PM Adjuvant Effects, Dendritic Cells Oxidative Stress

PM 佐剂作用、树突状细胞氧化应激

• 批准号: 7150194
• 负责人: Andre Elias Nel
• 金额: $ 31.77万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150194
• 关键词: aerosols; air pollution; airborne allergen; asthma; cell transplantation; cytoprotection; dendritic cells; diagnostic respiratory lavage; engine exhaust; genetically modified animals; helper T lymphocyte; immunogenetics; immunoregulation; inflammation; interleukin 4; laboratory mouse; leukocyte activation /transformation; oxidative stress; pollution related respiratory disorder; proteomics; respiratory hypersensitivity; respiratory pharmacology; short chain fatty acid; thiocyanates; transcription factor

Relevance: The goal of this application is to understand the pathway by which participate air pollutants (a.k.a. particulate matter or PM) lead to worsening of allergic asthma by impacting dendritic cells (DC) in the immune system (IS). This research is relevant to understanding how air pollutants contribute to the development of asthma, and proposes rational therapy to block the impact of of PM on asthma through the use of a novel class of antioxidants. The principal hypothesis is that PM and adsorbed redox cycling organic chemicals alter DC function to favor Th2 skewing of the IR. The proposal is that oxidative stress perturbs DC activities such as antigen presentation, cellular maturation, cytokine production and/or co-stimulatory activity that are key for T-cell activation and Th2 differentiation. A pathway that is regulated by the transcription factor, Nrf2, protects against the pro-inflammatory and adjuvant effects of PM. Nrf2 accomplishes this by inducing the expression of a battery of phase II antioxidant enzymes that exert anti-inflammatory effects. Aim 1 will determine in a DC adoptive transfer model the mechanism(s) by which oxidative stress promotes Th2 skewing in vitro and in vivo. Diesel exhaust particles, ambient ultrafine particles and pro-oxidative PM chemical fractions will be used to determine their effect on DC immunoregulatory properties, including antigen uptake, antigen presentation, maturation, cytokine/chemokine production, transgenic T-cell activation, and co-stimulatory activity. In vivo skewing of the IR will be further expored in transgenic mice that express a nlL-4-GFP transgene knocked into the IL-4 promoter. Aim 2 will determine whether the Nrf2-mediated antioxidant defense pathway, by modification of DC function, regulates PM-induced oxidative stress and asthma. This will be accomplished by comparing wild type with Nrf2-deficient animals. This study will determine whether interference in phase II enzyme expression leads to exaggerated PM effects on DC antigen presenting activity and whether Nrf2 deficiency promotes Th2 skewing and allergic inflammation in vivo. Proteome analysis will be conducted to reveal in vivo oxidative stress markers in the BAL fluid that can used to study PM oxidative stress effects. In collaboration with Projects 2 & 3, proteome analysis will also be conducted on human nasal lavage fluid to develop a comprehensive understanding of the allergic inflammatory effects of DEP in the nose, including the dynamic equilibrium between pro-and antioxidant pathways. Aim 3 will determine whether Nrf2-mediated phase II enzyme expression during treatment with alpha-lipoic acid and sulfurophane protects against PM oxidative stress effects and asthma exacerbation in vivo and modulation of DC function in vitro.

相关性：本应用的目标是了解空气污染物参与的途径 （又名颗粒物或 PM）通过影响体内的树突状细胞 (DC) 导致过敏性哮喘恶化 免疫系统（IS）。这项研究有助于了解空气污染物如何影响 哮喘的发展，并提出合理的治疗方法，通过以下方式阻断PM对哮喘的影响 使用一类新型抗氧化剂。 主要假设是 PM 和吸附的氧化还原循环有机化学物质改变 DC 功能以有利于 IR 的 Th2 偏移。该提议认为，氧化应激会扰乱 DC 活性，例如抗原 T 细胞关键的呈递、细胞成熟、细胞因子产生和/或共刺激活性 激活和 Th2 分化。受转录因子 Nrf2 调节的途径可保护 对抗 PM 的促炎和辅助作用。 Nrf2 通过诱导表达式来实现这一点 一组具有抗炎作用的 II 期抗氧化酶。目标 1 将在 DC 中确定 过继转移模型 氧化应激在体外和体内促进 Th2 倾斜的机制 体内。柴油机尾气颗粒、环境超细颗粒和促氧化性 PM 化学成分将被 用于确定它们对 DC 免疫调节特性的影响，包括抗原摄取、抗原 呈递、成熟、细胞因子/趋化因子产生、转基因 T 细胞激活和共刺激 活动。 IR 的体内偏差将在表达 nlL-4-GFP 的转基因小鼠中进一步暴露 转基因敲入 IL-4 启动子。目标 2 将确定 Nrf2 介导的抗氧化剂是否 防御途径通过改变 DC 功能来调节 PM 诱导的氧化应激和哮喘。这 将通过比较野生型与 Nrf2 缺陷动物来完成。这项研究将确定是否 II 相酶表达的干扰导致 PM 对 DC 抗原呈递的影响过大 活性以及 Nrf2 缺乏是否会促进体内 Th2 倾斜和过敏性炎症。蛋白质组 将进行分析以揭示 BAL 液中的体内氧化应激标记物，可用于研究 PM 氧化应激的影响。与项目 2 和 3 合作，蛋白质组分析也将进行 人类鼻腔灌洗液以全面了解过敏性炎症的影响 鼻子中的 DEP，包括促氧化剂和抗氧化剂途径之间的动态平衡。目标3将 确定在用α-硫辛酸治疗期间是否Nrf2介导的II相酶表达和 硫磺烷可防止体内 PM 氧化应激效应和哮喘恶化，并调节 DC 体外功能。