Oxidative stress determinant human inflammatory response

氧化应激决定人类炎症反应

• 批准号: 7150200
• 负责人: DAVID DIAZ-SANCHEZ
• 金额: $ 25.78万
• 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/7150200
• 关键词: aerosols; air pollution; airborne allergen; antiinflammatory agents; antioxidants; carbon; cytokine; diagnostic respiratory lavage; engine exhaust; enzyme activity; gene expression; glutathione transferase; heme oxygenase; human subject; immunogenetics; inflammation; monocyte; oxidative stress; oxidoreductase; pollution related respiratory disorder; proteomics; respiratory epithelium; respiratory hypersensitivity

Relevance: The goal of this project is to determine the role of oxidative stress in determing the ability of different particles to cause inflammation in the airways and why some individuals are far more susceptible to the adverse effects of particles than others. The ability of diesel exhaust particles (DEP), a major constituent of particulate matter (PM), to exacerbate and initiate allergic airway disease is now firmly established. While other particles can have similar effects, their potency can vary considerably. The central hypothesis to be tested in this study is that oxidative stress is the key mechanism by which DEP and ambient PM induce these pro-inflammatory effects in the human respiratory tract. We propose that responsiveness to PM is determined by the equilibrium between injuryprovoking oxidative stress and the antioxidant/anti-inflammatory effects of Phase II enzymes that normally protect the airways. Moreover, we propose that differences in this equilibrium can explain why some individuals are more susceptible to the adverse effects of PM than others. Oxidative stress in the respiratory tract is a natural consequence of inflammation in these diseases. A hierarchical model has been proposed in which at low levels of oxidative stress, an antioxidant response predominates and as the oxidative stress levels increase, yields to pro-inflammatory responses. We will use our established human nasal exposure model in already identified cohorts of high and low DEP responders to test the validity of the hierarchical oxidative stress model in vivo by studying these responses to PM with strong (ultrafine particles from ambient concentrated air), moderate (fine particles from ambient concentrated air) and weak (inert carbon black) intrinsic abilities to generate oxidative stress: In Aim 1 we will test the hypothesis that the intrinsic ability of different types of ambient PM to induce reactive oxygen species determines nasal inflammatory responses in humans. In Aim 2 we will test the hypothesis that the intrinsic ability of defined high and low responder individuals to generate antioxidant/anti-inflammatory responses determines the level of their PM driven nasal and peripheral blood monocyte inflammatory responses. In Aim 3, we will study the genetic basis for PM susceptibility in humans and test the hypothesis that gene and protein expression profiles differ between high vs. low DEP responders by performance of gene expression networks and proteomics.

相关性：该项目的目标是确定氧化应激在确定氧化应激能力中的作用。 不同的颗粒会引起呼吸道炎症，以及为什么有些人更容易受到感染 颗粒物的不利影响比其他颗粒物大。 柴油机尾气颗粒 (DEP)（颗粒物 (PM) 的主要成分）能够加剧 并引发过敏性气道疾病现已牢固确立。虽然其他粒子也能产生类似的效果， 它们的效力可能相差很大。本研究要检验的中心假设是氧化应激 是 DEP 和环境 PM 在人体中诱导这些促炎症作用的关键机制 呼吸道。我们认为对 PM 的反应是由引起伤害之间的平衡决定的 通常情况下，氧化应激和 II 相酶的抗氧化/抗炎作用 保护呼吸道。此外，我们认为这种均衡的差异可以解释为什么有些 个体比其他人更容易受到 PM 的不利影响。呼吸系统的氧化应激 肠道是这些疾病中炎症的自然结果。提出了层次模型 在低水平的氧化应激下，抗氧化反应占主导地位，并且随着氧化应激 水平增加，产生促炎症反应。我们将使用我们已建立的人类鼻腔暴露 在已确定的高 DEP 反应者和低 DEP 反应者队列中建立模型，以测试分层的有效性 通过研究这些对来自强（超细颗粒）PM的反应，建立了体内氧化应激模型 环境浓缩空气）、中等（环境浓缩空气中的细颗粒）和弱（惰性碳 黑色）产生氧化应激的内在能力：在目标 1 中，我们将测试以下假设：内在能力 不同类型的环境 PM 诱导活性氧的能力决定了鼻腔炎症 人类的反应。在目标 2 中，我们将检验以下假设：定义高低的内在能力 产生抗氧化/抗炎反应的反应者个体决定了他们的 PM 水平 驱动鼻腔和外周血单核细胞炎症反应。在目标 3 中，我们将研究遗传 人类 PM 易感性的基础并检验基因和蛋白质表达谱不同的假设 通过基因表达网络和蛋白质组学的性能来区分高 DEP 反应者与低 DEP 反应者。