Control of Pulmonary Inflammation by Leukotriene E4

白三烯 E4 控制肺部炎症

基本信息

批准号：
10296403
负责人：
Joshua A Boyce
金额：
$ 70.07万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-13 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10296403
关键词：
Agonist Arachidonate 5-Lipoxygenase Asthma Automobile Driving Basophils Blood Platelets Bronchial Hyperreactivity Brush Cell Cells Clinical Complex Cyclooxygenase Inhibitors Development Epithelial Epithelial Cells Functional disorder Generations Grant Hematopoietic Individual Inflammation Inflammation Mediators Inhalation Leukotriene C4 Leukotriene D4 Leukotriene E4 Leukotriene Production Leukotriene Receptor Lipids Lung Lung diseases Lymphoid Cell Mediating Modeling Mucous Membrane Nasal Polyps Nucleotides P2Y2 receptor Pathway interactions Patients Pharmaceutical Preparations Phenotype Production Prostaglandin D2 Pulmonary Inflammation Reaction Regulation Role Series Severity of illness Signal Transduction Smooth Muscle Structure System Testing Therapeutic Tissues Transgenic Mice Urine airway epithelium airway inflammation aspirin-exacerbated respiratory disease asthmatic cell type chronic rhinosinusitis cyclooxygenase 1 cysteinyl leukotriene receptor cysteinyl-leukotriene cytokine eosinophil immunopathology improved individual variation inhibitor/antagonist novel novel therapeutics receptor receptor function recruit respiratory respiratory smooth muscle urinary

项目摘要

Abstract/Summary This application for continuing support focuses on the mechanisms by which the cysteinyl leukotrienes (cysLTs), a class of potent lipid inflammatory mediators, facilitate type 2 (eosinophilic) immunopathology (T2I) that underlies prevalent and burdensome respiratory diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). The proposal tests the hypothesis that leukotriene E4 (LTE4) initiates respiratory T2I through engagement of the type 3 cysLT receptor (CysLT3R) and nucleotide signaling to P2Y2 receptors on brush cells (BrCs). A second hypothesis is that LTE4-induced BrC activation elicits activation of group 2 innate lymphoid cells (ILC2s) and type 2 cytokine generation through synergistic actions of IL-25 and endogenously generated LTC4. A third hypothesis is that IL-25-driven eosinophil recruitment provides a pool of LTC4-driven platelet-derived IL-33 to incrementally activate ILC2s and MCs, further amplifying T2I and its consequences, including upstream BrC expansion. The proposal uses a combination of novel transgenic mice, ex vivo approaches, and unique models to dissect a complex pathway by which cysLTs act in series downstream of epithelial perturbation by leukotriene E4, the most stable cysLT, to activate MC, potently elicit ILC2 activation, and induce severe immunopathology. The studies seek to explain the selective hyperresponsiveness of asthmatic subjects to leukotriene E4, and to develop therapeutic strategies through the selective targeting of receptors other than CysLT1R.

摘要/摘要该持续支持的应用侧重于白细胞三烯的机制（CYSLTS），一类有效的脂质炎症介质，促进2型（嗜酸性）免疫病理学（T2I）这是普遍和繁重的呼吸道疾病的基础，包括哮喘和慢性鼻鼻涕鼻息肉（CRSWNP）。该提案检验了白三烯E4（LTE4）启动呼吸T2I的假设通过3型Cyslt受体（Cyslt3R）和核苷酸信号传导的参与到P2Y2受体上刷细胞（BRC）。第二个假设是LTE4诱导的BRC激活引发了第2组的激活先天淋巴样细胞（ILC2）和2型细胞因子通过IL-25和内源产生的LTC4。第三个假设是IL-25驱动的嗜酸性粒细胞募集提供了一个池 LTC4驱动的血小板衍生的IL-33逐渐激活ILC2和MC，进一步扩增T2i及其后果，包括上游BRC扩展。该提案结合了新型转基因小鼠，离体方法和独特的模型，以剖析CYSLT串联起作用的复杂途径最稳定的Cyslt的白三烯E4上皮扰动的下游，以激活MC，有效地引起 ILC2激活并诱导严重的免疫病理学。研究试图解释选择性哮喘患者对白三烯E4的过度反应性，并通过除Cyslt1r以外的受体的选择性靶向。