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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 6

ATP-induced BHR is mediated by P2X7 receptors on mast cells.

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ATP-induced BHR is mediated by P2X7 receptors on mast cells.
(A) ATP-ind...
(A) ATP-induced BHR is P2X7 dependent. WT and P2X7–/– mice (females, aged 9–25 weeks) were exposed to aerosolized ATP (50 mg/mL) and challenged with methacholine 30 minutes later. Black circles represent PBS-treated WT mice (n = 4), red circles represent ATP-treated WT mice (n = 16), black triangles represent PBS-treated P2X7–/– mice (n = 2), and red triangles represent ATP-treated P2X7–/– mice (n = 4); *P < 0.05 by mixed effects analysis for repeated measures between ATP-treated groups. (B) ATP-induced BHR is mediated by P2X7 receptors on mast cells. C57BL/6-KitW-sh/W-sh mice (females, aged 4–5 weeks) were reconstituted with either P2X7–/– or WT BMMCs. After 16 weeks, mice were exposed to aerosolized ATP (50 mg/mL) and challenged with methacholine 30 minutes later. Black diamonds represent mice reconstituted with WT mast cells (n = 7), black triangles represent mice reconstituted with P2X7–/– mast cells (n = 7), open red squares represent nonreconstituted C57BL/6-KitW-sh/W-sh controls (n = 2); *P < 0.05 by mixed effects analysis between reconstituted groups. Data are shown as mean ± SEM.

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