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A7559 - Ozone-Induced Airway Hyperresponsiveness Involves an ATP-P2X7-Mast Cell Pathway
Author Block: S. L. Tilley, Z. A. German, C. M. Jania, S. D. Budney, K. D. Chason; Medicine, Univ of N Carolina At Chapel Hill, Chapel Hill, NC, United States.
RATIONALE: Ozone is a well-recognized environmental cause of asthma exacerbation; however, the underlying mechanisms remain poorly understood. Ozone exposure results in substantial ATP release from airway epithelia, so we hypothesized that ATP-induced mast cell activation might contribute to ozone-induced airway hyperresponsiveness (AHR). METHODS: Wild type (WT), mast cell-deficient, and P2X7 receptor-deficient mice were exposed to ozone and ATP, and AHR to methacholine was measured. Mast cells were cultured from bone marrow from WT and P2X7-deficient mice, and from human umbilical cord blood. Mast cells were exposed to ATP, and degranulation, lipid mediator production, and cytokine synthesis measured. RESULTS: Ozone- and ATP-induced AHR was markedly attenuated in mast cell-deficient and P2X7-deficient mice, compared to WT mice where AHR was robust. Murine mast cells deficient in P2X7, and human mast cells treated with a P2X7 antagonist demonstrated marked attenuation or abolishment of ATP-induced mast cell activation compared to vehicle-treated controls. CONCLUSIONS: These results support a role for ATP, mast cells, and P2X7 receptors in the pathogenesis of ozone-induced asthma exacerbation. Further investigation of these pathways in vivo in humans may reveal new avenues for intervention to reduce the impact of this common environmental pollutant on asthmatics.