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.

虽然这个项目的目标是确定EOS对呼吸道炎症和 重塑，气道嗜酸性粒细胞增多是哮喘加重、疾病严重程度的重要标志 以及对皮质类固醇治疗的反应，嗜酸性粒细胞(EOS)在哮喘中所起的确切作用 仍有待确定。根据目前对EOS功能的理解和我们的 初步数据，我们的假设是，EOS通过细胞间的相互作用，增强了 T细胞分泌细胞因子和成纤维细胞基质蛋白促进过敏反应 呼吸道炎症和纤维化形成。我们还提供了EOS促进呼吸道功能的证据 炎症通过产生T细胞活性趋化因子而增强！通过直接细胞实现细胞功能 相互作用，由整合素介导。我们提供的证据表明，EOS是 支气管灌洗液(BAL)中的转化生长因子(TGF)-β，它们可以增加 产生细胞外基质(ECM)蛋白，包括纤维连接蛋白(FN)和III型胶原 人支气管成纤维细胞(FB)。此外，我们还观察到BAL与 过敏原攻击后BAL液中Eos和FB样细胞的出现。因此， 现有的文献和我们发表的，以及初步的数据，为我们的 拟议研究的假设和理论基础。为了检验上述假设，并建立 EOS在过敏性气道炎症和纤维化/重塑启动中的作用 提出以下具体目标：1.确定EOS在过敏性气道中的作用 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对哮喘变态反应性气道炎症的体内作用；2.建立 嗜酸性粒细胞在启动气道重塑/纤维化中的作用，重点探讨 EOS-FB整合素相互作用在EOS产生转化生长因子-01及细胞外基质产生中的作用 FB，检测EOS对转化生长因子-β1和细胞外基质蛋白表达的体内影响 在哮喘患者身上。从这些研究中，可以期待新的和改进的 对EOS在过敏性炎症和哮喘中的作用的理解将会出现 治疗哮喘和其他嗜酸性粒细胞疾病的新范例的理论基础。