Oxidative stress in asthma initiation

哮喘发作时的氧化应激

• 批准号: 6883258
• 负责人: SANJIV SUR
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/6883258
• 关键词: Ambrosia; NAD(P)H dehydrogenase; airborne allergen; asthma; atopy; bronchial mucus; cell migration; clinical research; confocal scanning microscopy; dendritic cells; enzyme activity; flow cytometry; free radical oxygen; genetically modified animals; helper T lymphocyte; human subject; laboratory mouse; leukocyte oxidative burst; mitogen activated protein kinase; oxidative stress; oxidizing agents; patient oriented research; respiratory epithelium; respiratory hypersensitivity; tissue /cell culture

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。 哮喘的肺内过敏原激发可诱导“晚期哮喘表型”，包括气道高反应性（AHR）、气道粘液产生和Th 2嗜酸性粒细胞炎症。 大量的文献已经剖析了花粉来源的抗原蛋白的肽和表位如何与适应性免疫系统的关键组分（即抗原呈递细胞上的II类MHC和Th2细胞上的T细胞受体）相互作用以诱导晚期哮喘表型。 然而，从未显示花粉含有第二组蛋白质，其具有强烈增强晚期哮喘表型的独特生物化学性质。 已知豚草花粉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强大的促氧化活性。 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质（POP）组成的蛋白质复合物与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“前氧化蛋白和抗原复合物（POPAC）”来描述这种POP +抗原蛋白复合物。 纯化的阿拉伯A1，不像整个RW或Amb A1复合在POPAC中，不具有促氧化活性。 与促氧化活性的这种差异一致，POPAC致敏小鼠的肺内激发，而不是Amb A1，强烈诱导过敏性炎症。 我们建议，RW（和许多其他花粉和霉菌过敏原）含有POPAC，蛋白质复合物的至少两个物理相关的组件，众所周知的抗原成分，和一个新的POP.The总体目标，这一建议是确定的机制，POP大力增强晚期哮喘表型诱导的抗原成分POPAC。 在本研究中，我们将检验POPAC诱导的即刻氧化爆发与过敏性致敏和适应性免疫无关的假设（具体目的1），并且促氧化蛋白增强小鼠中的过敏性致敏和抗原诱导的晚期AHR、粘蛋白产生和Th2过敏性炎症（具体目标2），RW的促氧化剂活性增强特应性患者中的即时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一种新范式，该表型由存在于许多环境花粉和霉菌过敏原中的促氧化蛋白复合物（POPAC）引发。 未来对POPAC的研究可能会发现哮喘的新治疗方法。