Early detection of adverse respiratory effects from air pollution

描述(由申请人提供)：环境空气污染的浓度低于当前监管标准设定的限值，这与对儿童呼吸健康的严重不利影响有关。越来越多的研究表明，颗粒物(PM)和交通相关的近道路空气污染物(NRP)对健康有很大的不利影响，哮喘和表观遗传或基因变异可能会增加空气污染相关的肺部发育缺陷、支气管炎症状以及哮喘的发展和/或恶化的易感性。密集的公共卫生和监管干预降低了当前PM、臭氧和NO2的水平。目前减少的环境空气污染混合物的水平是否足以保护儿童的健康尚不清楚。需要改进在人口一级及早发现这些慢性影响的方法，以指导有效的公共卫生和监管干预，并确保儿童得到充分保护，使其免受这些空气污染暴露造成的长期不利影响。一种有希望的基于人群的早期检测方法是使用呼出的一氧化氮(FeNO)。FeNO50与急性不良呼吸影响有关，并受到空气污染暴露的短期急性变化的调节。此外，近端和远端呼吸道可能是PM2.5和NRP不良慢性影响的焦点。我们开发了一种新的方法，使用扩展呼出的一氧化氮参数[近端支气管壁流量(J‘awNO)、远端肺泡NO浓度(CANO)]来表征近端和远端气道室的反应。在这项应用中，我们建议使用关于长期空气污染、FeNO、NOS2的表观遗传和遗传变异的数据，以及在南加州儿童健康研究中纵向测量的健康结果，来研究FeNO在检测慢性暴露于空气污染的早期影响方面的效用，这是一项正在进行的基于人群的前瞻性队列研究，旨在研究南加州儿童呼吸健康的环境决定因素。在南加州空气污染水平大幅下降的7年多的跟踪调查中，我们收集了超过13,000个FeNO50的纵向测量数据。我们假设：1)FeNO50和CANO可用于早期检测长期暴露于PM2.5和元素碳EC2.5(衡量NRP)的慢性健康影响；以及2)使用NOS2的表观遗传(DNA CpG甲基化)和顺式基因序列变异可以加强对慢性影响的早期检测，这些变异与FeNO50、J‘awNO、CANO的急性和慢性差异以及EC2.5和PM2.5易感性的增加协同相关。这一研究项目的结果将填补我们在不可逆转的不良呼吸道影响发生之前快速识别空气污染的慢性影响的能力方面的关键空白。

DESCRIPTION (provided by applicant): Ambient air pollution at concentrations below the limits set by current regulatory standards is associated with significant adverse effects on children's respiratory health. A growing number of studies demonstrate that particulate matter (PM) and traffic-related near-roadway air pollutants (NRP) have substantial adverse health impacts, and that asthma and epigenetic or genetic sequence variants may increase susceptibility for air pollution-associated deficits in lung growth, bronchitis symptoms, and development and/or exacerbation of asthma. Intensive public health and regulatory interventions have reduced current levels of PM, ozone and NO2. It is unknown whether the reduced levels of the current ambient air pollution mixture are sufficient to protect children's health. Improved approaches for early detection of these chronic effects at the population level are needed to guide effective public health and regulatory interventions and to assure that children are fully protected from long-term adverse effects due to these air pollution exposures. One promising approach for population-based early detection is the use of exhaled nitric oxide (FeNO). FeNO50 is associated with acute adverse respiratory effects and is modulated by short-term acute changes in air pollution exposure. Furthermore, the proximal and distal airways may be focal points for adverse chronic effects of PM2.5, and NRP. We have developed new methods to characterize responses in the proximal and distal airway compartments using extended exhaled nitric oxide parameters [proximal bronchial wall flux (J'awNO), distal alveolar NO concentration (CANO)]. In this application, we propose to investigate the utility of FeNO for detecting the early effects of chronic exposures to air pollution, using data on long-term air pollution, FeNO, epigenetic and genetic variants in NOS2, and health outcomes measured longitudinally in the southern California Children's Health Study, an ongoing prospective population-based cohort study of environmental determinants of respiratory health in southern California children. Over 7 years of follow-up, which coincided with substantial reductions in levels of air pollution in southern California, we have collected more than 13,000 longitudinal measurements of FeNO50. We hypothesize that 1) FeNO50 and CANO can be used for early detection of chronic health effects from long-term exposure to PM2.5 and elemental carbon, EC2.5 (a measure of NRP); and 2) that early detection of chronic effects can be enhanced using epigenetic (DNA CpG methylation) and cis genetic sequence variants in NOS2 that are synergistically associated with both acute and chronic differences in FeNO50, J'awNO, CANO, and increased susceptibility to EC2.5 and PM2.5. The results from this program of research will fill crucial gaps in our ability to rapidly identify chronic effects of air pollution in the periodbefore irreversible adverse respiratory effects occur.