Air Pollution, Inflammation and New Onset Asthma

描述(由申请人提供)：环境空气污染被公认为哮喘加重的原因，但其在新发哮喘病因中的作用尚不清楚。环境空气污染物的病因学作用的证据正在从流行病学研究中浮现出来；然而，哮喘患病率增加的同时一些污染物水平下降的生态模式引发了对这些联系的有效性的质疑。更好地了解环境空气污染对哮喘发生的影响的生物学过程可能有助于回答这些问题。慢性氧化/亚硝化应激和呼吸道炎症可能是哮喘病因学中的关键过程，这些相互关联的过程可能介导了空气污染导致的哮喘风险增加。在这一应用中，我们建议使用呼出的一氧化氮(ENO)来研究炎症和氧化/亚硝化应激在新发哮喘的病理生物学中的作用，重点是环境空气污染和遗传易感性。我们根据对氧化/亚硝化压力的潜在贡献来选择环境污染物(臭氧；颗粒物(PM10和PM2.5及其化学成分、颗粒物计数、NOx(NO和NO2)、酸性蒸气；以及新鲜的尾气排放)。在拟议的研究计划中要评估的主要假设是：1)高环境空气污染暴露的儿童患有慢性呼吸道炎症，如eNO升高所示。2)环境空气污染对呼吸道炎症和氧化/亚硝化应激的易感性因NOS1、NOS2而异。NOS3.GSTM1。GSTP1。NQO1和HO-1单倍型和功能变异，以及3)ENO升高表明患有慢性呼吸道炎症的儿童新发哮喘的风险增加。为了验证这些假设，这项拟议的研究建立在哮喘发病风险(AIR)研究的人口资源、正在进行的对南加州13个社区6000名儿童新发哮喘决定因素的前瞻性队列研究以及这些社区环境空气污染暴露特征的广泛计划的基础上。在这项应用中，我们建议使用离线技术来测量eNO，并从空气队列中对3000名儿童进行基因分型。一些资源将加强拟议的研究，包括儿童环境健康中心，南加州环境健康科学中心的分子生物学核心，以及南加州粒子中心和Supersite的专业知识。拟议中的研究项目的发现可能有助于解决空气污染对哮喘风险影响的不确定性，为识别哮喘风险最高的儿童提供新的工具，并有助于哮喘预防工作。

DESCRIPTION (provided by applicant): Ambient air pollution is well accepted as a cause of asthma exacerbations, but its role in the etiology of new onset asthma is less clear. Evidence for an etiologic role of ambient air pollutants is emerging from epidemiologic studies; however, the ecologic patterns of increasing asthma prevalence concurrent with decreasing levels of some pollutants have raised questions about the validity of these associations. A better understanding of the biological processes that mediate the effects of ambient air pollution on asthma occurrence is likely to contribute to answering these questions. Chronic oxidative/nitrosative stress and airway inflammation are probably critical processes in asthma etiology and these inter-related processes may mediate the increased asthma risk from air pollution. In this application, we propose to use exhaled NO (eNO), to study the role of inflammation and oxidative/nitrosative stress in the pathobiology of new onset asthma, with a focus on ambient air pollution and genetic susceptibility. We choose ambient pollutants based on potential contribution to oxidative/nitrosative stress (O3; particulates (PM10 and PM2.5 and their chemical constituents, particle counts, NOx (NO and NO2), acid vapors; and fresh tailpipe emissions). The primary hypotheses to be assessed in the proposed program of research are: 1) children with high ambient air pollution exposures have chronic airway inflammation as indicated by elevated eNO. 2) susceptibility to airway inflammation and oxidative/nitrosative stress from ambient air pollution varies by NOS1, NOS2. NOS3. GSTM1. GSTP1. NQO1, and HO-1 haplotypes and functional variants, and 3) children with chronic airway inflammation as indicated by elevated eNO are at increased risk for new onset asthma. To test these hypotheses, the proposed study builds on the population resource of the Asthma Incidence Risk (AIR) study, an ongoing prospective cohort study of the determinants of new onset asthma in 6000 children in 13 southern California communities, and an extensive program of ambient air pollution exposure characterization in these communities. In this application, we propose to measure eNO using off-line techniques and to genotype 3000 children from the AIR cohort. A number of resources will enhance the proposed study, including the Children's Environmental Health Center, the Molecular Biology Core of Southern California Environmental Health Sciences Center, and expertise from the Southern California Particle Center and Supersite. The findings from the proposed research program is likely to contribute to resolving uncertainties about the effects of air pollution on asthma risk, provide new tools for identifying children at highest risk for asthma and aid in asthma prevention efforts.