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.

虽然本项目的目标是确定EOS对气道炎症的贡献， 气道重塑、气道嗜酸性粒细胞增多是哮喘急性发作、疾病严重程度的重要标志物 和对皮质类固醇治疗的反应，嗜酸性粒细胞（EOS）在哮喘中的确切作用 仍有待确定。根据目前对EOS功能的理解， 初步数据，这是我们的假设，EOS，通过细胞间的相互作用，增强 通过T细胞产生细胞因子和通过成纤维细胞产生基质蛋白以促进变应性 气道炎症和纤维化。我们还提供了证据表明，EOS有助于气道 炎症通过产生T细胞活性趋化因子和增强！细胞功能通过直接细胞 相互作用，由整合素介导。我们提供的证据表明，EOS是主要来源， 支气管灌洗液（BAL）中的转化生长因子（TGF）-β，它们可以增加支气管肺泡灌洗液（BAL）中的 产生细胞外基质（ECM）蛋白，包括纤连蛋白（FN）和胶原蛋白III， 人支气管成纤维细胞（Fb）。此外，我们还观察到BAL EOS和过敏原激发后获得的BAL液中的Fb样细胞的出现。因此，我们认为， 现有的文献和我们发表的，以及初步的数据，为我们提供了强有力的支持， 提出的研究的假设和理由。为了验证上述假设并建立 EOS在过敏性气道炎症和纤维化/重塑的启动中的作用，我们 提出以下具体目标：1.探讨EOS在过敏性气道反应中的作用 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 以及EOS在哮喘变应性气道炎症中的体内作用;和2.建立 EOS对气道重塑/纤维形成的启动的贡献，重点是探索 EOS-Fb整合素相互作用在EOS产生TGF-01和ECM产生中作用 通过Fb检测EOS对TGF-β 1和ECM蛋白存在的体内作用， 哮喘患者的情况。从这些研究中，预计新的和改进的 了解EOS在过敏性炎症和哮喘中的作用， 哮喘和其他嗜酸性粒细胞增多症治疗新范例的基本原理。