Interactions of Diesel Exhaust and Respiratory Viruses in Asthmatic Children

柴油机尾气与哮喘儿童呼吸道病毒的相互作用

• 批准号: 7731583
• 负责人: TOBY C LEWIS
• 金额: $ 65.57万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-13 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7731583
• 关键词: Acute; Adhesions; Affect; Air; Air Pollutants; Air Pollution; Animals; Arts; Asthma; Automobile Exhaust; Biological; Biological Markers; Budgets; Build-it; Characteristics; Child; Child health care; Childhood Asthma; Clinical; Clinical Pathways; Cohort Studies; Complex; Diesel Exhaust; Disease; Distant; Enrollment; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epidemiology; Epithelial Cells; Equation; Evaluation; Exhalation; Exposure to; Figs - dietary; Foundations; Free Radicals; Frequencies; Functional disorder; Funding; Health; Health Diary; Health Status; Home environment; Incidence; Inflammation; Inflammatory; Intercellular Adhesion Molecules; Intercellular adhesion molecule 1; Interferons; Interleukin-8; Irrigation; Knowledge; Laboratories; Life; Linear Models; Liquid substance; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Lower respiratory tract structure; Lung; Measures; Medical; Messenger RNA; Michigan; Modeling; Morbidity - disease rate; Nature; Nitric Oxide; Nitrogen Dioxide; Nose; Outcome; Outcome Measure; Oxidative Stress; Participant; Pathway interactions; Patient Self-Report; Pharmaceutical Preparations; Physiological; Policies; Pollution; Predisposition; Prospective Studies; Proteins; Public Health; Pulmonary Function Test/Forced Expiratory Volume 1; Rattus; Recruitment Activity; Reporting; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Respiratory System; Respiratory Tract Infections; Respiratory physiology; Reverse Transcriptase Polymerase Chain Reaction; Rhinovirus; Robin bird; Role; Schools; Screening procedure; Severities; Specimen; Sulfur Dioxide; Symptoms; Testing; United States; Upper Respiratory Infections; Vehicle Emissions; Viral; Viral Load result; Virus; Virus Diseases; Virus Receptors; Visit; Wheezing; Work; airway hyperresponsiveness; airway inflammation; base; biological adaptation to stress; child trafficking; cohort; cost; cytokine; experience; falls; human TLR3 protein; improved; inflammatory marker; insight; isoprostaglandin F2alpha type-III; oxidant stress; particle; pollutant; prospective; protein expression; public health relevance; receptor; respiratory; respiratory virus; response; trafficking; urinary

DESCRIPTION (provided by applicant): Traffic-associated air pollution and respiratory viral infections (URIs) are well-documented, independent stimulants of asthma symptoms, and both are associated with significant asthma morbidity. There is growing laboratory and epidemiologic evidence to suggest that air pollution and URIs have interactive effects on the respiratory system. We have shown, in a prior epidemiologic study, that asthmatics with cold symptoms show more changes in lung function associated with prior exposure to high pollution than those without colds. However, the independent and interactive effects of pollutants attributable to diesel and other vehicular emissions and URIs on asthma exacerbation in children have not been extensively studied. We propose to test the general hypothesis that traffic-associated air pollution, specifically diesel exhaust, and respiratory viral infections combine to induce exaggerated airway responses in children with asthma. Two potential mechanisms of interaction will be evaluated: a) traffic-associated air pollution increases susceptibility to viral URI, and b) combined traffic pollutant exposure and URI elicits augmented inflammatory and oxidative stress responses leading to worse clinical asthma outcomes. To test this hypothesis of interaction, we propose these Specific Aims: 1. Compare asthmatic children living near highways with diesel truck traffic to those living distant from high volume roads for a) the frequency and characteristics of viral upper respiratory infections (URIs) and b) changes in nasal expression of viral adhesion proteins and interferons. 2. Prospectively evaluate the interactions between air pollution and viral upper respiratory infections on a) asthma morbidity, and b) markers of inflammation and oxidative stress. These hypotheses will be tested in a prospective study of a cohort of children with persistent asthma with extensively characterized exposure to diesel and other vehicular emissions. We will study the effects of diesel exhaust on incidence of viral infection and susceptibility to virus by evaluating nasal lavage specimens for viral infection, viral load, intercellular adhesion molecule (ICAM)-1, low-density lipoprotein receptor (LDL)-R, Toll-like receptor (TLR)-3, interferons (IFNs)-2, 3, and ; mRNA and protein expression using RT-PCR and ELISA, respectively. We will characterize interactive effects of diesel exhaust and PCR-confirmed viral infection on asthma health outcomes (primarily: fluctuations in daily measures of forced expiratory volume in 1 second (FEV1) and frequency of self-reported wheezing). We will also evaluate the role of enhanced inflammation and oxidative stress in these interactions by assessing markers of early physiologic response to exposures: exhaled nitric oxide (eNO), urinary 8-isoprostane, and nasal inflammatory cytokines (interleukin- 8/CXCL8, IP-10/CXCL10, RANTES/CCL5). The proposed studies will provide insight into the underlying biologic mechanisms and public health impacts of diesel-virus interactions in aggravation of childhood asthma. PUBLIC HEALTH RELEVANCE: This project will evaluate the impact on the health of asthmatic children of two very common "real world" asthma triggers: air pollution (especially diesel and vehicular exhaust) and respiratory viral infections. Enhanced knowledge of the extent and mechanisms of the interactions of these triggers will: a) give a more complete view of the public health impact of air pollution, facilitating scientifically-based air quality and traffic emissions policy; and b) enhance our understanding of the pathophysiology of asthma, a complex disease affecting 22.2 million people in the United States, thus pointing the way towards targeted therapies and public health approaches.

描述（由申请人提供）：与交通相关的空气污染和呼吸道病毒感染（URI）是有据可查的、独立的哮喘症状刺激因素，并且两者都与显着的哮喘发病率相关。越来越多的实验室和流行病学证据表明，空气污染和 URI 对呼吸系统具有交互作用。我们在之前的流行病学研究中表明，与没有感冒的哮喘患者相比，有感冒症状的哮喘患者与之前暴露于高污染环境相关的肺功能变化更多。然而，柴油和其他车辆排放的污染物以及URI对儿童哮喘恶化的独立和交互影响尚未得到广泛研究。我们建议检验以下一般假设：与交通相关的空气污染（特别是柴油机尾气）和呼吸道病毒感染结合起来会引起哮喘儿童过度的气道反应。将评估两种潜在的相互作用机制：a) 与交通相关的空气污染增加对病毒性 URI 的易感性，b) 交通污染物暴露和 URI 相结合会引发炎症和氧化应激反应增强，导致临床哮喘结果更差。为了检验这种相互作用的假设，我们提出了以下具体目标： 1. 将居住在有柴油卡车交通的高速公路附近的哮喘儿童与居住在远离交通繁忙道路的儿童进行比较：a) 病毒性上呼吸道感染 (URI) 的频率和特征，以及 b) ）病毒粘附蛋白和干扰素鼻表达的变化。 2. 前瞻性评估空气污染和病毒性上呼吸道感染之间对 a) 哮喘发病率和 b) 炎症和氧化应激标志物的相互作用。这些假设将在一项前瞻性研究中得到检验，该研究对一组患有持续性哮喘的儿童进行了检验，这些儿童广泛接触柴油和其他车辆排放物。我们将通过评估鼻腔灌洗标本的病毒感染、病毒载量、细胞间粘附分子（ICAM）-1、低密度脂蛋白受体（LDL）-R、Toll，研究柴油机尾气对病毒感染发生率和病毒易感性的影响-样受体 (TLR)-3​​、干扰素 (IFN)-2、3 和 ;分别使用 RT-PCR 和 ELISA 进行 mRNA 和蛋白表达。我们将描述柴油机尾气和 PCR 确认的病毒感染对哮喘健康结果的交互影响（主要是：每日 1 秒用力呼气量 (FEV1) 测量值的波动和自我报告的喘​​息频率）。我们还将通过评估对暴露的早期生理反应标志物来评估增强的炎症和氧化应激在这些相互作用中的作用：呼出一氧化氮（eNO）、尿8-异前列烷和鼻炎性细胞因子（白细胞介素-8/CXCL8、IP- 10/CXCL10、RANTES/CCL5)。拟议的研究将深入了解柴油机病毒相互作用导致儿童哮喘恶化的潜在生物学机制和公共卫生影响。公共健康相关性：该项目将评估两种非常常见的“现实世界”哮喘诱因对哮喘儿童健康的影响：空气污染（尤其是柴油和汽车尾气）和呼吸道病毒感染。增强对相互作用的程度和机制的了解 这些触发因素将：a) 更全面地了解空气污染对公共卫生的影响，促进 科学的空气质量和交通排放政策； b) 增强我们对哮喘病理生理学的理解，这是一种影响美国 2220 万人的复杂疾病，从而为靶向治疗和公共卫生方法指明了道路。