Eosinophil priming and activation in asthma

哮喘中嗜酸性粒细胞的启动和激活

• 批准号: 6565039
• 负责人: William W. Busse
• 金额: $ 19.62万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-05 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6565039
• 关键词: allergens; asthma; bronchomotion; bronchoscopy; cell migration; clinical research; colony stimulating factor; corticosteroids; diagnostic respiratory lavage; eosinophil; flow cytometry; human subject; immunoregulation; inflammation; interleukin 5; leukocyte activation /transformation; patient oriented research; respiratory hypersensitivity; respiratory therapy; secretion

(Applicant's Abstract) Bronchial inflammation is a characteristic feature and proposed mechanism for altered airway function in asthma. Because eosinophils (EOS) are often increased in the circulation, airway fluids, and bronchial mucosa of asthmatic patients, and their products can cause features of asthma, this cell is presumed to be a pivotal component of the inflammatory response and altered pulmonary physiology of asthma. However, recent preliminary results, which have been unable to show any significant benefit following administration of anti-interleukin (IL)-5, a cytokine that promotes EOS activity and survival, to asthmatic patients have now caused reappraisal of current concepts of the eosinophil's role in asthma. To address this controversy, antigen provocation has been used as a model to define inflammatory mechanisms in asthma and has shown circulating EOS are primed and then, as they enter the airway, become activated to generate an inflammatory response leading to alterations in pulmonary physiology. As a consequence, we now hypothesize that development of eosinophilic inflammation and a subsequent asthmatic exacerbation is the result of (1) an initial priming, or "first hit," of circulating EOS to promote survival, endothelial adhesion, and migration to the lung; (2) activation, through a "second hit," of primed EOS in the airway by a variety of stimuli, including chemokines/cytokines acting via 7-transmembrane receptors, to release granule proteins; (3) an increased retention of EOS in the airway walls of asthma patients; and (4) that these EOS-generated effects lead to specific preliminary function changes, including increased hyperresponsiveness through neurogenic pathways, and airflow obstruction via airway-parenchymal uncoupling. Moreover, we propose that the initial phase of an acute exacerbation of asthma, i.e. following antigen (AG) exposure or withdrawal of inhaled corticosteroid (ICS), is IL-5 dependent followed by a transition to persistent inflammation, which is IL-5 independent and characterized by a loss of IL-5 receptors on airspace EOS, a shift to granulocyte-macrophage colony stimulating factor (GM-CSF) regulation of EOS function, and a phenotype alteration such that airspace EOS act as antigen presenting cells. To establish this hypothesis and more precisely define a role for EOS in asthma, asthmatic subjects will be selected for study and both AG challenge and withdrawal of ICS will be used to provoke asthmatic symptoms that are predicted to elicit changes in circulating and lung EOS function which can then be analyzed in relationship to altered pulmonary histopathology, physiology and structure to provide a more precise understanding of the role of eosinophilic inflammation in persistent symptoms of asthma.

(申请人摘要)支气管炎是一种特征性特征， 提出哮喘患者呼吸道功能改变的机制。因为嗜酸性粒细胞 (Eos)通常在循环、气道液和支气管中增加 哮喘患者的粘膜，及其产品可引起哮喘的特征， 这种细胞被认为是炎症反应的关键成分。 和哮喘的肺生理学改变。然而，最近的初步调查 结果，一直无法显示出以下任何显著好处 抗白介素5，一种促进EOS的细胞因子的应用 活跃度和存活率，对哮喘患者现在引起了重新评价 目前关于嗜酸性粒细胞在哮喘中的作用的概念。要解决这个问题 有争议的是，抗原激发一直被用作定义 哮喘的炎症机制，并已显示循环中的EOS被启动和 然后，当它们进入呼吸道时，被激活以产生炎症 导致肺部生理改变的反应。因此，我们 现在假设嗜酸性炎症的发展和随后的 哮喘的加重是(1)初始激发的结果，也就是“第一次 HIT，循环中的EOS促进存活，内皮黏附，以及 迁移到肺；(2)通过“二次打击”激活已启动的EOS 通过各种刺激，包括作用于呼吸道的趋化因子/细胞因子 通过7-跨膜受体，释放颗粒蛋白；(3)增加 哮喘患者气道壁中EOS的滞留；及(4)这些 EOS产生的效应会导致特定的初步功能变化，包括 通过神经源性通路和气流增加高反应性 通过呼吸道-实质解偶联造成的阻塞。此外，我们建议 哮喘急性加重的初始阶段，即跟随抗原(AG) 吸入皮质类固醇(ICS)的暴露或停用依赖于IL-5 随后转变为持续性炎症，这是不依赖于IL-5的 并以空域EOS上IL-5受体丢失为特征，转变为 粒细胞-巨噬细胞集落刺激因子对EOS的调节 功能和表型改变，使空域EOS充当抗原 呈现细胞。为了建立这一假说并更准确地定义 EOS在哮喘中的作用，哮喘受试者将被选为研究对象，两者 AG激发和停用ICS将被用来引发哮喘症状 预计会引起循环和肺EOS功能的变化 然后可以分析其与改变的肺组织的关系 为组织病理学、生理学和结构提供更精确的 了解嗜酸性炎症在持续性症状中的作用 哮喘的症状。