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: 8530855
• 负责人: NIZAR N JARJOUR
• 金额: $ 47.38万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8530855
• 关键词: Abbreviations; Address; Allergens; Antigens; Asthma; Attenuated; Biology; Blood; Bone Marrow; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cell surface; Cells; Cytokine Signaling; Cytoplasmic Granules; Data; Deposition; Development; Disease; Disease Outcome; Drug Targeting; Eosinophilia; Extracellular Matrix Proteins; Extrinsic asthma; Family; Fibroblasts; Fibrosis; Functional disorder; Funding; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; In Vitro; Inflammation; Inflammatory; Instruction; Integrins; Interleukin-1; Interleukin-16; Interleukin-17; Interleukin-3; Interleukin-5; Knowledge; Lead; Link; Lymphocyte; Measures; Mediating; Mediator of activation protein; Membrane Proteins; Messenger RNA; Modeling; Molecular; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Play; Principal Investigator; Production; Proteins; Refractory; Regulation; Research; Role; Semaphorins; Severities; Severity of illness; Signal Transduction; Stream; Testing; Therapeutic; Tissues; airway inflammation; airway remodeling; allergic response; base; cell motility; chemokine; cytokine; eosinophil; in vivo; innovation; mRNA Stability; mepolizumab; new therapeutic target; novel; receptor; repaired; research study; response; tool

There is a fundamental gap in understanding how eosinophils (EOS) participate in inflammation and remodeling in asthmatic subjects. The lack of knowledge in this field is problematic to develop appropriate drugs to better treat a heterogenic disease such as asthma. The long-term goal is to understand the mechanisms by which EOS contribute to the development of asthma, particularly the more severe phenotypes. The objective in this Project 1 is to identify how activated EOS produce pro-inflammatory and remodeling factors that are relevant in allergic asthma. The central hypothesis is that IL-3 activates EOS to produce 1) the pro-inflammatory cytokine IL-1B and 2) the pro-fibrotic membrane protein, semaphorin7A (SEMA7A). We propose that IL-1 B drives the increase of the highly inflammatory cytokine, IL-17 in lymphocytes in the context of an allergic response. SEMA7A induces fibroblasts (Fb) differentiation toward myoFb, amplifying airway remodeling. Our preliminary data will allow us to test this hypothesis by pursuing three specific aims: 1) Determine the expression of IL-17 in the ainways after segmental allergen challenge in patients with asthma. Measure IL-1B release from blood and ainway EOS, and connect the release of IL-1B with IL-17 expression in vivo and with EOS ability to increase IL-17 by CD4+ T lymphocytes in vitro. 2) Define the mechanisms responsible for IL-3-induced IL-1B. The mechanisms analyzed include mRNA stability and IL-1B maturation through the inflammasome. 3) Analyze the expression and regulation of SEMA7A on blood and ainway EOS and determine the effect of SEMA7A on human bronchial Fb. The approach is innovative addressing new functions attributed to EOS. The release of bioactive IL-1B by EOS, as well as the expression of SEMA7A on EOS, are both novel. The implication of EOS in IL-17 production has never been shown and the function of SEMA7A on human Fb is unknown. These mechanisms will be analyzed in IL-3-activated EOS in vitro or in vivo in the context of a segmental allergen challenge. This latter in vivo approach, which mimics natural allergic asthma, arguably sets our group apart in our abilities to analyze airway EOS in humans. The proposed research is significant because it is expected to advance our understanding ofthe role of EOS in asthma, and of EOS potential function in the development of severe asthma. Ultimately, the knowledge acquired by these studies, will help to define new potential targets for drugs in needs for patients refractory to current treatments. RELEVANCE (See instructions): We propose that IL-3 contributes to eosinophil function in asthma by 1) influencing CD4+ T cell production of the pro-inflammatory cytokine IL-17, and 2) inducing expression ofthe profibrotic molecule semaphorin 7 A. The focus on IL-3 is a paradigm shift from current IL-5-targeted therapies. Understanding the cellular and biomolecular mechanisms down-stream of eosinophil activation by IL-3 will reveal novel pathways with therapeutic implications in asthma and other eosinophils-related diseases.

在理解嗜酸性粒细胞（EOS）如何参与炎症和炎症反应方面存在根本性的差距。 哮喘患者的重塑。缺乏这一领域的知识， 更好地治疗哮喘等异质性疾病的药物。长期目标是了解 EOS促进哮喘发展的机制，特别是更严重的哮喘。 表型本项目1的目的是确定激活的EOS如何产生促炎性和 与过敏性哮喘相关的重塑因子。中心假设是IL-3激活EOS， 产生1）促炎细胞因子IL-1B和2）促纤维化膜蛋白semaphorin 7A （SEMA7A）。我们认为，IL-1 B驱动高度炎性细胞因子IL-17的增加， 淋巴细胞在过敏反应的背景下。SEMA 7A诱导成纤维细胞（Fb）向 myoFb，放大气道重塑。我们的初步数据将使我们能够通过追踪 三个具体的目的：1）确定在节段性过敏原攻击后， 哮喘患者。测定血IL-1B和气道EOS的释放，并与IL-1B的释放相联系 体内IL-17表达和体外EOS通过CD 4 + T淋巴细胞增加IL-17的能力。（二） 定义负责IL-3诱导IL-1B的机制。分析的机制包括mRNA 稳定性和IL-1B通过炎性小体成熟。3)分析其表达与调控 SEMA 7A对血液和气道EOS的影响，并确定SEMA 7A对人支气管Fb的影响。的 方法是创新的，解决了EOS的新功能。EOS释放具有生物活性的IL-1B， 以及SEMA 7A在EOS上的表达，都是新的。EOS在IL-17产生中的意义 SEMA 7A对人Fb的功能尚不清楚。这些机制将 在节段性过敏原激发的背景下，在体外或体内IL-3激活的EOS中分析。后一 模拟自然过敏性哮喘的体内方法，可以说使我们的小组在我们的能力方面与众不同， 分析人体气道EOS。拟议的研究是重要的，因为它有望推动我们的 了解EOS在哮喘中的作用，以及EOS在严重哮喘发生中的潜在功能， 哮喘最终，这些研究所获得的知识将有助于确定新的潜在目标， 目前治疗难治性患者所需的药物。 相关性（参见说明）： 我们认为IL-3通过以下方式参与哮喘患者嗜酸性粒细胞的功能：1）影响哮喘患者外周血中CD 4 + T细胞的产生， 促炎细胞因子IL-17，和2）诱导促纤维化分子semaphorin 7A的表达。 对IL-3的关注是当前IL-5靶向治疗的范式转变。了解细胞和 IL-3激活嗜酸性粒细胞下游的生物分子机制将揭示新的途径， 在哮喘和其它嗜酸性粒细胞相关疾病中的治疗意义。