Environmentally Persistent Free Radicals Alter Pulmonary Immunologic Homeostasis

环境持久性自由基改变肺免疫稳态

• 批准号: 10116406
• 负责人: Stephania A Cormier
• 金额: $ 40.28万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116406
• 关键词: Address; Affect; Agonist; Air; Archives; Aryl Hydrocarbon Receptor; Asthma; Back; Biological Markers; Biophysics; Birth; Carbazoles; Cardiac; Cells; Child; Collaborations; Complex; Cytochrome P450; Cytochromes b5; Data; Data Analyses; Dendritic Cells; Disease; Environment; Environmental Health; Environmental Monitoring; Enzymes; Epidemiology; Epithelial Cells; Exposure to; Family; Free Radicals; Functional disorder; Funding; Genetic Transcription; Government Agencies; Hazardous Waste; Health; Health Policy; Helper-Inducer T-Lymphocyte; Homeostasis; House Dust; Human; Immune; Immune response; Immunologics; In Vitro; Inflammatory Response; Inhalation; Inhalation Toxicology; Kinetics; Laboratories; Life; Ligands; Link; Liquid substance; Lung; Measurement; Mediating; Mediation; Metabolic; Metabolism; Metals; Mus; NADPH-Ferrihemoprotein Reductase; National Institute of Environmental Health Sciences; Neutrophilia; Organic Chemicals; Organism; Outcomes Research; Oxidation-Reduction; Oxidative Stress; Particulate Matter; Phenotype; Play; Process; Production; Protocols documentation; Public Health; Receptor Activation; Receptor Signaling; Regulation; Research; Role; Signal Recognition Particle; Silicon Dioxide; Site; Superfund; System; Testing; Translating; Tryptophan; Urine; Work; airway epithelium; aryl hydrocarbon receptor ligand; biological systems; biophysical techniques; cohort; cytokine; data management; environmental particulate; glutathione sulfonamide; in vivo; man; mouse model; neutrophil; oxidative damage; pollutant; programs; pulmonary function; receptor function; remediation; respiratory; respiratory health; response; superfund site; web portal

Project Summary/Abstract: Project 1 Nearly 53 million people live within 3 miles of a Superfund remediation site. Superfund sites contain a wide va- riety of pollutants, including organic chemicals, metals, carbonaceous material, and silica. Although each of these components is capable of damage to organisms, their potential to combine into unique hazardous agents has been understudied. Interestingly, when these agents are present together, particularly during thermal re- mediation, they combine to form particulate matter (PM) with chemisorbed free radicals that persist in the envi- ronment and biological systems. Over the prior funding cycle, we established that these environmentally per- sistent free radicals (EPFRs) represent underappreciated pollutant species, induce oxidative stress and dam- age, and negatively impact respiratory health. EPFRs are produced during thermal treatment (TT) of hazard- ous wastes and nearly 30% of all Superfund sites (excluding groundwater) are remediated by TT. EPFR con- centrations near Superfund sites range from 1x1018 - 4x1019 EPFRs/g (spins/g) of PM. This suggests a vast number of US residents are exposed to PM containing EPFRs. Short-term inhalational EPFR exposure elicited a Th17 inflammatory response similar to the severe asthma phenotype in humans. Mechanistically, we demonstrated a role for Th17 cells driven by the aryl hydrocarbon receptor (AhR) in this response. EPFRs also cause alterations in foreign compound metabolism. Not only is there a direct inhibition of P450-dependent activities, mediated by disruption of the complex between P450s and their redox partners, but EPFRs also induced P450s from the CYP1A family via AhR. Although there are unique features within the immunologic and metabolic aspects of the proposal, they share a common feature—AhR. Our hypothesis is that EPFRs modu- late AhR signaling leading to a pleiotropic response that alters both immunologic and P450 function resulting in poor respiratory health. Aim 1 will demonstrate that EPFR mediated activation of AhR in airway epithelial cells (AEC) induces Th17 responses. To test our hypothesis, we will employ mice in which AhR is selectively de- pleted from AECs. As part of this aim we will test the role of the tryptophan metabolite 6-formylindolo[3,2-b]car- bazole (FICZ) to activate AhR. Aim 2 will define the mechanism of EPFR inhibition of P450 function, focusing on P450 interactions with their redox partners NADPH-cytochrome P450 reductase (CPR) and cytochrome b5. These studies will show how inhibition of P450 function affects disposition of FICZ and ultimately Th17-medi- ated asthma. This will be accomplished by kinetic and biophysical examination of the effect of EPFRs on com- plex formation. Aim 3 will demonstrate an epidemiologic link between EPFR exposure and poor respiratory health in children. Measurements of glutathione sulfonamide, a biomarker of pulmonary neutrophilia and asso- ciated with Th17 mediated asthma, will be used to relate EPFR exposure and respiratory health. Responding to SRP Mandate 1 and 2, Project 1 will demonstrate that EPFR exposure impacts child respiratory health and provide mechanism(s) by which EPFRs contribute to disease.

项目摘要/摘要：项目1 近5300万人居住在超级基金修复地点的3英里范围内。超级基金站点包含宽阔的va- 尽管每种污染物，包括有机化学品，金属，碳质物质和二氧化硅。 这些成分能够损坏生物，它们有可能将其结合成独特的危险剂 已被理解。有趣的是，当这些药物在一起时，尤其是在热重复期间 调解，它们结合了形成颗粒物（PM）与持续存在的化学吸附的自由基 Ronment和生物系统。在先前的资金周期中，我们确定这些在环境上 纯正自由基（EPFR）代表未被污染物的物种，诱导氧化应激和大坝 年龄，并对呼吸健康产生负面影响。 EPFR是在危害热处理（TT）期间产生的 TT对OUS废物和几乎30％的超级基金站点（不包括地下水）进行了补救。 EPFR 超级基金站点附近的核心范围从1x1018-4x1019 EPFRS/g（Spins/g）的PM。这表明鞋面 美国居民的数量暴露于包含EPFR的PM。短期吸入EPFR暴露引起 TH17炎症反应类似于人类严重的哮喘表型。从机械上讲，我们 在此反应中证明了由芳基烃受体（AHR）驱动的Th17细胞的作用。也是EPFR 导致外国复合代谢的改变。不仅有直接抑制P450依赖性的 活动，由P450及其氧化还原合作伙伴之间的复合物的破坏介导，但EPFR也 通过AHR从CYP1A家族诱导P450。尽管免疫学和 提案的代谢方面，它们具有共同的特征-Ahr。我们的假设是EPFRS模型 晚期AHR信号传导导致多效反应改变免疫学和P450功能，从而导致 呼吸健康不良。 AIM 1将证明EPFR介导的气道上皮细胞中AHR的激活 （AEC）诱导Th17响应。为了检验我们的假设，我们将采用小鼠AHR有选择地脱离的小鼠 从AECs开始。作为此目的的一部分，我们将测试色氨酸代谢产物6-甲基内迪洛[3,2-B] Car-的作用 Bazole（FICZ）激活AHR。 AIM 2将定义EPFR抑制P450功能的机制，聚焦 在与氧化还原伙伴的P450相互作用上，NADPH-CYTOCHROME P450还原（CPR）和细胞色素B5。 这些研究将表明对P450功能的抑制如何影响FICZ的处置，并最终影响Th17-Medi- 哮喘。这将通过对EPFR对COM-的影响的动力学和生物物理检查来实现 plex形成。 AIM 3将证明EPFR暴露与呼吸不良之间的流行病学联系 儿童健康。谷胱甘肽磺胺酰胺的测量，硫酸磺酰胺，肺嗜中性粒细胞和辅助的生物标志物 与Th17介导的哮喘相结合，将用于将EPFR暴露和呼吸健康联系起来。回应 对于SRP任务1和2，项目1将证明EPFR暴露会影响儿童呼吸健康和 提供EPFR促进疾病的机制。