Childhood Asthma, Susceptibility and Biological Activity of Ambient Particles

描述（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，交通相关的颗粒空气污染可能有助于儿童哮喘和哮喘相关的支气管炎症状的发生。可吸入颗粒物（PM）会产生哮喘特有的氧化应激和急性炎症和过敏反应，但关于这些影响如何导致慢性疾病发展的研究很少。更好地了解哪些特定的PM诱导的生物学效应导致哮喘可能导致有针对性的临床干预和新的预防策略，重点关注PM的生物活性。我们提出了一种针对复杂空气污染混合物的人群研究的新方法，该方法将基于PM对关键生物途径的体外影响来评估暴露，并检查其与慢性疾病发展的关系。这些途径包括炎症，以pm诱导的细胞因子（IL-8、GM-CSF和IL-12）、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期酶诱导）为特征。我们还将基于pm在表达GSTM1的细胞和使用siRNA降低GSTM1表达的细胞中诱导的生物活性变化来研究遗传易感性。我们选择这个基因作为我们研究方法的原型，因为它具有一个常见的零基因型，增加了与氧化性PM暴露相关的哮喘风险。我们将使用体外毒理学试验来预测哮喘的风险，并评估与GSTM1基因型相关的易感性。我们在南加州儿童健康研究中对3372名儿童进行的空气污染、遗传和呼吸系统疾病的前瞻性队列研究提供了一个使用新方法评估哮喘发病率和支气管炎加重是否与PM诱导促氧化、炎症和过敏作用的体外能力相关的机会；2) pm诱导的生物活性对健康影响的易感性受GSTM1体外表达和参与者的GSTM1基因型的影响。在八个研究社区的社区监测站、学校和家庭样本中，将测量空气动力学直径小于2.5米的PM的体外生物反应以及气态氧化共污染物（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跨研究社区交通相关的颗粒生物活性变化，代表南加州环境PM暴露的范围。每个生物暴露指数将针对研究参与者的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对……的理解上的重要空白

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.