Therapeutic anti-inflammatory phase II "anti-oxidant"

相关性：该项目的目标是定义一种新的治疗方法，以治疗未解决的方面 过敏性呼吸道疾病，由参与污染的成分驱动。目前没有抗过敏或抗炎的药物 治疗旨在解决这一重要的健康问题。 我们将检验这一假说，即诱导第二相“抗氧化剂”酶将减轻炎症。 空气颗粒物污染，即柴油废气颗粒物(DEP)在人体呼吸道挑战模型中的影响。 治疗将口服萝卜硫素(SFN)，在西兰花芽匀浆中，作为一种营养食品，即 通过激活驱动II相酶的转录因子NRF-2而成为II相酶的有效诱导剂 基因，因为它们包含抗氧化反应基序。我们的方法是基于研究表明，a) 氧化应激反应参与DEP对人和动物的观察到的影响，b)诱导 A相II酶可以防止炎症反应的发展，以及c)抗氧化剂 可阻断DEP的促炎作用。此外，我们已经完成了人体剂量研究， SFN营养食品显示了对血液中II相酶的强劲诱导，更重要的是在 人类受试者的航空。通过SFN获得第二阶段细胞保护性抗氧化酶的好处将是 在三个不同的人类挑战模型中进行了实验测试，确定了DEP对1)诱导 局部炎症，2)已建立的过敏-LGE反应的增强，以及3)原发的增强 对一种新的过敏原过敏。这些研究将在选定的受试者中进行 他们对DEP的易感性导致了炎症。在目标1中，我们将测试口服SFN对局部抑制的能力。 以细胞渗出为主要终点的单纯鼻腔DEP激发的炎症效应。目标2 将测试SFN治疗是否可以钝化DEP引发的继发性过敏性呼吸道炎症 DEP联合CAT变应原抑制DEP诱导的猫IgE抗体增强。目标3将 确定通过SFN诱导抗氧化反应是否可以防止DEP依赖的原发反应 粘膜对新抗原K1H的变态反应。Diaz-Sanchez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合作，使用蛋白质组学提供信息 受试者的鼻部样本，以调查人体对DEP加变应原的体内反应的新方面。

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.