Specialized Pro-Resolving Mediators in Asthma

哮喘专业解决调解员

• 批准号: 10239859
• 负责人: Bruce D Levy
• 金额: $ 75.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10239859
• 关键词: Acute; Address; Adverse effects; Agonist; Allergic; Anabolism; Anti-Inflammatory Agents; Arachidonic Acids; Asthma; Biological; Biopsy; CD59 Antigen; Cell Communication; Cell membrane; Cells; Chronic; Chronic Obstructive Airway Disease; Dependence; Disease; Docosahexaenoic Acids; Dose; Drug Design; Enzymes; Epithelial; Epithelial Cells; Essential Fatty Acids; Experimental Models; Family; Fatty Acids; Funding; Gene Expression; Generations; Head; Health; Homeostasis; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Laboratories; Lead; Leukocytes; Lipids; Lipoxins; Lung; Lung Inflammation; Measures; Mediator of activation protein; Modeling; Modification; Molecular; Morbidity - disease rate; Mucous Membrane; Mus; Pathway interactions; Pharmaceutical Preparations; Play; Process; Production; Publishing; Regulation; Resolution; Role; Severities; Signal Transduction; Sorting - Cell Movement; Stimulus; Structure of parenchyma of lung; Testing; Therapeutic; Thinking; Tissues; Translations; Validation; Work; airway hyperresponsiveness; airway inflammation; asthma exacerbation; asthma model; asthmatic; asthmatic airway; base; cell type; cellular transduction; cysteinyl-leukotriene; design; eosinophil; experimental study; granulocyte; high dimensionality; in vivo; insight; lipid mediator; macrophage; molecular imaging; mouse model; novel; pre-clinical; prevent; programs; receptor; response; spatiotemporal; stem; translation to humans; volunteer

Abstract The proposed experiments will test the hypothesis that specialized pro-resolving mediators (SPMs) and cysteinyl-containing SPMs (CysSPMs) are produced in the lung to counter-regulate pro-phlogistic responses and to promote resolution of lung inflammation, in part via activation of a pro-resolving subset of eosinophils. Although we are accustomed to viewing the increase in airway inflammation and hyper-responsiveness in asthma as the result of an over-abundance of pro-inflammatory stimuli, the severity and duration of an asthma exacerbation could also result from insufficient endogenous anti-inflammatory effectors. Cysteinyl leukotrienes are well appreciated to play pro-phlogistic roles in asthma, but not all lipid mediators initiate inflammation. There are now several families of specialized pro-resolving mediators (SPM) that have been identified and characterized in acute inflammation. These protective mediators are enzymatically derived from essential fatty acids and serve as agonists at specific receptors to transduce cell type specific functional responses, including in eosinophil subsets that are relevant in asthma. With several drugs already developed to block CysLT formation or action, the notion that select endogenous lipid-derived mediators are generated to promote resolution of asthmatic airway responses would turn conventional thinking on its head and identify CysSPMs as natural pro-resolving mediators and novel templates for drug design. To test our hypothesis, we propose three specific aims to:  Determine lung SPM and CysSPM production in acute and chronic allergic lung inflammation,  Establish SPM and CysSPM actions in the resolution of lung inflammatory responses, and  Define roles for lung eosinophil subsets in promoting inflammation resolution. This proposal’s specific aims are directed towards uncovering basic mechanisms that govern the resolution of allergic airway responses in health and disease.

抽象的 拟议的实验将检验以下假设：专门的促解决中介（SPM）和 肺部产生含有半胱氨酰的 SPM (CysSPM)，以对抗调节促炎反应 并促进肺部炎症的消退，部分是通过激活促消退的嗜酸性粒细胞亚群。 尽管我们习惯于看到气道炎症和高反应性的增加 哮喘是由于过多的促炎刺激引起的，哮喘的严重程度和持续时间 内源性抗炎效应物不足也可能导致病情加重。 人们普遍认为脂质介质在哮喘中发挥促炎作用，但并非所有脂质介质都会引发炎症。 现在有几个专门的促解决调解员（SPM）家族已被识别并用于治疗。 这些保护性介质以酶促方式衍生自必需脂肪。 酸并作为特定受体的激动剂来转导细胞类型特异性功能反应，包括 与哮喘相关的嗜酸性粒细胞亚群中，已经开发出几种阻断 CysLT 的药物。 形成或作用，选择内源性脂质衍生介质产生以促进的概念 解决哮喘气道反应将颠覆传统思维并识别 CysSPM 作为天然的促解决介质和药物设计的新颖模板。 为了检验我们的假设，我们提出三个具体目标：  确定急性和慢性过敏性肺部炎症中肺部 SPM 和 CysSPM 的产生，  建立 SPM 和 CysSPM 在解决肺部炎症反应中的作用，以及  定义肺嗜酸性粒细胞亚群在促进炎症消退中的作用。 该提案的具体目标是揭示管理解决问题的基本机制 健康和疾病中的过敏性气道反应。