Xenobiotics and Allergic Inflammation

加州大学洛杉矶分校中心的提案包括四个相关的研究项目，主题是化石燃料燃烧产生的异种化合物增强气道过敏性炎症。所有的项目都是由AAIDCRC的原始参与者来解决与途径相关的关键问题。第四个项目引入了一位新的年轻研究员作为项目负责人。该项目检查了上皮细胞、巨噬细胞、肥大细胞、嗜碱性细胞和淋巴细胞的临床、细胞和分子方面，这些细胞都与过敏性炎症有关。在项目1 （SAXON）中，该中心开发的人体体内挑战模型将用于测试抑制DEP和过敏原过敏反应的治疗方法。这将包括使用原发性致敏和继发性过敏性炎症增强的模型。“原理证明：”方法将针对i)抗氧化剂，ii)阻断细胞因子信号（sIL-4R）和iii)通过CpG给药局部免疫反应的偏差。在Project 2， （NEL）中，将重点研究氧化应激在DEP化学物产生生物效应中的作用，重点研究促炎和抗氧化防御途径。这将包括体外组织培养巨噬细胞和上皮细胞的使用，以及动物和人类的体内暴露，以确定敏感的氧化应激酶血红素加氧酶1 （HO-1）如何防止DEP的促氧化和促炎作用。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容易产生夸大的过敏性炎症反应。在项目3 （HERSCHMAN）中，DEP抑制前列腺素产物的机制和后果将在细胞中进行研究，并在小鼠过敏性气道炎症模型和人类气道（PG）的产生中进行遗传和药理学研究，并在细胞和动物刺激模型中进行研究。将阐明花生四烯酸在COX-1和COX-2 PG合成中的隔离基础，目的是利用这一信息来调节炎症反应期间肥大细胞即刻和延迟的PGD2生成。将阐明肥大细胞和巨噬细胞中调节COX-2诱导的信号通路的差异，为细胞类型特异性的药物调节PG的产生提供方法。项目4 （Diaz-Sanchez）将确定DEP外源物的代谢途径及其相关基因/基因产物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。我们还将利用已知的功能性人类多态性（重要的氧化应激途径GST和NQO1）来测试它们是否会改变体内鼻腔DEP挑战的反应。这些研究确定了DEP作为一种模型外源性药物诱导其对过敏性炎症的影响的途径，将为中心的其他项目提供信息。本中心的研究以柴油废气颗粒为原型，重点研究粘膜过敏性炎症的外源性调节。项目负责人包括三名高级研究人员和一名年轻研究人员，他们每个人都有独立的职能，但中心的资助是这些DEP研究的唯一支持来源。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提供支持。

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.