Therapeutic anti-inflammatory phase II "anti-oxidant"

治疗性抗炎II期“抗氧化剂”

• 批准号: 7150197
• 负责人: ANDREW SAXON
• 金额: $ 25.03万
• 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/7150197
• 关键词: Cruciferae; airborne allergen; antigen presentation; antioxidants; biomarker; cytokine; cytoprotection; engine exhaust; enzyme activity; glutathione transferase; helper T lymphocyte; heme oxygenase; hemocyanin; human subject; human therapy evaluation; immunoglobulin E; inflammation; oxidoreductase; plant extracts; pollution related respiratory disorder; respiratory disorder chemotherapy; respiratory epithelium; respiratory hypersensitivity; respiratory pharmacology; thiocyanates

Relevance: The goal of this project is to define a novel therapeutic approach to an unaddressed aspect of allergic airways disease, the component driven by participate pollution. No current anti-allergic or antiinflammatory treatment is designed to address this important health issue. We will test the hypothesis that induction of phase II "anti-oxidant" enzymes will mitigate the inflammatory effects of particulate air pollution, i.e. diesel exhaust particles (DEP) in human airway challenge models. Treatment will be oral sulforaphane (SFN), in a broccoli sprout homogenate, as a nutraceutical that is a potent inducer of phase II enzymes via activation of the transcription factor Nrf-2 that drives these phase II genes as they contain an anti-oxidant response motif. Our approach is based on studies showing that a) oxidative stress responses participate in the observed effects of DEP in humans and animal, b) induction of a phase II enzymes can protect against development of an inflammatory response, and c) that anti-oxidants can block the proinflammatory effects of DEP. Furthermore, we have completed human dosing studies with the SFN nutraceutical that show robust induction of phase II enzymes in the blood and importantly in the airways of human subjects. Benefit from phase II cytoprotective "anti-oxidant" enzymes via SFN will be experimentally tested in three distinct human challenge models defining effects of DEP on 1) induction of local inflammation, 2) enhancement of established allergic-lgE responses and 3) enhancement of primary sensitization to a neoallergen. These studies will be carried out using in a population of subjects selected for their susceptibility to DEP driven inflammation. In Aim 1, we will test the ability of oral SFN to inhibit the local inflammatory effects of nasal DEP challenge alone using cellular infiltration as the primary endpoint. Aim 2 will test whether SFN treatment can blunt DEP driven secondary allergic airway inflammation following challenge with DEP plus cat allergen inhibition of DEP driven enhancement of IgE antibody to cat. Aim 3 will determine whether induction of an anti-oxidant response via SFN can prevent DEP dependent primary mucosal allergic sensitization to the neoantigen KLH. Dr. Diaz-Sanchez (Project 3) will assist in the laboratory studies. We will also work with Dr. Nel (Project 1) and Core C using proteomics with informative subjects' nasal samples to investigate novel aspects of the human in vivo response to DEP plus allergen.

相关性：该项目的目标是定义一种新的治疗方法，以解决 过敏性气道疾病，由参与污染驱动的成分。目前无抗过敏药或抗生素 治疗旨在解决这一重要的健康问题。 我们将检验这样的假设，即诱导II相"抗氧化"酶将减轻炎症反应。 颗粒空气污染的影响，即柴油机排气颗粒（DEP）在人体气道挑战模型。 治疗将是口服萝卜硫素（SFN），在西兰花芽匀浆，作为一种营养品， 通过激活驱动这些II相酶的转录因子Nrf-2， 基因，因为它们含有抗氧化反应基序。我们的方法是基于研究表明，a） 氧化应激反应参与DEP在人类和动物中观察到的作用，B）诱导 a）II相酶可以防止炎症反应的发展，以及c）抗氧化剂 可以阻断DEP的促炎作用此外，我们已经完成了人体给药研究， SFN营养药物显示出对血液中II相酶的强烈诱导， 人类受试者的气道。通过SFN从II期细胞保护"抗氧化"酶中获益将是 在三种不同的人类挑战模型中进行了实验测试，定义了DEP对1）诱导 局部炎症，2）增强已建立的过敏-IgE应答和3）增强原发性过敏反应， 对新过敏原致敏。这些研究将在选择的受试者人群中进行， 他们对DEP驱动的炎症的易感性。在目标1中，我们将测试口服SFN抑制局部炎症的能力。 使用细胞浸润作为主要终点的单独鼻DEP激发的炎症作用。目的2 将测试SFN治疗是否可以减弱DEP驱动的继发性过敏性气道炎症， 用DEP加猫过敏原攻击DEP驱动的猫IgE抗体增强的抑制。目的3将 确定通过SFN诱导抗氧化反应是否可以防止DEP依赖性原发性高血压， 对新抗原KLH的粘膜过敏性致敏。迪亚兹-桑切斯博士（项目3）将协助 实验室研究我们还将与Nel博士（项目1）和Core C一起使用蛋白质组学， 受试者的鼻样品，以研究人对DEP加过敏原的体内应答的新方面。