Role of Eosinophils in T-Cells Function and Remodeling

嗜酸性粒细胞在 T 细胞功能和重塑中的作用

• 批准号: 7843278
• 负责人: NIZAR N JARJOUR
• 金额: $ 46.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843278
• 关键词: Adrenal Cortex Hormones; Allergens; Allergic; Antigens; Appearance; Asthma; Bronchial Lavages; Bronchoalveolar Lavage; CCL17 gene; CXCL10 gene; Cell Communication; Cell physiology; Cells; Collagen; Data; Deposition; Disease; Eosinophilia; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Functional disorder; Generations; Goals; Human; Inflammation; Inflammatory; Integrins; Literature; Lung Lavage Fluid; Matrix Metalloproteinases; Mediating; Messenger RNA; Patients; Play; Production; Proteins; Publishing; Reporting; Role; Severity of illness; Source; Sputum; T-Lymphocyte; Testing; Th1 Cells; Th2 Cells; Transforming Growth Factors; airway inflammation; airway remodeling; allergic airway inflammation; base; chemokine; cytokine; eosinophil; fibrogenesis; improved; in vivo; mepolizumab; novel; response; treatment planning

While the goal of this project is to determine the contributions of EOS to airway inflammation and remodeling, airway eosinophilia is an important marker of asthma exacerbations, disease severity and response to corticosteroid therapy, the exact role that eosinophils (EOS) play in asthma remains to be established. Based upon current understanding of the function of EOS and our preliminary data, it is our hypothesis that EOS, through cell-cell interactions, enhance the production of cytokines by T cells and matrix proteins by fibroblasts to promote allergic airway inflammation and fibrogenesis. We also provide evidence that EOS contribute to airway inflammation by producing T cell active chemokines and enhancing! cell function via direct cellcell interaction, mediated by integrins. We provide evidence that EOS are the major source of transforming growth factor (TGF)-p in bronchial lavage (BAL) fluid and that they can augment the generation of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen III by human bronchial fibroblasts (Fb). Furthermore, we have observed a correlation between BAL EOS and the appearance of Fb-like cells in BAL fluid obtained after allergen challenge. Therefore, existing literature and our published, as well as preliminary data, provide strong support for our hypothesis and rationale for the proposed studies. To test the above hypothesis and establish the role of EOS in allergic airway inflammation and the initiation of fibrogenesis/remodeling, we propose the following specific aims: 1. To establish the contribution of EOS to allergic airway inflammation including the contribution of EOS-T cell integrin interactions to cytokine generation and the in vivo effect of EOS on allergic airway inflammation in asthma; and 2. To establish the contribution of EOS to the initiation of airway remodeling/fibrogenesis, with a focus on exploring the role of EOS-Fb integrin interactions in TGF-01 generation by EOS and production of ECM proteins by Fb, and testing the in vivo effect of EOS on the presence of TGF-pl and ECM proteins in patients with asthma. From these studies, it is expected that novel and improved understanding of the role of EOS in allergic inflammation and asthma will emerge providing rationale for new paradigms in the treatment of asthma and other eosinophitic disorders.

虽然该项目的目的是确定EOS对气道炎症的贡献和 重塑，气道嗜酸性粒细胞是哮喘恶化，疾病严重程度的重要标志 和对皮质类固醇治疗的反应，嗜酸性粒细胞（EOS）在哮喘中起的确切作用 还有待确定。基于当前对EOS和我们的功能的理解 初步数据，我们的假设是，EOS通过细胞 - 细胞相互作用增强了EOS T细胞和基质蛋白通过成纤维细胞产生细胞因子以促进过敏 气道炎症和纤维化。我们还提供了EOS有助于气道的证据 通过产生T细胞活性趋化因子并增强炎症！通过直接细胞电池函数 相互作用，由整联蛋白介导。我们提供的证据表明EOS是 转化生长因子（TGF）-P在支气管灌洗（BAL）流体中，它们可以增加 通过包括纤连蛋白（FN）和胶原蛋白III的细胞外基质（ECM）蛋白的产生 人支气管成纤维细胞（FB）。此外，我们已经观察到BAL之间的相关性 在过敏原挑战后获得的EOS和FB样细胞在BAL流体中的出现。所以， 现有文献和我们已发布的以及初步数据为我们的 拟议研究的假设和理由。检验上述假设并建立 EOS在过敏性气道炎症中的作用以及纤维化/重塑的启动，我们 提出以下具体目的：1。建立EOS对过敏气道的贡献 炎症，包括EOS-T细胞整合素相互作用对细胞因子产生的贡献 EOS对哮喘过敏气道炎症的体内影响；和2。建立 EOS对气道重塑/纤维发生的贡献，重点是探索 EOS-FB整联蛋白相互作用在TGF-01生成中的作用和ECM的产生 蛋白质通过FB，测试EOS对TGF-PL和ECM蛋白的存在的体内效应 在哮喘患者中。从这些研究中，可以预期新颖和改善 了解EOS在过敏性炎症和哮喘中的作用将出现 新范式治疗哮喘和其他嗜酸性疾病的基本原理。