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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 3

Ozone stimulates ATP release in murine airways and human epithelia in vitro.

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Ozone stimulates ATP release in murine airways and human epithelia in vi...
(A) Ozone stimulates ATP release in murine BALF. Mice (females, aged 12–22 weeks) were exposed to 2 ppm ozone or air for 1 hour, and BALF was collected immediately after exposure. ATP was measured via luciferin-luciferase assay. n = 4; *P < 0.05 by Student’s t test. (B) Ozone stimulates nucleotide release in murine BALF. Mice were exposed to 2 ppm ozone or air for 3 hours, and BALF was collected immediately after exposure. Samples were heat-inactivated for 2 minutes and frozen, and purines measured by etheno-derived HPLC. Yellow and blue circles represent nucleotide/side levels from air-treated mice and ozone-treated mice, respectively. n = 13–14; *P < 0.05 by Student’s t test. (C) Ozone stimulates nucleotide release from 16HBE cells. 16HBE epithelial cells were cultured for 28–35 days at ALI and exposed apically to 0.8 ppm ozone or air for 1 hour or 3 hours, and basolateral media was collected immediately after exposure. Purines measured as described in B. Data represent total purines (ATP + ADP + AMP + adenosine). Yellow and blue circles represent air- and ozone-treated cells, respectively. n = 5–6; *P < 0.05 by 2-way ANOVA with Tukey’s test for multiple comparisons with exposure type (air or ozone) and time as independent variables. (D) Ozone stimulates nucleotide release from HBE cells. HBE cells from normal volunteers were obtained, cultured at ALI, and exposed apically to 0.8 ppm ozone or air for 1 hour or 3 hours. Total purines in the basolateral media were measured as described in B. Data represent total purines (ATP + ADP + AMP + adenosine). Yellow and blue circles represent air and ozone-treated cells, respectively. n = 6–11; *P < 0.05 by 2-way ANOVA with Tukey’s test for multiple comparisons applied with exposure type (air or ozone) and time as independent variables. Data are shown as mean ± SEM.

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