Exposure-induced Systemic Oxidative Stress in Children with Asthma

哮喘儿童暴露引起的全身氧化应激

• 批准号: 7851057
• 负责人: Melinda Sue ButschKovacic
• 金额: $ 17.76万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851057
• 关键词: 6 year old; Address; Affect; Age; Air Pollution; Allergic; Allergic Disease; Amino Acids; Animal Model; Antioxidants; Area; Asthma; Attenuated; Biological Assay; Biological Markers; Biological Markers; Birth; Blood; Body Weight; Breathing; Bronchoalveolar Lavage Fluid; Cells; Child; Childhood; Childhood Asthma; Clinical; Clinics and Hospitals; Communities; DNA; DNA Damage; Data; Databases; Demographic Factors; Development; Diagnosis; Diagnostic; Diesel Exhaust; Disease; Dose; Enrollment; Environment; Environmental Exposure; Environmental Policy; Environmental Risk Factor; Environmental Tobacco Smoke; Epithelial Cells; Ethnic Origin; Exhalation; Foundations; Future; Gender; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; German population; Goals; Health; Health Policy; Human; Hypersensitivity; Individual; Infant; Inflammation; Inflammatory; Intervention; Knowledge; Life; Link; Lipids; Lung; Measurement; Measures; Medical; Medical center; Methods; Modeling; Mus; NF-kappa B; Obesity; Ohio; Outcome; Outpatients; Oxidative Stress; Particulate Matter; Partner in relationship; Pathogenesis; Pathway interactions; Pediatric Hospitals; Persons; Physicians; Plasma; Predictive Value; Prevention approach; Production; Proteins; Public Health; Pulmonary function tests; Quality of life; Questionnaires; Race; Reactive Oxygen Species; Reporting; Risk; Schiff Bases; Severities; Severity of illness; Signal Pathway; Source; Sputum; Stratification; Susceptibility Gene; Symptoms; Tail; Testing; Time; Wheezing; Work; World Health Organization; air sampling; asthma prevention; base; chemokine; cohort; cost; cytokine; design; evidence base; gene environment interaction; in vivo; innovation; macrophage; multidisciplinary; novel; oxidation; particle; particle exposure; prevent; primary outcome; public health relevance; response; secondary outcome; therapy development; tool; trafficking

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.

描述（由申请人提供）：该R21应用程序的总体目标是实现我们的长期目标的一步，是证明/反驳荧光血浆氧化应激产品（FPOP）是柴油机颗粒（DEP）暴露于氧化应激的生物学生物标志物（DEP）诱导的氧化压力和/或/或/或/或/或标记疾病的儿童。目前，人们对卡车交通中的DEP在多大程度上修饰哮喘和合并症过敏性疾病的程度仍然不完整。缺乏DEP暴露的生物学标志物，这将使医生能够在一个儿童的实际暴露与生物学相关或有效的DEP暴露之间的区别，从而阻碍预防或减轻疾病的疗法的发展。 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确定系统性氧化应激产物是否可以预测更严重的儿童哮喘和更大的过敏性疾病负担（生物标志物 - 疾病关系）。这项研究利用了独特的辛辛那提儿童医院医疗中心儿科哮喘和过敏研究，独特的能力，可以测量全身氧化应激产物的水平，并在高度暴露和显着影响的社区中估算DEP暴露。主要结果将包括全身氧化应激产物的水平（AIM 1）和由医师诊断/肺功能测试，症状评分和生活质量度量（AIM 2）定义的哮喘。次要结果将包括现有合并过敏状况的负担和严重性。为了确定面临更严重哮喘和过敏性疾病负担的风险的儿童，将直接比较全身氧化应激产物和严重哮喘的DEP暴露的预测值。抗氧化剂/氧化应激和炎症途径，人口统计学因素和其他重要的炎症性氧化应激暴露暴露的基因中多态性的影响将被视为潜在的混杂因子和/或修饰符。无论发现如何，这项提出的探索性R21都很重要，因为它将降低与寻求发现生物标志物的更确定研究相关的风险，以鉴定出在环境扩散后患有更严重的哮喘和更严重的哮喘和过敏性疾病的儿童。如果努力支持中心假设，那么该研究的完成将为首先寻求更好地表征Dep暴露，氧化压力和哮喘之间的关系打开大门 关于环境暴露的知识。公共卫生相关性：该R21提案对公共卫生具有重要意义，因为它将确定氧化应激产物是否是柴油排气暴露引起的氧化应激和儿童哮喘严重程度的生物学相关的生物标志物。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基于新的基于证据的环境政策中的重要性。

项目成果

Increased nasal epithelial cell responsiveness to IL-17A in paediatric asthmatics with low blood neutrophil count, low traffic-related air pollution exposure and good asthma control.

• DOI: 10.1111/cea.14080
• 发表时间: 2022-04
• 期刊: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
• 作者: McAlees JW;Baker T;Houshel L;McKnight C;Lindsley A;Strait RT;Zhang X;Cannata A;Biagini JM;Butsch Kovacic M;Lewkowich IP
• 通讯作者: Lewkowich IP