Role of Eosinophils in Airway Inflammation and Remodeling

嗜酸性粒细胞在气道炎症和重塑中的作用

• 批准号: 7760624
• 负责人: NIZAR N JARJOUR
• 金额: $ 208.02万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760624
• 关键词: Role; Eosinophils; Airway; Inflammation; Remodeling

DESCRIPTION (provided by applicant): The overall goal of this program project is to establish the contributions of eosinophils (EOS) to allergic inflammation and pathophysiology of asthma by understanding the mechanisms leading to eosinophil priming, activation, adhesiveness, generation of chemokines to promote T cell recruitment and activation as well as stimulation of fibroblasts to produce collagen and other extracellulr matrix (ECM) proteins. It is our hypothesis that EOS play a pivotal role in asthma pathogenesis by enhancing airway inflammation and promoting airway remodeling via interactions with lymphocytes and fibroblasts rather than as primary effector cells of atopy. Our proposed studies in this Program Project application will first identify the mechanism(s) by which EOS amplify airway inflammation by generating T cell-active chemokines and enhancing T cell production of proinflammatory cytokines. Likewise, we propose that eosinophils enhance ECM generation by fibroblasts to promote airway remodeling (Project 1). Second, we will define the mechanisms of eosinophil adhesion and transmigration focusing on the interaction of alpha4beta1 integrin on EOS with its VCAM-1 ligand, the role of P-selectin in activation of beta1 integrin and the transient appearance of a structure known as the podosome, which promotes EOS adhesion (Project 2). Third, the molecular mechanisms by which EOS are "primed" by IL-5 family cytokines will be studied with a focus on the role of intracellular signaling cascades (JAK-STAT and Ras- MAP kinase) in potentiating EOS responsiveness to chemokines (e.g. RANTES). The relationship of these signaling events to increased EOS adherence, migration, viability and release of proinflammatory or profibrotic mediators will be identified (Project 3). Fourth, to determine critically the mechanisms regulating the generation of the profibrotic cytokine, TGF-beta1, by EOS we will focus on the role of an isomerase, Pin-1, in stabilizing TGF-beta1 mRNA in EOS and mediating TGF-beta1 signaling in fibroblasts (Project 4). Studies will be performed at three levels: (1) cell function and cell-cell interaction; (2) intracellular signaling; and (3) gene expression and pre-/post-transcriptional control. We will test the hypotheses, generated from ex vivo experiments using blood EOS and cells obtained from the in vivo model of allergic airway inflammation that employs bronchoscopy with segmental bronchoprovocation with antigen at baseline as well as following treatment with the anti-IL-5 antibody. These projects will be facilitated by 3 cores (clinical, laboratory and administrative). From these collaborative and integrated approaches, we will directly address the role of EOS in allergic airway inflammation, and, as a consequence, determine novel and comprehensive insight into the mechanisms of EOS up-regulation and its role in airway disease.

描述(由申请人提供)： 该项目的总体目标是通过了解嗜酸性粒细胞启动、激活、黏附、产生趋化因子以促进T细胞募集和激活以及刺激成纤维细胞产生胶原和其他细胞外基质(ECM)蛋白的机制，确定嗜酸性粒细胞(EOS)在哮喘过敏性炎症和病理生理学中的作用。我们的假设是，EOS通过与淋巴细胞和成纤维细胞相互作用，而不是作为特应性的主要效应细胞，在哮喘发病机制中发挥关键作用，从而促进气道炎症和气道重塑。我们在本项目申请中提出的研究将首先确定EOS通过产生T细胞活性趋化因子和促进T细胞产生促炎细胞因子来放大呼吸道炎症的机制(S)。同样，我们提出，嗜酸性粒细胞促进成纤维细胞产生ECM，从而促进气道重塑(项目1)。其次，我们将定义嗜酸性粒细胞黏附和迁移的机制，重点是EOS上α4β1整合素与其VCAM-1配体的相互作用，P-选择素在β1整合素激活中的作用，以及促进EOS黏附的足体结构的瞬时出现(项目2)。第三，将研究IL-5家族细胞因子“启动”EOS的分子机制，重点是细胞内信号级联(JAK-STAT和RAS-MAP激酶)在增强EOS对趋化因子(例如RANTES)反应中的作用。这些信号事件与促炎症或促纤维化介质增加的EOS黏附、迁移、活性和释放的关系将被确定(项目3)。第四，为了准确地确定EOS产生促纤维化细胞因子--转化生长因子--β1的调控机制，我们将重点研究异构酶--Pin-1在稳定转化生长因子--转化生长因子1mRNA和调节成纤维细胞转化生长因子--转化生长因子--β1信号中的作用(项目4)。研究将在三个层面进行：(1)细胞功能和细胞间相互作用；(2)细胞内信号；(3)基因表达和转录前/后调控。我们将使用血液EOS和从过敏性气道炎症的体内模型中获得的细胞进行体外实验，该模型使用支气管镜检查，以抗原为基础的节段性支气管刺激，以及随后的抗IL-5抗体治疗，我们将测试这些假设。这些项目将由3个核心(临床、实验室和行政)推动。通过这些协作和集成的方法，我们将直接解决EOS在过敏性气道炎症中的作用，并因此确定对EOS上调的机制及其在呼吸道疾病中的作用的新的和全面的见解。