Oxidative Mechanisms in Asthma

研究计划的项目3的总体目标是从化学上定义氧化途径， 参与哮喘炎症反应的启动和传播。白细胞发挥着重要的作用 在体内发挥重要作用，摧毁病原微生物和肿瘤细胞。他们也有很棒的 有可能损害健康组织。因为氧化损伤是累积的，所以这种潜力在 慢性炎症性疾病，如哮喘。我们已经用质谱仪证明了嗜酸性粒细胞和 中性粒细胞通过其各自独特的血红素过氧化物酶、嗜酸性粒细胞过氧化物酶(EPO)和 髓过氧化物酶(MPO)，促进人哮喘呼吸道蛋白质氧化损伤。最新研究 这也表明了乳过氧化物酶(LPO)的重要作用，LPO是血红素过氧化物酶的相关成员 超家族，在维持呼吸道天然免疫防御中发挥作用。 目前的提议是基于这样一种假设，即氧化反应，如那些被介导的反应 通过氧化还原活性的过渡金属离子、一氧化氮衍生的氧化剂和哺乳动物的血红素过氧化物酶，影响 疾病过程的急性和慢性特征，包括呼吸道重塑。我们的证据表明 机械上不同的氧化途径促进脂肪和蛋白质结构上可定义的变化 哮喘呼吸道细支气管壁的成分。我们建议整合对基础设施的研究 寻找特定反应产物的机制，揭示相关途径是否在 肺部炎症和人类哮喘的动物模型。 我们将使用小鼠模型来定义特定的酶参与者，这些参与者有助于形成 特定的生物活性二十烷类化合物、抗蛋白酶的共价交联物和其他已定义的氧化物质 变应原激发后肺和呼吸道的改变。在项目2中，我们将探讨 细胞外基质对哮喘呼吸道明确氧化过程的调控作用。通过人类临床 研究和与项目1的合作我们将探索特定的临床应用 结构信息丰富的氧化加合物作为疾病存在、严重程度、肺部疾病的非侵入性标记物 功能，以及呼吸道重塑的程度。所有核心都被本项目广泛使用。总而言之， 拟议的研究将提供对参与炎症损伤和 哮喘的重塑。

The overall goal of Project 3 of the Research Program is to chemically define oxidative pathways that participate in the initiation and propagation of the inflammatory responses in asthma. Leukocytes play an essential role in the body, destroying pathogenic microorganisms and tumor cells. They also have great potential to harm healthy tissue. Because oxidative damage is cumulative, this potential is enhanced in chronic inflammatory diseases like asthma. We have used mass spectrometry to show that eosinophils and neutrophils, via their respective unique heme peroxidases, eosinophil peroxidase (EPO) and myeloperoxidase (MPO), promote protein oxidative damage in human asthmatic airways. Recent studies also suggest an important role for lactoperoxidase (LPO), a related member of the heme peroxidase superfamily, in maintenance of airway innate immune defenses. The present proposal is predicated upon the hypothesis that oxidative reactions, such as those mediated by redox-active transition metal ions, nitric oxide-derived oxidants, and mammalian heme peroxidases, affect acute and chronic features of the disease process, including airways remodeling. Our evidence suggests mechanistically distinct oxidative pathways promote structurally definable alterations to lipid and protein components of the bronchiole wall in asthmatic airways. We propose to integrate studies on basic mechanisms with a search for specific reaction products that reveal whether relevant pathways operate in animal models of pulmonary inflammation and in human asthma. We will use murine models to define specific enzymatic participants that contribute to formation of specific bioactive eicosanoids, protease resistant covalent cross-links, and other defined oxidative modifications in lung and airways following allergen challenge. With Project 2 we will explore the role of extracellular matrix on modulating defined oxidative processes in asthmatic airways. Through human clinical investigations and collaborations with Project 1 we will explore the potential clinical utility of specific structurally informative oxidative adducts as non-invasive markers for disease presence, severity, pulmonary function, and the extent of airways remodeling. All cores are extensively used by this Project. Collectively, the proposed studies will provide insights into oxidative processes participating in inflammatory injury and remodeling in asthma.