Exposure-induced Systemic Oxidative Stress in Children with Asthma

描述(申请人提供)：这份R21申请的总体目标是为了证明/驳斥荧光血浆氧化应激产物(FPOP)是接触柴油废气(DEP)诱导的氧化应激和/或哮喘儿童疾病严重程度的标记这一概念，这是迈向我们长期目标的一步。目前，对卡车交通中的DEP在多大程度上改变哮喘和合并过敏性疾病的程度仍存在不完全的了解。缺乏接触DEP的生物标记物将使医生能够区分一个儿童的实际接触和导致另一名儿童疾病的生物相关或有效的DEP接触，这继续阻碍预防或减轻疾病的治疗方法的发展。为了验证这样一种假设，即高水平的DEP暴露将显著增加全身氧化应激，并且测量氧化应激比单独估计DEP实际暴露更能预测严重儿童哮喘和过敏性疾病负担的风险，将追求以下两个具体目标：1)确定全身氧化应激产物是否是哮喘儿童生物相关DEP暴露的内部标志物(暴露-生物标记物关系)，2)确定系统性氧化应激产物是否预测更严重的儿童哮喘和更重的过敏性疾病负担(生物标记物与疾病的关系)。这项研究利用了辛辛那提儿童医院医疗中心独特的儿科哮喘和过敏研究，该研究具有独特的能力，可以测量全身氧化应激产物的水平，并在高度暴露和严重受影响的社区估计DEP暴露。主要结果将包括全身氧化应激产物水平(目标1)和由医生诊断/肺功能测试、症状评分和生活质量测量(目标2)确定的哮喘。次要结果将包括现有共病过敏疾病的负担和严重程度。为了确定患有更严重哮喘和过敏性疾病负担的儿童的风险，将直接比较全身氧化应激产物和估计的DEP暴露对严重哮喘的预测值。抗氧化剂/氧化应激和炎症途径、人口因素和其他重要的炎性氧化应激暴露中基因多态性的影响将被评估为潜在的混杂和/或修饰物。无论结果如何，这项拟议的探索性R21具有重要意义，因为它将降低与更明确的研究相关的风险，这些研究寻求发现生物标记物，以确定在环境暴露后易患更严重哮喘和过敏性疾病的儿童。如果这项努力支持中心假设，这项研究的完成将为以下努力打开大门：首先寻求更好地表征DEP暴露、氧化应激和哮喘之间的关系，最终优化哮喘预防方法，开发和定制新的治疗方法，并加强基于 关于环境暴露的知识。公共卫生相关性：这项R21提案对公共健康具有重要意义，因为它将确定氧化应激产物是否为柴油尾气暴露诱导的氧化应激和儿童哮喘严重程度的生物相关生物标志物。因此，这些和计划的未来努力将强调环境暴露在哮喘治疗、诊断工具的开发和新的以证据为基础的环境政策中的重要性。

DESCRIPTION (provided by applicant): The overall objective of this R21 application, which is a step toward attainment of our long-term goal, is to prove/refute the concept that fluorescent plasma oxidative stress products (FPOP) are biologically relevant biomarkers of diesel exhaust particle (DEP) exposure-induced oxidative stress and/or markers of disease severity in asthmatic children. Currently, there remains an incomplete understanding of the extent to which DEP from truck traffic modifies asthma and comorbid allergic disease. The lack of biological markers of DEP exposure, which would enable physicians to make the distinction between actual exposure in one child and biologically relevant or effective DEP exposure leading to disease in another child, continues to hamper development of therapies to prevent or attenuate disease. To test the hypothesis that high levels of DEP exposure will significantly increase systemic oxidative stress and that measurement of oxidative stress will better predict risk of severe childhood asthma and allergic disease burden than estimation of actual DEP exposure alone, the following two specific aims will be pursued: 1) to determine if systemic oxidative stress products are internal markers of biologically relevant DEP exposure in asthmatic children (exposure-biomarker relationship), and 2) to determine if systemic oxidative stress products are predictive of more severe childhood asthma and greater allergic disease burden (biomarker-disease relationship). The study capitalizes on the distinctive Cincinnati Children's Hospital Medical Center Pediatric Asthma and Allergy Study, unique ability to measure levels of systemic oxidative stress products and estimate DEP exposure in a highly exposed and significantly affected community. Primary outcomes will include the level of systemic oxidative stress products (Aim 1) and asthma defined by physician diagnoses/pulmonary function tests, symptom scores and quality of life measures (Aim 2). Secondary outcomes will include the burden and severity of existing co-morbid allergic conditions. To identify children at risk for more severe asthma and allergic disease burden, the predictive values of systemic oxidative stress products and estimated DEP exposure on severe asthma will be directly compared. The influences of polymorphisms in genes within the antioxidant/oxidative stress and inflammatory pathways, demographic factors and other important inflammatory oxidative stress-inducing exposures will be evaluated as potential confounders and/or modifiers. Regardless of the findings, this proposed exploratory R21 is significant because it will diminish the risk associated with more definitive studies seeking to discover biomarkers to identify children predisposed to more severe asthma and allergic disease following environmental exposures. If the endeavor supports the central hypothesis, completion of the study will open the door for efforts seeking first to better characterize relationships between DEP exposure, oxidative stress and asthma and ultimately to optimize asthma prevention approaches, develop and tailor novel therapies, and strengthen public health policies based on knowledge of environmental exposure. PUBLIC HEALTH RELEVANCE: This R21 proposal is significant to public health because it will determine if products of oxidative stress are biologically relevant biomarkers of diesel exhaust exposure-induced oxidative stress and asthma severity in children. Consequently, these and planned future efforts will underscore the importance of environmental exposures in asthma treatment, development of diagnostic tools and new evidenced-based environmental policies.