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建立嗜酸性粒细胞（EOS）对过敏性的贡献 哮喘的炎症和病理生理学通过了解导致嗜酸性粒细胞启动，激活，粘附性，趋化因子的产生，促进T细胞募集和激活的趋化因子以及刺激成纤维细胞产生胶原蛋白和其他外ellululrRix（ECM）蛋白的刺激。我们的假设是，通过与淋巴细胞和成纤维细胞的相互作用，EOS通过增强气道炎症并促进气道重塑，在哮喘发病机理中起关键作用，而不是作为特应性的主要效应细胞。我们在该计划项目应用中提出的研究将首先确定通过产生T细胞活性趋化因子并增强促炎细胞因子的T细胞产生的EOS扩增气道炎症的机制。同样，我们建议嗜酸性粒细胞通过成纤维细胞增强ECM的产生，以促进气道重塑（项目1）。其次，我们将定义嗜酸性粒细胞粘附和移民的机制，重点是α4Beta1整合素在EOS上的相互作用EOS与其VCAM-1配体的相互作用，P-Selectin在激活Beta1整合蛋白激活中的作用以及已知的Podosome的瞬时外观，该结构已知podosome，该结构促进EOS（促进EOS eos粘附2）。第三，将研究IL-5家族细胞因子“启动” EOS的分子机制，重点是细胞内信号传导级联反应（JAK-STAT和RAS-MAP激酶）在增强EOS对趋化因子的反应性中的作用（例如Rantes）。这些信号事件与EOS依从性，迁移，生存能力和促炎性介体的释放的关系将得到确定（项目3）。第四，为了批判性地确定EOS的调节纤维化细胞因子TGF-BETA1的产生的机制，我们将重点介绍异构酶在EOS中稳定TGF-BETA1 mRNA在EOS中的作用，并介导TGF-BETA1在纤维细胞中介导TGF-BETA1信号（Project 4）。研究将在三个级别进行：（1）细胞功能和细胞 - 细胞相互作用； （2）细胞内信号传导； （3）基因表达和转录后控制。我们将使用从过敏性气道炎症的体内模型获得的血液EOS和细胞产生的假设，这些假设使用基线时的抗原和抗原和抗Anti-IL-5抗体处理的抗原和抗原治疗的细胞体内模型。这些项目将由3个核心（临床，实验室和行政）促进。从这些协作和集成的方法中，我们将直接解决EOS在过敏性气道炎症中的作用，因此，确定了对EOS上调机制及其在气道疾病中的作用的新颖和全面的见解。