EOSINOPHIL PEROXIDASE AND THE ORIGINS OF ASTHMA

描述 嗜酸性粒细胞在体内发挥重要作用， 微生物、寄生虫和肿瘤细胞。 为了履行这些职能， 已经进化出酶机制来产生反应性氧化剂的军火库 物种;然而，它们的强效氧化剂也有很大的潜在危害 健康组织 嗜酸性粒细胞活化的氧化产物与 在哮喘组织损伤的发生中的作用。 嗜酸性粒细胞过氧化物酶（EPO）， 在嗜酸性粒细胞活化过程中分泌大量血红素蛋白， 过氧化氢产生强效细胞毒性的氧化电位 氧化剂 EPO在模型系统中产生的活性氧化剂物质 重现哮喘的病理生理特征。 虽然数量可观， 有证据表明EPO依赖性氧化损伤参与了 哮喘，直接证明氧化途径， 在体内还有待建立。 已经确定了EPO依赖性氧化损伤的两种途径， 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 硝化作用。 EPO是唯一已知的人类酶， 在生理浓度的卤化物下的反应性溴化物种; 因此，体内溴化产物的鉴定可作为“分子鉴定”， “指纹”识别EPO催化的氧化组织损伤部位。 活性氮类参与了细胞的发生， 损伤的主机炎症性疾病，但既不是他们的生产， 嗜酸性粒细胞及其在哮喘期间氧化损伤中的作用， 确立了习 本提案的总体目标是检验假设 嗜酸性粒细胞过氧化物酶在体内催化氧化性组织损伤， 导致哮喘细胞损伤的发生 具体目的是：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）研究 嗜酸性粒细胞产生活性氮的生化途径 物种;和3）表征溴化氧甾醇家族 嗜酸性粒细胞过氧化物酶合成，并检测其细胞毒性 特性.

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.