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：该项目的目的是确定氧化应激在确定能力中的作用 不同的颗粒会引起气道炎症，以及为什么有些人更容易受到 粒子的不利影响比其他颗粒的不利影响。 柴油排气颗粒（DEP）的能力，即颗粒物（PM）的主要组成部分，使其恶化 并且启动过敏性气道疾病现已牢固确定。虽然其他颗粒可能会产生相似的影响，但 他们的效能可能会有很大差异。在这项研究中要检验的中心假设是氧化应激 是DEP和环境PM在人类中诱导这些促炎作用的关键机制 呼吸道。我们建议对PM的反应能力取决于伤害发动机之间的平衡 II期酶的氧化应激和抗氧化剂/抗炎作用 保护气道。此外，我们建议这种平衡的差异可以解释为什么有些 比其他人更容易受到PM的不利影响。呼吸道中的氧化应激 道是这些疾病中炎症的自然结果。已经提出了分层模型 在低水平的氧化应激下，抗氧化剂反应主要是氧化应激 水平增加，促炎反应的产量。我们将使用我们已建立的人类鼻暴露 在已经确定的高dep响应者队列中的模型中，以测试层次结构的有效性 通过研究这些对PM的响应的氧化应激模型（从 环境集中空气），中等（来自环境集中空气的细颗粒）和弱（惰性碳 黑色）产生氧化应激的内在能力：在AIM 1中，我们将检验以下假设。 不同类型的环境PM诱导活性氧的能力决定鼻部炎症 人类的回应。在AIM 2中，我们将检验以下假设，即定义高和低的固有能力 响应者个体产生抗氧化剂/抗炎反应确定其PM的水平 驱动的鼻和外周血单核细胞炎症反应。在AIM 3中，我们将研究遗传 PM在人类中敏感性的基础，并检验了基因和蛋白质表达谱不同的假设 通过基因表达网络的性能和蛋白质组学的性能，在高和低的DEP响应者之间。