Acute Asthma Outcomes, Endotoxin and Oxidative Potential of Pollutant Particles

描述（由申请人提供）：实验数据表明，内毒素可能与颗粒物（PM）空气污染的有机成分相互作用，诱导气道急性炎症反应，但没有重复测量数据来评估这种情况是否发生在哮喘儿童中。我们之前在南加州对58名9-18岁哮喘学童进行的一项小组队列研究中发现，每日个人空气污染物暴露的10项重复测量与每日急性哮喘结局之间存在关联。利用这些现有数据，我们将首次评估反复暴露于内毒素是否是反复暴露于空气污染与确诊哮喘受试者急性哮喘结局之间关系的效应修饰因子（目的1）。健康结果将包括气道炎症（呼出一氧化氮）和呼气肺功能。空气污染物将包括个人接触二氧化氮和PM2.5质量、元素碳和有机碳。此外，实验数据还表明，来自交通源化石燃料燃烧的PM成分可能具有诱导活性氧引发的氧化应激的潜力。然而，这些氧化还原活性成分的浓度可以独立于总调节PM质量（PM2.5）。先前观察到的哮喘恶化与PM2.5之间的关联可能与颗粒混合物诱导氧化应激和炎症反应的能力有关，这是哮喘潜在病理的标志。为了解决这个问题，我们将使用存档的日常颗粒样本的体外生物测定来分析哮喘结局与环境PM2.5氧化电位的关系（目的2）。我们假设哮喘的结果将与所收集的颗粒样品的氧化电位有关。我们进一步假设哮喘结果与PM2.5氧化电位的关联程度将大于PM2.5质量。最后，为了将前两个目标结合在一起，我们将评估暴露于内毒素的哮喘结局与环境PM2.5氧化电位之间关联的效应修正（目的3）。环境颗粒混合物的氧化电位与内毒素的相互作用可能比内毒素与促氧化有机颗粒成分（如元素碳）的替代示踪剂的相互作用更强（Aim 1）。在拟议的研究中，我们将从一项小组队列研究中得出新的发现，以解决知识上的空白，并证明新的暴露评估方法的潜在用途。这包括关于内毒素和空气污染联合暴露对哮喘健康重要性的新数据，以及暴露于根据关键空气污染物性质（其氧化电位）而变化的PM的新数据。我们的长期目标是通过与实验毒理学建立更大的一致性，推进研究空气污染和健康的流行病学方法。

DESCRIPTION (provided by applicant): Experimental data suggest that endotoxin may interact with organic components of particulate matter (PM) air pollution to induce acute inflammatory response in the airways, but there are no repeated measures data to assess whether this occurs in children with asthma. We previously found associations between 10 repeated measures of daily personal air pollutant exposures and daily acute asthma outcomes in a panel cohort study of 58 school children with asthma ages 9-18 years who were followed in southern California. Using these existing data we will assess for the first time whether repeated personal exposure to endotoxin is an effect modifier of the relation between repeated exposure to air pollution and acute asthma outcomes in subjects with diagnosed asthma (Aim 1). Health outcomes will include airway inflammation (exhaled nitric oxide) and expiratory lung function. Air pollutants will include personal exposure to NO2 and to PM2.5 mass, elemental carbon, and organic carbon. Furthermore, experimental data also show that components of PM derived from the combustion of fossil fuels from traffic sources may have the potential to induce oxidative stress initiated by reactive oxygen species. However, the concentrations of these redox active components can be independent of total regulated PM mass (PM2.5). It is possible that associations previously observed between worsening asthma and PM2.5 were related to the ability of particle mixtures to induce oxidative stress and inflammatory responses, which are hallmarks of the underlying pathology of asthma. To address this issue, we will analyze the relation of asthma outcomes to the oxidant potential of ambient PM2.5 using in vitro bioassays of archived daily particle samples (Aim 2). We hypothesize that asthma outcomes will be related to the oxidant potential of the collected particle samples. We further hypothesize that the magnitude of associations of asthma outcomes with PM2.5 oxidant potential will be greater than that for PM2.5 mass. Finally, to tie the previous two aims together, we will evaluate effect modification of associations between asthma outcomes and the oxidant potential of ambient PM2.5 by exposure to endotoxin (Aim 3). The oxidant potential of ambient particle mixtures may interact more strongly with endotoxin than interactions of endotoxin with surrogate tracers of pro-oxidant organic particle components such as elemental carbon (Aim 1). In the proposed study, we will produce new findings from a panel cohort study to address gaps in knowledge and to demonstrate the potential usefulness of new methods of exposure assessment. This includes new data on the importance to asthma health from joint exposures to endotoxin and air pollution, and from exposure to PM that varies according to a key air pollutant property, its oxidant potential. Our long-term goal is to advance epidemiologic methods of researching air pollution and health by establishing greater coherence with experimental toxicology. PUBLIC HEALTH RELEVANCE: The knowledge that will emerge from the proposed study of these subjects will be of benefit to public health by identifying whether the joint exposure to endotoxin and air pollution affects respiratory health outcomes among children with asthma. We will address major gaps in scientific knowledge by advancing understanding on the components of particulate air pollution that are responsible for associations of acute changes in asthma outcomes with total mass concentrations of regulated fine particulate matter. Our proposed use of repeated measurements of personal exposure to particles with different oxidant potential may influence the way future studies of air pollution and asthma are conducted.