Xenobiotics and Allergic Inflammation

加州大学洛杉矶分校的这项中心提案包括四个相关的研究项目，围绕着化石燃料燃烧产生的异物化合物增强呼吸道、过敏性炎症的主题。所有项目都解决了与路径有关的关键问题，调查人员是这一AAIDCRC的原始参与者。第四个项目引入了一位新的年轻调查员，担任项目负责人。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，所有这些都与过敏性炎症有关。在项目1(撒克逊人)中，在这个项目中开发的人类活体挑战模型将被用于测试抑制对DEP和过敏原反应的过敏的治疗方法。这将包括使用过敏性炎症的初级致敏和次级强化模型。原则证明：方法将针对i)抗氧化剂，ii)阻断细胞因子信号转导(sIL-4R)和iii)通过给予CpG而偏离局部免疫反应。在项目2中，(NEL)将通过重点研究促炎和抗氧化防御途径来研究氧化应激在DEP化学物质产生生物效应中的作用。这将包括使用体外组织培养巨噬细胞和上皮细胞，以及动物和人类在体内的暴露，以确定一种敏感的氧化应激酶--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受到夸大的过敏性炎症反应的影响。在项目3(Herschman)中，将在细胞中检测DEP抑制前列腺素产物的机制和后果，在过敏性呼吸道炎症的小鼠模型中和在人类呼吸道(PG)的产生中，将在细胞和动物挑战模型中从遗传学和药理学的角度进行检测。花生四烯酸在COX-1和COX-2 PG合成中的基础将被阐明，目的是利用这一信息来调节炎症反应期间肥大细胞PGD2的即时和延迟产生。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，为药物调节PG的产生提供细胞类型的特异性途径。项目4(Diaz-Sanchez)将确定DEP外源化合物及其相关基因/基因产物的特定代谢途径在介导吸入DEP引起的哮喘小鼠模型过敏性炎症反应中的作用。还将利用已知的人类重要氧化应激途径(GST和NQO1)的功能多态来测试它们是否会改变体内鼻部DEP挑战的反应。这些研究确定了DEP作为异种生物模型诱导其对过敏性炎症的影响的途径，这将在其他中心的项目中提供信息。该中心的研究以柴油机尾气微粒为相关原型，重点研究异源生物对粘膜变态反应性炎症的调节作用。项目负责人由三名高级调查员和一名年轻调查员组成，他们每个人都有独立的职能，但中心对他们的资助是对这些关于环境保护部的研究的唯一支持来源。这些项目得到了DEP收集和分级核心、鼠标核心以及行政、病人和样本协调核心的支持。

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.