Early detection of adverse respiratory effects from air pollution

描述（由申请人提供）：浓度低于现行监管标准规定的限值的环境空气污染与对儿童呼吸健康的重大不利影响有关。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）对健康有重大不利影响，哮喘和表观遗传或基因序列变异可能增加与空气污染相关的肺生长缺陷、支气管炎症状、哮喘发展和/或加重的易感性。密集的公共卫生和监管干预措施降低了目前的PM、臭氧和二氧化氮水平。目前尚不清楚当前环境空气污染混合物的降低水平是否足以保护儿童的健康。需要改进在人口一级早期发现这些慢性影响的方法，以指导有效的公共卫生和管制干预措施，并确保充分保护儿童免受这些空气污染暴露造成的长期不利影响。一种基于人群的早期检测方法是使用呼出一氧化氮（FeNO）。FeNO50与急性呼吸道不良反应有关，并受空气污染暴露的短期急性变化的调节。此外，近端和远端气道可能是PM2.5和NRP不良慢性影响的焦点。我们开发了新的方法来表征近端和远端气道隔室的反应，使用延长的呼出一氧化氮参数[近端支气管壁通量（J'awNO），远端肺泡一氧化氮浓度（CANO）]。在这项应用中，我们建议利用南加州儿童健康研究中长期空气污染、FeNO、NOS2的表观遗传和遗传变异以及纵向测量的健康结果数据，研究FeNO在检测慢性空气污染早期影响方面的效用。南加州儿童健康研究是一项正在进行的前瞻性人群队列研究，旨在研究南加州儿童呼吸健康的环境决定因素。在长达7年的跟踪调查中，我们收集了13000多个FeNO50的纵向测量值，这与南加州空气污染水平大幅下降的时间相一致。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 （NRP的一种度量）对慢性健康的影响；2) NOS2的表观遗传（DNA CpG甲基化）和顺式基因序列变异与急性和慢性FeNO50、J'awNO、CANO的差异以及对EC2.5和PM2.5易感性的增加有协同关系，可以增强对慢性效应的早期检测。这个研究项目的结果将填补我们在不可逆转的呼吸不良影响发生之前迅速识别空气污染的慢性影响的能力的关键空白。

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.