EOSINOPHIL PEROXIDASE AND THE ORIGINS OF ASTHMA

嗜酸性粒细胞过氧化物酶和哮喘的起源

• 批准号: 6390198
• 负责人: Stanley L Hazen
• 金额: $ 25.38万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390198
• 关键词: clinical research; cytotoxicity; eosinophil; free radical oxygen; free radicals; human subject; inflammation; molecular pathology; oxidative stress; oxysteroid; pathologic process; peroxidases; phlebotomy

DESCRIPTION Eosinophils play an essential role in vivo, destroying pathogenic microorganisms, parasites and tumor cells. To perform these functions they have evolved enzymatic mechanisms to generate an arsenal of reactive oxidant species; however, their potent oxidants also have great potential to harm healthy tissue. Oxidative products of eosinophil activation are implicated in the genesis of tissue injury in asthma. Eosinophil peroxidase (EPO), an abundant heme protein secreted during eosinophil activation, amplifies the oxidizing potential of hydrogen peroxide to generate potent cytotoxic oxidants. Reactive oxidant species generated by EPO in model systems reproduce the pathophysiologic features of asthma. Although substantial evidence implicates EPO-dependent oxidative damage in the pathogenesis of asthma, direct demonstration of the oxidation pathways which are operational in vivo has yet to be established. Two pathways have been identified for EPO-dependent oxidative damage of cellular proteins and lipids which might contribute to the origins of cellular injury in the inflammatory response in asthma: bromination and nitration. EPO is the only known human enzyme which selectively generates reactive brominating species under physiologic concentrations of halides; identification of brominated products in vivo can thus serve as "molecular fingerprints" identifying sites of EPO-catalyzed oxidative tissue damage. Reactive nitrogen species have been implicated in the genesis of cellular injury in a host of inflammatory disorders, yet neither their production by eosinophils nor their role in oxidative damage during asthma are established. The overall goals of this proposal are to test the hypothesis that eosinophil peroxidase catalyzes oxidative tissue damage in vivo and contributes to the onset of cellular injury in asthma. The specific aims are: 1) to determine the role of eosinophil peroxidase in oxidative damage of proteins in individuals with asthma; 2) to investigate the biochemical pathways by which eosinophils generate reactive nitrogen species; and 3) to characterize a family of brominated oxysterols synthesized by eosinophil peroxidase and to examine their cytotoxic properties.

描述 嗜酸性粒细胞在体内发挥着重要作用，可消灭致病菌 微生物、寄生虫和肿瘤细胞。 为了执行这些功能，他们 已经进化出酶促机制来产生活性氧化剂库 物种;然而，它们的强氧化剂也有很大的潜在危害 健康的组织。 涉及嗜酸性粒细胞活化的氧化产物 哮喘组织损伤的发生过程。 嗜酸性粒细胞过氧化物酶（EPO） 嗜酸性粒细胞活化期间分泌的丰富血红素蛋白，放大 过氧化氢的氧化潜力产生有效的细胞毒性 氧化剂。 模型系统中 EPO 产生的活性氧化剂物质 再现哮喘的病理生理特征。 虽然实质性 有证据表明 EPO 依赖性氧化损伤参与了疾病的发病机制 哮喘，直接展示有效的氧化途径 体内尚未确定。 已确定 EPO 依赖性氧化损伤的两条途径 细胞蛋白质和脂质可能有助于起源 哮喘炎症反应中的细胞损伤：溴化和 硝化。 EPO是唯一已知的人类酶，可以选择性地产生 卤化物生理浓度下的反应性溴化物质； 因此，体内溴化产物的鉴定可以作为“分子 指纹”识别 EPO 催化氧化组织损伤的位点。 活性氮物种与细胞的发生有关 一系列炎症性疾病中的损伤，但它们的产生都不是 嗜酸性粒细胞及其在哮喘期间氧化损伤中的作用尚未确定 已确立的。 该提案的总体目标是检验假设 嗜酸性粒细胞过氧化物酶催化体内氧化组织损伤 导致哮喘细胞损伤的发生。 具体目标是：1）确定嗜酸性粒细胞过氧化物酶在 哮喘患者蛋白质的氧化损伤； 2）调查 嗜酸性粒细胞产生活性氮的生化途径 物种; 3) 表征溴化氧甾醇家族 由嗜酸性粒细胞过氧化物酶合成并检测其细胞毒性 特性。