Eosinophil priming and activation in asthma

哮喘中嗜酸性粒细胞的启动和激活

• 批准号: 6630924
• 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 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630924
• 关键词: allergens; asthma; bronchomotion; bronchoscopy; cell migration; 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.

（申请人的摘要）支气管炎症是一个特征， 提出的哮喘气道功能改变的机制。因为嗜酸性粒细胞 （EOS）在循环，气道流体和支气管中通常会增加 哮喘患者的粘膜及其产品可能引起哮喘特征， 假定该细胞是炎症反应的关键成分 并改变了哮喘的肺部生理。但是，最近的初步 结果，这些结果无法显示出任何重大好处 抗Interleukin（IL）-5的给药，一种促进EOS的细胞因子 活动和生存，哮喘患者现已引起重新评估 嗜酸性粒细胞在哮喘中作用的当前概念。解决这个问题 争议，抗原挑衅已被用作定义的模型 哮喘中的炎症机制，显示循环EOS已引发，并且 然后，当他们进入气道时，被激活以产生炎症 反应导致肺部生理的改变。结果，我们 现在假设嗜酸性粒细胞炎症的发展和随后的 哮喘加重是（1）初始启动的结果，或者是“首先 点击，“循环EO促进生存，内皮粘附和 迁移到肺部； （2）激活，通过“第二击”，启动EOS的激活 在气道中，各种刺激，包括趋化因子/细胞因子作用 通过7跨膜受体释放颗粒蛋白； （3）增加 在哮喘患者的气道壁上保留EOS； （4）这些 EOS生成的效应导致特定的初步功能变化，包括 通过神经源性途径和气流提高了过度反应性 通过气道 - 范围解偶联的阻塞。而且，我们建议 哮喘急性加重的初始阶段，即抗原（Ag） 吸入皮质类固醇（ICS）的暴露或戒断为IL-5依赖 然后过渡到持续的炎症，这是IL-5独立的 并以空域EOS上的IL-5受体损失为特征，转向 EOS的粒细胞巨噬细胞刺激因子（GM-CSF）调节 功能和表型改变，使得空域EOS充当抗原 呈现细胞。建立这一假设并更精确地定义 EOS在哮喘中的作用，将选择哮喘学科进行研究，两者既 AG挑战和撤回ICS将用于挑衅哮喘症状 预计会引起循环和肺EOS功能的变化 然后可以在与肺部改变的关系中分析 组织病理学，生理和结构，以提供更精确的 了解嗜酸性粒细胞炎症在持续症状中的作用 哮喘。