Oxidative Mechanisms in Asthma

哮喘的氧化机制

• 批准号: 8052722
• 负责人: Stanley Hazan
• 金额: $ 40.3万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052722
• 关键词: 3-nitrotyrosine; Acute; Affect; Allergens; Animal Model; Architecture; Asthma; Basement membrane; Biochemical; Biological Models; Biopsy; Bronchioles; Bronchoalveolar Lavage Fluid; CD44 Antigens; CD44 gene; Cell surface; Characteristics; Chemicals; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Development; Disease; Disease Marker; Eicosanoids; Electrospray Ionization; Enzymes; Event; Extracellular Matrix; Free Radicals; Funding; Generations; Goals; Halogens; Heme; High Pressure Liquid Chromatography; Human; Hydroxyl Radical; Hyperplasia; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Ions; Isomerism; Leukocytes; Link; Lipid Peroxidation; Lipids; Lipoxygenase; Lung; Maintenance; Mass Spectrum Analysis; Mediating; Modeling; Modification; Molecular; Monitor; Mucous body substance; Mucus-Secreting Cell; Mus; Nitric Oxide; Nitrogen; Obstruction; Obstructive Lung Diseases; Oxidants; Oxidation-Reduction; Participant; Pathway interactions; Peptide Hydrolases; Peroxidases; Phase; Play; Pneumonia; Post-Translational Protein Processing; Prevalence; Principal Investigator; Process; Proteins; Reaction; Research; Resistance; Role; Severities; Source; System; Testing; Time; Tissues; Transition Elements; Tyrosine; adduct; airway obstruction; airway remodeling; asthmatic airway; base; crosslink; dityrosine; eosinophil; eosinophil peroxidase; in vivo; insight; lactoperoxidase; leukocyte activation; member; microorganism; molecular marker; neoplastic cell; neutrophil; nitrogen dioxide radical; novel; oxidation; oxidative damage; oxidized lipid; programs; pulmonary function; response; tandem mass spectrometry

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.

研究计划项目3的总体目标是化学定义氧化途径， 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。他们还有很好吃 可能伤害健康组织。由于氧化损伤是累积性的， 慢性炎症性疾病如哮喘。我们已经用质谱法表明嗜酸性粒细胞和 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），促进人哮喘气道蛋白质氧化损伤。最近的研究 也表明乳过氧化物酶（LPO），血红素过氧化物酶的相关成员的重要作用 超家族，在维持气道先天免疫防御。 目前的建议是基于这样的假设，即氧化反应，如那些介导的 氧化还原活性的过渡金属离子，一氧化氮衍生的氧化剂，和哺乳动物血红素过氧化物酶，影响 疾病过程的急性和慢性特征，包括气道重塑。我们的证据表明 机制不同的氧化途径促进脂质和蛋白质的结构上可定义的改变 哮喘气道中细支气管壁的成分。我们建议将基础研究 寻找特定的反应产物，揭示相关的途径是否在 肺部炎症和人类哮喘的动物模型。 我们将使用鼠模型来定义有助于形成 特异性生物活性类二十烷酸、蛋白酶抗性共价交联和其它限定的氧化性交联剂， 过敏原激发后肺和气道的变化。在项目2中，我们将探讨 细胞外基质对调节哮喘气道中确定的氧化过程的作用。通过人类临床 研究和与项目1的合作，我们将探索特定的潜在临床效用， 结构信息氧化加合物作为疾病存在、严重程度、肺 功能和气道重塑的程度。本工程广泛使用所有岩心。总的来说， 拟议的研究将提供对参与炎性损伤的氧化过程的深入了解， 哮喘的重塑