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

可溶性抗氧化剂调节：臭氧诱导反应计算模型的测试

• 批准号: 8771103
• 负责人: EDWARD S SCHELEGLE
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-22 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771103
• 关键词: Address; Affect; Air; Air Pollution; American Lung Association; Antioxidants; Ascorbic Acid; Attenuated; Breathing; Bronchoconstriction; Complex; Computer Simulation; County; Diet; Dose; Epithelial Cells; Event; Exercise; Goals; Human; Individual; Inflammation; Inflammation Mediators; Inspiratory Capacity; Kinetics; Link; Lipids; Liquid substance; Lung; Measures; Metabolism; Methods; Modeling; Output; Ozone; Pattern; Physiological; Population; Pulmonary Function Test/Forced Expiratory Volume 1; Reaction; Reflex action; Regimen; Reporting; Respiratory System; Respiratory tract structure; Risk; Role; Sensory Receptors; Staging; Symptoms; System; Systems Biology; Testing; Time; Uric Acid; afferent nerve; improved; insight; oxidant stress; ozone exposure; public health relevance; pulmonary function; research study; response; uptake

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.

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发生肺功能减退风险的策略至关重要。我们最近开发并验证了一个两室模型的个别主题臭氧的破坏响应。第一个隔室代表生理反应开始时臭氧的延迟或累积剂量。第二个隔室是一个固定体积，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降低（即FEV 1降低）。然后将这两个串联连接的隔室的输出乘以比例系数A。我们的中心假设是维生素C和 包含在呼吸道衬里流体中的尿酸有助于气道的抗氧化能力和延迟臭氧诱导的反射的发生，从而降低肺功能和主观症状。我们的目标是更好地了解可溶性抗氧化剂在确定臭氧暴露反应动力学中的作用。这些发现将进一步深入了解维生素C和尿酸饮食调节如何降低暴露于环境臭氧水平的个体发生肺功能减退的风险。我们将专注于个别受试者的臭氧消耗反应动力学，以及它们是如何改变的维生素C和尿酸的饮食调制。将个体受试者臭氧暴露-反应动力学建模与维生素C和尿酸饮食调节相结合的系统生物学方法将提高对人类臭氧诱导反应的综合理解。拟议的实验将测量系统及其关键响应，而计算模型将用于整合信息以验证我们的假设。我们预计，维生素C和尿酸的饮食调节，同时衰减臭氧引起的FEV 1的下降，也将增加受试者的数量与剂量的发病超过总累积剂量的暴露，因此没有肺功能或主观症状反应与臭氧暴露。