Oxidative Mechanisms in Asthma

哮喘的氧化机制

• 批准号: 7160725
• 负责人: Stanley Hazan
• 金额: $ 34.65万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160725
• 关键词: CD44 molecule; biomarker; biopsy; biosynthesis; breath tests; bronchial mucus; crosslink; diagnostic respiratory lavage; eicosanoids; electrospray ionization mass spectrometry; enzyme substrate complex; eosinophil; extracellular matrix; free radicals; genetically modified animals; heme oxygenase; high performance liquid chromatography; laboratory mouse; lipids; molecular dynamics; myeloperoxidase; neutrophil; oxidation reduction reaction; pathologic process; regeneration; respiratory airflow disorder; respiratory epithelium; secretion; stereochemistry; tyrosine

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 参与哮喘中炎症反应的启动和传播。白细胞发挥作用 在体内的重要作用，破坏致病性微生物和肿瘤细胞。他们也很棒 损害健康组织的潜力。由于氧化损伤是累积的，因此该潜力在 诸如哮喘之类的慢性炎症疾病。我们已经使用质谱法来表明嗜酸性粒细胞和 中性粒细胞通过各自的独特血红素过氧化物酶，嗜酸性粒细胞过氧化物酶（EPO）和 脊髓过氧化物酶（MPO）促进人类哮喘气道中的蛋白质氧化损伤。最近的研究 还提出了乳酸氧化酶（LPO）的重要作用，这是血红素过氧化物酶的相关成员 超家族，维持气道先天免疫防御。 目前的建议是基于以下假设：氧化反应（例如介导的反应） 通过氧化还原活性过渡金属离子，一氧化氮衍生的氧化剂和哺乳动物血红素过氧化物酶会影响 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 机械上明显的氧化途径促进了对脂质和蛋白质的结构定义的改变 哮喘气道中支气管墙的组成部分。我们建议整合基本的研究 搜索特定反应产品的机制，这些产品揭示了相关途径是否在 肺部炎症和人类哮喘的动物模型。 我们将使用鼠模型来定义有助于形成的特定酶参与者 特异性生物活性类固醇，抗蛋白酶的共价交联和其他定义的氧化 过敏原挑战后肺和气道的修饰。使用项目2，我们将探讨 在调节哮喘气道中定义的氧化过程的细胞外基质。通过人类临床 调查和与项目1的合作我们将探讨特定的临床实用性 在结构上有用的氧化加合物作为疾病存在，严重程度，肺的非侵入性标记 功能和气道重塑的程度。所有核心均被该项目广泛使用。共同 拟议的研究将提供有关参与炎症损伤和的氧化过程的见解 重塑哮喘。