Soluble antioxidant modulation: Test of a computational model of ozone-induced re

描述（由申请人提供）：美国肺脏协会最近的2011年空气状况报告发现，50.3%的美国人口生活在臭氧空气污染水平不健康的县，因此确定降低暴露于环境臭氧水平的个体肺功能下降风险的策略至关重要。我们最近开发并验证了个体受试者臭氧暴露反应的双室模型。第一个隔室表示生理反应开始时臭氧的延迟或累积剂量。第二个室是一个固定的体积，具有恒定的生物活性物质消除速率，该生物活性物质激活深肺神经受体，诱导快速浅呼吸和吸气量减少（即FEV1减少）。然后这两个连续相连的隔间的输出乘以一个比例系数a。我们的中心假设是维生素C和

DESCRIPTION (provided by applicant): The recent 2011 State of the Air report from the American Lung Association found that 50.3% of the US population lives in counties that have unhealthy levels of ozone air pollution and as a result the identification of strategies that reducs the risk of developing pulmonary function decrements in individuals exposed to ambient levels of ozone is of critical importance. We have recently developed and validated a two-compartment model of individual subject ozone exposure-response. The first compartment represents the delay to or cumulative dose of ozone at the onset of physiologic response. The second compartment is a fixed volume with a constant rate of elimination of a bioactive substance that activates the deep lung neural receptors that induce rapid shallow breathing and reductions in inspiratory capacity (ie decreased FEV1). The output of these two serially linked compartments is then multiplied by a proportionality coefficient A. Our central hypothesis is that vitamin C and uric acid contained within the respiratory tract lining fluid contributes to the antioxidant capaciy of the airway and the delay in onset of ozone-induced reflex decrements in pulmonary function and subjective symptoms. Our goal is a better understanding of the role of soluble antioxidants in determining ozone exposure response kinetics. These findings will provide further insight into how vitamin C and uric acid dietary modulation reduces the risk of developing pulmonary function decrements in individuals exposed to ambient levels of ozone. We will focus on individual subject ozone exposure-response kinetics and how they are altered by dietary modulation of vitamin C and uric acid. The systems biology approach of combining modeling of individual subject ozone exposure-response kinetics with vitamin C and uric acid dietary modulation will improve the integrated understanding of ozone-induced responses in humans. The proposed experiments will measure the system and its key responses while the computational model will be used to integrate the information to test our hypothesis. We expect that vitamin C and uric acid dietary modulation while attenuating ozone-induced decrements in FEV1 will also increase the number of subjects with a dose of onset in excess of the total cumulative dose of exposure and as a result have no pulmonary function or subjective symptom response with ozone exposure.