Specialized Pro-Resolving Mediators in Asthma

哮喘专业解决调解员

• 批准号: 10472044
• 负责人: Bruce D Levy
• 金额: $ 73.58万
• 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/10472044
• 关键词: Acute; Address; Adverse effects; Agonist; Allergic; Anabolism; Anti-Inflammatory Agents; Arachidonic Acids; Asthma; Biological Products; Biopsy; CD59 Antigen; Cell Communication; Cell membrane; Cells; Chronic; Chronic Obstructive Pulmonary 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; Measures; Mediator of activation protein; Modeling; Modification; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Pharmaceutical Preparations; Play; Process; Production; Publishing; Pulmonary Inflammation; Regulation; Resolution; Respiratory Mucosa; 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.

摘要 拟议的实验将检验这样一种假设，即专门的促分解调节剂(SPM)和 含有半胱氨酰的SPM(CysSPM)是在肺中产生的，用于反调节炎症反应。 促进肺部炎症的消退，部分是通过激活嗜酸性粒细胞的促消解亚群。 尽管我们习惯于看到呼吸道炎症和高反应性的增加 促炎症刺激过多所致的哮喘，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恶化。半胱氨基白三烯 被认为在哮喘中起致炎作用，但并不是所有的脂质介质都会引发炎症。 现在已经确定了几个专门的亲解决调解人(SPM)家族，并 以急性炎症为特征。这些保护性介质是从必需脂肪中酶促衍生出来的。 作为特定受体的激动剂，转导细胞类型的特定功能反应，包括 与哮喘相关的嗜酸性粒细胞亚群。已经开发了几种药物来阻断CysLT 形成或作用，即选择内源性脂质衍生介质的概念被产生以促进 哮喘呼吸道反应的解决将颠覆传统思维并识别CysSPM 作为天然的亲分解体和药物设计的新型模板。 为了验证我们的假设，我们提出了三个具体目标： 测定急、慢性变态反应性肺部炎症的肺SPM和CysSPM的产生， 确定Spm和CysSpm在化解肺炎性反应中的作用，以及 定义了肺嗜酸性粒细胞亚群在促进炎症消退中的作用。 这项提案的具体目标是揭示管理解决 健康和疾病中的过敏性呼吸道反应。