM ATP for 30 minutes (A) or 4 hours (B), and then supernatants were used to measure hexosaminidase release (A) or PGD2 concentrations by ELISA (B). Black circles represent WT cells; red triangles represent P2X7–/– cells. n = 2 cell lines per genotype over 3 separate experiments (C and D) CBMCs incubated 30 minutes with P2X7 antagonist A740003 (3 μM) or vehicle containing equivalent DMSO for 30 minutes prior to 0 μM or 1000 μM ATP for 30 minutes (C) or 4 hours (D). Black circles represent vehicle treatment; red triangles represent A74003 treatment. n = 2 pooled cell lines over 3 separate experiments. (E) ATP-induced IL-13 synthesis by BMMCs is attenuated in P2X7–/– cells. WT and P2X7–/– BMMCs were incubated with 0 μM or 300 μM ATP for 20–24 hours and IL-13 measured in supernatants by ELISA. Black circles represent WT cells; red triangles represent P2X7–/– cells. n = 2 cell lines per genotype over 3 separate experiments (A–E); **P < 0.005, ***P < 0.001 by 2-way ANOVA with Tukey’s test for multiple comparisons. Data are shown as mean ± SEM.

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