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: 7824378
• 负责人: NIZAR N JARJOUR
• 金额: $ 1.79万
• 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: 2009-06-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7824378
• 关键词: Address; Adherence; Adhesions; Adhesiveness; Allergic; Antibodies; Antigens; Appearance; Asthma; Bronchoscopy; CD29 Antigen; Cell Communication; Cell physiology; Cells; Clinical; Collagen; Disease; Effector Cell; Event; Family; Fibroblasts; Functional disorder; Gene Expression; Generations; Goals; Inflammation; Integrin alpha4beta1; Interleukin-5; Isomerase; Laboratories; Ligands; Lymphocyte; Mediating; Mediator of activation protein; Messenger RNA; Mitogen-Activated Protein Kinases; Molecular; P-Selectin; Pathogenesis; Play; Post-Transcriptional Regulation; Production; Proteins; RANTES; Role; Signal Transduction; Structure; T-Lymphocyte; Testing; Up-Regulation; Vascular Cell Adhesion Molecule-1; airway inflammation; airway remodeling; allergic airway inflammation; atopy; chemokine; cytokine; eosinophil; human TGFB1 protein; in vivo Model; insight; migration; novel; programs; research study

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）： 该计划项目的总体目标是确定嗜酸性粒细胞 (EOS) 对过敏的贡献 通过了解导致嗜酸性粒细胞启动、激活、粘附、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蛋白和其他细胞外基质 (ECM) 蛋白的机制，了解哮喘的炎症和病理生理学。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，增强气道炎症并促进气道重塑，从而在哮喘发病机制中发挥关键作用。我们在此计划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增强 T 细胞促炎细胞因子的产生来放大气道炎症的机制。同样，我们建议嗜酸性粒细胞增强成纤维细胞 ECM 的生成，从而促进气道重塑（项目 1）。其次，我们将定义嗜酸性粒细胞粘附和迁移的机制，重点关注 EOS 上的 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称为足小体的结构的短暂出现。 ，促进 EOS 粘附（项目 2）。第三，将研究 EOS 被 IL-5 家族细胞因子“引发”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）反应性中的作用。 ）。这些信号事件与促炎症或促纤维化介质增加的 EOS 粘附、迁移、活力和释放之间的关系将被确定（项目 3）。第四，为了关键地确定 EOS 调节促纤维化细胞因子 TGF-β1 生成的机制，我们将重点关注异构酶 Pin-1 在稳定 EOS 中的 TGF-β1 mRNA 和介导 EOS 中的 TGF-β1 信号传导方面的作用。成纤维细胞（项目 4）。研究将在三个层面上进行：（1）细胞功能和细胞间相互作用； (2) 细胞内信号传导； (3)基因表达和转录前/转录后控制。我们将使用血液 EOS 和从过敏性气道炎症体内模型获得的细胞来测试由离体实验产生的假设，该模型采用支气管镜检查和基线抗原分段支气管激发以及抗 IL-5 抗体治疗后。这些项目将由三个核心（临床、实验室和行政）推动。通过这些协作和综合方法，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 上调机制及其在气道疾病中的作用的新颖且全面的见解。