Oxidative stress in asthma initiation

哮喘发作时的氧化应激

基本信息

批准号：
7056690
负责人：
SANJIV SUR
金额：
$ 36.86万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-15 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Asthma is a major health problem in this country. Intrapulmonary allergen challenge in asthma induces a "late phase asthma phenotype," consisting of airway hyperresponsiveness (AHR), airway mucus production, and Th2 eosinophilic inflammation. A large body of literature has dissected out how peptides and epitopes of pollen-derived antigenic proteins interact with critical components of the adaptive immune system namely Class II MHC on antigen presenting cells, and T-cell receptor on Th2 cells, to induce late phase asthma phenotype. However, it has never been shown that pollens contain a second set of protein(s) with unique biochemical properties that vigorously augments late phase asthma phenotype. Ragweed pollens are known to induce allergic rhinitis and asthma in humans. We discovered that ragweed extract (RW) and many environmental pollen extracts contain potent pro-oxidant activity. Using RW as a prototypic pro-oxidant allergen, we demonstrated that this activity was due to a protein complex consisting of several distinct Pro-Oxidant Proteins (POP) tightly associated with Amb A1 (antigen E), the major antigenic component of RW. We coined a term" Pro-Oxidant Protein and Antigen Complex, (POPAC)" to describe this POP + antigen protein complex. Purified Arab A1, unlike whole RW or Amb A1 complexed in POPAC, did not possess pro-oxidant activity. Consistent with this difference in pro-oxidant activity, intrapulmonary challenge of sensitized mice with POPAC, but not Amb A1, potently induced allergic inflammation. We propose that RW (and many other pollen and mold allergens) contains POPAC, a protein complex of at least two physically associated components, the well-known antigenic component, and a novel POP. The overarching goal of this proposal is to determine the mechanism by which POP vigorously augments the late phase asthma phenotype induced by the antigenic component of POPAC. In this proposal, we will test the hypotheses that POPAC-induced immediate oxidative burst is independent of allergic sensitization and adaptive immunity (specific aim 1), and that pro-oxidant proteins augment allergic sensitization and antigen-induced late phase AHR, mucin production and Th2 allergic inflammation in mice (specific aim 2), pro-oxidant activity of RW augments immediate ROS production and late phase symptoms, mucus production and Th2 allergic inflammation in atopic patients (specific aim 3). These studies are designed to elucidate a novel paradigm of late phase asthma phenotype that is initiated by pro-oxidant protein complex (POPAC) present in many environmental pollen and mold allergens. Future studies of POPAC may identify novel therapeutic approaches in asthma.

描述（由申请人提供）：哮喘是这个国家的一个主要健康问题。哮喘中的肺内过敏原激发会诱发“晚期哮喘表型”，包括气道高反应性 (AHR)、气道粘液产生和 Th2 嗜酸性粒细胞炎症。大量文献剖析了花粉衍生抗原蛋白的肽和表位如何与适应性免疫系统的关键成分（即抗原呈递细胞上的 II 类 MHC 和 Th2 细胞上的 T 细胞受体）相互作用，从而诱发晚期哮喘表型。然而，从未证明花粉含有具有独特生化特性的第二组蛋白质，可以大力增强晚期哮喘表型。豚草花粉已知会诱发人类过敏性鼻炎和哮喘。我们发现豚草提取物 (RW) 和许多环境花粉提取物含有有效的促氧化活性。使用 RW 作为原型促氧化过敏原，我们证明了这种活性是由于由几种不同的促氧化蛋白 (POP) 组成的蛋白质复合物，该复合物与 RW 的主要抗原成分 Amb A1（抗原 E）紧密相关。我们创造了一个术语“促氧化剂蛋白和抗原复合物，(POPAC)”来描述这种 POP + 抗原蛋白复合物。与在 POPAC 中复合的完整 RW 或 Amb A1 不同，纯化的阿拉伯 A1 不具有促氧化活性。与促氧化剂活性的这种差异一致，用 POPAC（而非 Amb A1）对致敏小鼠进行肺内攻击，可有效诱导过敏性炎症。我们认为 RW（以及许多其他花粉和霉菌过敏原）含有 POPAC，这是一种至少由两种物理相关成分、众所周知的抗原成分和一种新型 POP 组成的蛋白质复合物。该提案的首要目标是确定 POP 大力增强 POPAC 抗原成分诱导的晚期哮喘表型的机制。在本提案中，我们将测试以下假设：POPAC 诱导的立即氧化爆发独立于过敏致敏和适应性免疫（具体目标 1），并且促氧化蛋白增强过敏致敏和抗原诱导的晚期 AHR、粘蛋白产生和小鼠的 Th2 过敏性炎症（具体目标 2），RW 的促氧化活性可增强特应性患者的立即 ROS 产生和晚期症状、粘液产生和 Th2 过敏性炎症（具体目标 3）。这些研究旨在阐明晚期哮喘表型的新范例，该表型是由许多环境花粉和霉菌过敏原中存在的促氧化蛋白复合物（POPAC）引发的。 POPAC 的未来研究可能会确定哮喘的新治疗方法。