Childhood Asthma, Susceptibility and Biological Activity of Ambient Particles

儿童哮喘、环境颗粒物的易感性和生物活性

• 批准号: 8092713
• 负责人: ROB S MCCONNELL
• 金额: $ 44.91万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8092713
• 关键词: Acute; Affect; Air Pollution; Alleles; Allergic; Allergic inflammation; Antioxidants; Asthma; Biological; Biological Assay; Bronchitis; Caliber; California; Cell Line; Cells; Characteristics; Child; Child health care; Childhood; Childhood Asthma; Chronic; Chronic Disease; Clinical; Cohort Studies; Communities; Complex Mixtures; Development; Disease; Enzyme Induction; Enzymes; Etiology; Exposure to; GSTM1 gene; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Health Hazards; Histamine Release; Home environment; Hypersensitivity; IL8 gene; IgE; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-12; Intervention; Joints; Lead; Liquid substance; Location; Lung; Lung diseases; Measurement; Measures; Modeling; Monitor; Outcome; Oxidants; Oxidative Stress; Oxidative Stress Pathway; Ozone; Participant; Particulate; Particulate Matter; Pathogenesis; Pathway interactions; Phase; Population; Population Study; Predisposition; Prevalence; Prevention strategy; Primary Prevention; Production; Reactive Oxygen Species; Research; Resources; Risk; Risk Assessment; Role; Sampling; Schools; Severities; Site; Small Interfering RNA; Source; Statistical Models; Symptoms; Variant; allergic response; ambient particle; base; cohort; cytokine; enzyme activity; extracellular; glutathione S-transferase M1; human data; in vivo; indexing; innovation; novel; novel strategies; particle; pollutant; population based; prospective; prototype; research study; respiratory; response; trafficking

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.

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，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）产生氧化应激和哮喘的急性炎症和过敏性影响，但很少有研究这些影响如何导致慢性疾病的发展。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措施和新的预防策略，重点是PM的生物活性。我们提出了一种新的方法来人口研究的复杂混合物的空气污染，将评估暴露的基础上，在体外的PM对关键的生物途径的影响，并检查与慢性疾病的发展的关系。这些途径包括炎症，其特征在于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相酶诱导）。我们还将研究遗传易感性的基础上的变化，在PM诱导的生物活性的细胞表达GSTM 1和GSTM 1表达减少使用siRNA的细胞。我们选择这个基因作为我们研究方法的原型，因为它有一个共同的空基因型，增加了与氧化剂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GSTM 1基因型相关的易感性。我们正在进行的对南加州儿童健康研究中的3372名儿童进行的空气污染、遗传学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来评估以下问题的机会：1）哮喘发病率和支气管炎恶化是否与PM诱导促氧化、炎症和过敏作用的体外能力有关;对PM诱导的生物活性的健康效应的易感性受体外GSTM 1表达和参与者的GSTM 1基因型的影响。空气动力学直径小于2.55米的PM的体外生物反应将在8个研究社区的社区监测器、学校和家庭样本中沿着气态氧化剂共污染物（NOx和臭氧）进行测量。结果将整合在分析中使用创新的分层建模策略，以预测在社区内和跨研究社区代表的范围内的环境PM暴露在南加州的交通相关的颗粒生物活性的变化。每个生物暴露指数，这将是特定的研究参与者的GSTM 1基因型，将被分配到整个队列，并将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这一问题的理解中的重要空白。 颗粒空气污染在儿童呼吸道疾病发展中的作用。这种新的暴露评估方法有可能更好地估计由于暴露于颗粒空气污染而引起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，以控制空气污染对健康的危害。