Xenobiotics and Allergic Inflammation

该UCLA中心的提案包括四个相关的研究项目，围绕化石燃料燃烧产生的异生物质化合物增强气道过敏性炎症的主题。所有项目都解决了研究者的途径相关的关键问题，这些研究者是本AAIDCRC的原始参与者。第四个项目带来了一个新的年轻调查员作为项目负责人。这些项目检查了上皮细胞、巨噬细胞、肥大细胞、嗜碱性粒细胞和淋巴细胞的临床、细胞和分子方面，所有这些都涉及过敏性炎症。在项目1（SAXON）中，本研究中开发的人体体内激发模型将用于测试抑制对DEP和过敏原过敏的治疗方法。这将包括使用过敏性炎症的原发性致敏和继发性增强模型。“原理证明：“方法将针对i）抗氧化剂，ii）中断细胞因子信号传导（sIL-4 R）和iii）通过CpG施用偏离局部免疫应答。在项目2（NEL）中，将通过关注促炎和抗氧化防御途径来研究氧化应激在DEP化学品产生生物效应中的作用。这将包括使用组织培养巨噬细胞和上皮细胞在体外，以及在动物和人类的体内暴露，以确定如何敏感的氧化应激酶，血红素加氧酶1（HO-1），保护免受促氧化和促炎作用的DEP。这些研究将确定HO-1基因反应途径的修饰如何使动物和人类易于发生夸张的过敏性炎症反应。在项目3（HERSCHMAN）中，将在细胞中检查前列腺素产物的DEP抑制机制和后果，并将在过敏性气道炎症的小鼠模型和人气道（PG）产生中进行遗传学检查，并在细胞和动物激发模型中进行免疫学检查。将阐明花生四烯酸螯合在考克斯-1与考克斯-2 PG合成中的基础，目的是利用这些信息来调节炎症反应期间肥大细胞PGD 2的即时与延迟产生。将阐明肥大细胞与巨噬细胞中调节考克斯-2诱导的信号通路的差异，以提供PG产生药理学调节的细胞类型特异性方法。项目4（Diaz-Sanchez）将确定DEP外源性物质及其相关基因/基因产物的确定代谢途径在哮喘小鼠模型中介导吸入DEP的过敏性炎症反应中的作用。还将利用已知的重要氧化应激途径（GST和NQO 1）的功能性人类多态性来测试它们是否改变对体内鼻DEP激发的反应。这些研究确定了DEP作为一种模型外源性物质诱导其对过敏性炎症作用的途径，将为中心的其他项目提供信息。该中心的研究重点是粘膜过敏性炎症的外源性调节，使用柴油机尾气颗粒作为相关原型。项目负责人包括三名高级研究员和一名年轻的研究员，他们每个人都有独立的职能，但对他们来说，中心的赠款是支持这些DEP研究的唯一来源。这些项目由DEP收集和分离核心、小鼠核心以及管理、患者和样本协调核心支持。

This UCLA Center proposal comprises four related research projects centered about the theme of the enhancement of airway, allergic inflammation by xenobiotic compounds generated from fossil fuel combustion. All projects address key issues regarding the pathways by investigators are original participants in this AAIDCRC. The fourth project brings on a new young investigator as Project Leader. The Projects examine clinical, cellular and molecular aspects of epithelial cells, macrophages, mast cells, basophils and lymphocytes all of which involved in allergic inflammation. In Project 1 (SAXON), the human in vivo challenge models developed in this enter will be used to test therapeutic approaches to inhibiting allergic in response to DEP and allergen. This will include the use of models of both primary sensitization and secondary boosting of allergic inflammation. "Proof of Principle:" approaches will be directed at i) anti-oxidants, ii) interrupting cytokine signaling (sIL-4R) and iii) deviation of the local immune response via CpG administration. In Project 2, (NEL) the role of oxidative stress in the generation of biological effects by DEP chemical will be studied by focusing on pro-inflammatory and anti-oxidant defense pathways. This will include the use of tissue culture macrophages and epithelial cells in vitro, as well as in vivo exposure of animals and humans to determine how a sensitive oxidant stress enzyme, heme oxygenase 1 (HO-1), protects against the pro-oxidative and pro-inflammatory effects of DEP. These studies will determine how modification of the HO-1 gene response pathway may predispose animals and humans to exaggerated allergic inflammatory responses. In Project 3 (HERSCHMAN), the mechanisms and consequences of DEP inhibition of prostaglandin products will be examined in cells, and in murine model of allergic airway inflammation and in human airway (PG) production will be examined genetically and pharmacologically in cells and in the animal challenge model. The basis for arachidonic acid sequestration in COX-1 vs. COX-2 PG synthesis will be elucidated, with a goal of utilizing this information to modulate immediate vs. delayed mast cell PGD2 production during inflammatory response. Difference in signaling pathways modulating COX-2 induction in mast cells vs. macrophages will be clarified, to provide cell-type specific approaches to pharmacologic modulation of PG production. Project 4 (Diaz-Sanchez) will determine the role of defined metabolic pathways for DEP xenobiotics and their relevant genes/gene products in mediating the allergic inflammatory responses to inhal4ed DEP in murine models of asthma. Advantage will also be taken of known functional human polymorphisms important oxidative stress pathways (GST and NQO1) to test whether they alter the responses to in vivo nasal DEP challenge. These studies identifying the pathways by which DEP, as a model xenobiotic, induce their effects on allergic inflammation will provide information in the other Center projects. The studies in this Center focus on xenobiotic modulation of mucosal allergic inflammation, using diesel exhaust particles as a relevant prototype. The project leaders comprise three senior investigators and one young investigator, each of whom has independent functioning but for whom the Center grant is the sole source of support for these studies on DEP. The projects are supported by a DEP collection and fractionation core, a mouse core, and a administrative, patient and sample coordination core.