Childhood Asthma, Susceptibility and Biological Activity of Ambient Particles

描述（由申请人提供）：哮喘是儿童最常见的慢性疾病。病因尚不清楚，但最近的研究表明，与交通相关的颗粒物空气污染可能会导致儿童哮喘和哮喘相关支气管症状的发生。可吸入颗粒物 (PM) 会产生氧化应激以及哮喘特有的急性炎症和过敏反应，但很少有人研究这些影响如何长期导致疾病的发展。更好地了解 PM 引起的哪些特定生物效应会导致哮喘，可以制定有针对性的临床干预措施，并制定针对 PM 生物活性的新预防策略。我们提出了一种对空气污染的复杂混合物进行人群研究的新方法，该方法将根据PM对关键生物途径的体外影响来评估暴露情况，并检查其与慢性疾病发展的关系。这些途径包括以 PM 诱导的细胞因子（IL-8、GM-CSF 和 IL-12）为特征的炎症、过敏（IgE 反应和组胺释放）和氧化应激（活性氧产生、GST 活性和 II 相酶诱导）。我们还将根据 PM 诱导的表达 GSTM1 的细胞和使用 siRNA 降低 GSTM1 表达的细胞中生物活性的变化来研究遗传易感性。我们选择该基因作为我们研究方法的原型，因为它具有常见的无效基因型，会增加与氧化剂 PM 暴露相关的哮喘风险。我们将使用体外毒理学测定来预测哮喘风险并评估与 GSTM1 基因型相关的易感性。我们正在进行的一项针对南加州儿童健康研究中 3372 名儿童的空气污染、遗传和呼吸道疾病的前瞻性队列研究提供了一个使用新方法来评估是否：1) 哮喘发病率和支气管炎恶化是否与 PM 在体外诱导促氧化、炎症和过敏作用的能力相关的机会； 2) PM 诱导的生物活性对健康影响的易感性受到体外 GSTM1 表达和参与者 GSTM1 基因型的影响。将在八个研究社区的社区监测器、学校和家庭样本中测量空气动力学直径小于 2.5-5m 的 PM 的体外生物反应以及气态氧化剂共污染物（氮氧化物和臭氧）。结果将被整合到分析中，使用创新的分层建模策略来预测与社区内和研究社区之间的交通相关的颗粒生物活性的变化，代表南加州环境 PM 暴露的范围。每个生物暴露指数针对研究参与者的 GSTM1 基因型，将分配给整个队列，并用于预测哮喘和支气管炎症状。这项研究有可能填补我们理解的重要空白 颗粒空气污染在儿童呼吸道疾病发展中的作用。公共卫生相关性 这种新的暴露评估方法有可能更好地估计因暴露于颗粒空气污染而导致的哮喘风险和易感性。这些信息将有助于风险评估，并可能导致新的监管和监测方法来控制空气污染的健康危害。

DESCRIPTION (provided by applicant): Asthma is the most common chronic disease of children. The etiology is not clear, but recent studies suggest that traffic-related particulate air pollution may contribute to the occurrence of childhood asthma and asthma- related bronchitic symptoms. Respirable particulate matter (PM) produces oxidative stress and acute inflammatory and allergic affects characteristic of asthma, but there has been little study of how these effects may lead chronically to the development of disease. A better understanding of which specific PM-induced biological effects result in asthma could lead to targeted clinical interventions and to new prevention strategies focused on the biological activity of PM. We propose a new approach to population studies of complex mixtures of air pollution that will assess exposure based on the in vitro effects of PM on key biological pathways and examine the relationship to the development of chronic disease. These pathways include inflammation, characterized by PM-induced cytokines (IL-8, GM-CSF, and IL-12), allergy (IgE response and release of histamine) and oxidative stress (reactive oxygen species production, GST activity and Phase II enzyme induction). We will also investigate genetic susceptibility based on the change in PM-induced biological activity in cells expressing GSTM1 and in cells with GSTM1 expression reduced using siRNA. We selected this gene as a prototype for our research approach because it has a common null genotype that increases the risk of asthma associated with oxidant PM exposure. We will use the in vitro toxicological assays to predict the risk of asthma and assess susceptibility associated with GSTM1 genotype. Our ongoing prospective cohort study of air pollution, genetics and respiratory disease among 3372 children in the southern California Children's Health Study provides an opportunity to use the new approach to evaluate whether: 1) asthma incidence and bronchitic exacerbation are associated with the in vitro ability of PM to induce pro- oxidant, inflammatory and allergic effects; and 2) susceptibility to health effects of PM-induced biological activity is influenced by in vitro GSTM1 expression and by participants' GSTM1 genotype. The in vitro biological responses to PM less than 2.5 5m in aerodynamic diameter will be measured along with gaseous oxidant co-pollutants (NOx and ozone) at community monitors, schools and a sample of homes in each of the eight study communities. Results will be integrated in the analyses using an innovative hierarchical modeling strategy to predict variation in particle biological activity related to traffic within communities and across study communities representing the range of ambient PM exposure in southern California. Each biological exposure index, which will be specific for study participants' GSTM1 genotype, will be assigned to the entire cohort and will be used to predict asthma and bronchitic symptoms. The study has the potential to fill important gaps in our understanding of the role of particulate air pollution in the development of childhood respiratory disease. PUBLIC HEALTH RELEVANCE This new approach to exposure assessment has the potential to provide better estimates of asthma risk and susceptibility due to exposure to particulate air pollution. This information will be useful for risk assessment and could lead to new regulatory and monitoring approaches for controlling the health hazards of air pollution.