MECHANISMS OF VIRUS-INDUCED ASTHMA

病毒引起哮喘的机制

• 批准号: 2221308
• 负责人: William W. Busse
• 金额: $ 16.26万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2221308
• 关键词: asthma; cell adhesion molecules; cytokine; enzyme linked immunosorbent assay; eosinophil; host organism interaction; human subject; immunology; inflammation; leukocyte activation /transformation; macrophage; monocyte; receptor binding; respiratory epithelium; respiratory infections; respiratory virus; rhinovirus; secretion; solution hybridization; virus diseases

DESCRIPTION (Adapted from the Applicant's Abstract): Rhinovirus (RV) respiratory infections are major causes of acute wheezing in asthma patients. The overall objectives of this application are to establish the mechanisms of the immune response to RV and to determine how this reaction can promote wheezing in patients with asthma. Previous studies have shown that experimental rhinovirus infections enhance both airway responsiveness and the probability of a late allergic reaction to antigen. These observations suggest that viral respiratory illnesses promote asthma by increasing bronchial inflammation. From these findings and new in vitro observations, the investigators hypothesize that rhinovirus-induced production of cytokines augments existing airway inflammation and, thus, leads to persistent lower airway dysfunction in allergic, but not normal subjects. It is proposed that an initial and key step in this process is RV-induced activation of airway macrophage via intercellular adhesion molecule-1 (ICAM-1) receptors. Cytokines produced by activated macrophages, and lymphocytes, can then initiate a series of interrelated cellular processes which increase ICAM-1 on bronchial epithelium, prime eosinophil inflammatory capabilities, and increase eosinophil mediated damage to the airway. To establish, at the cellular and molecular level, how the immune response to RV can induce asthma, isolated human cells will be used for study and compare these findings to ex vivo observations. First, RV-induced production of cytokines (IL-1-beta, TNF-gamma, and GM-CSF) by monocytes/macrophages will be determined by ELISA and a semi-quantitative mRNA assay. RV16, a strain which interacts with ICAM-1 will be used to initiate this response. Next, the contribution of ICAM-1 activation to monocyte/macrophage secretion of cytokines will be determined by the use of anti-ICAM-1 monoclonal antibodies and non-ICAM-1 dependent RV (strain 49); furthermore, the contribution of cell infection by RV will be evaluated by specific RV RNA probes, intercellular virus replication, and ultrastructural morphology. In addition, the subsequent activation of lymphocytes, and generation of cytokines, by either RV-activated monocytes, cytokine generation, or virus itself will be established. Of particular interest will be a comparison of the cytokine profile produced by lymphocytes (Th1 versus Th2), and change in immune function following RV encounter. Finally, the effects of RV activation of monocytes/macrophages and/or lymphocytes will be determined on eosinophil effector function including secretion of inflammatory mediators, interaction with a bronchial epithelial cell line, and damage to the airway tissue.

描述（改编自申请人的摘要）：鼻病毒（RV） 呼吸道感染是哮喘急性喘息的主要原因 患者。 该应用程序的总体目标是建立 对 RV 的免疫反应机制并确定如何 这种反应会促进哮喘患者喘息。 先前的研究表明，实验性鼻病毒感染 增强气道反应性和延迟发生的可能性 对抗原的过敏反应。 这些观察结果表明，病毒 呼吸系统疾病通过增加支气管扩张而促进哮喘 炎。 根据这些发现和新的体外观察， 研究人员推测，鼻病毒诱导产生 细胞因子会加剧现有的气道炎症，从而导致 过敏者持续性下呼吸道功能障碍，但不正常 科目。 建议在此过程中迈出初步且关键的一步 过程是 RV 诱导气道巨噬细胞的激活 细胞间粘附分子-1 (ICAM-1) 受体。 细胞因子 由活化的巨噬细胞和淋巴细胞产生，然后可以 启动一系列相互关联的细胞过程，增加 支气管上皮上的 ICAM-1，主要嗜酸性粒细胞炎症 能力，并增加嗜酸性粒细胞介导的气道损伤。 在细胞和分子水平上确定免疫如何 对 RV 的反应可诱发哮喘，将使用分离的人体细胞 用于研究并将这些发现与离体观察进行比较。 首先，RV 诱导产生细胞因子（IL-1-β、TNF-γ、 和 GM-CSF）通过单核细胞/巨噬细胞将通过 ELISA 测定 半定量 mRNA 测定。 RV16，一种与 ICAM-1 将用于发起此响应。 接下来， ICAM-1 激活对单核细胞/巨噬细胞分泌的贡献 细胞因子的含量将通过使用抗 ICAM-1 来确定 单克隆抗体和非 ICAM-1 依赖性 RV（菌株 49）； 此外，还将评估 RV 细胞感染的贡献 通过特定的 RV RNA 探针、细胞间病毒复制，以及 超微结构形态。另外，后续激活 淋巴细胞的产生，以及细胞因子的产生，通过 RV 激活 单核细胞、细胞因子生成或病毒本身将被建立。 特别感兴趣的是细胞因子谱的比较 由淋巴细胞（Th1 与 Th2）产生，以及免疫系统的变化 遇到 RV 后的功能。 最后来说一下RV的效果 单核细胞/巨噬细胞和/或淋巴细胞的激活 确定嗜酸性粒细胞效应功能，包括分泌 炎症介质，与支气管上皮细胞的相互作用 线，并损伤气道组织。