Control of Pulmonary Inflammation by Leukotriene E4

白三烯 E4 控制肺部炎症

• 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
• 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

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/总结 此持续支持申请重点关注半胱氨酰白三烯的机制 (cysLT) 是一类有效的脂质炎症介质，促进 2 型（嗜酸性）免疫病理学 (T2I) 它是流行和繁重的呼吸系统疾病的基础，包括哮喘和慢性鼻窦炎 鼻息肉（CRSwNP）。该提案测试了白三烯 E4 (LTE4) 引发呼吸性 T2I 的假设 通过 3 型 cysLT 受体 (CysLT3R) 和 P2Y2 受体的核苷酸信号传导 刷细胞（BrC）。第二个假设是 LTE4 诱导的 BrC 激活引发第 2 组的激活 通过 IL-25 和 IL-25 的协同作用产生先天淋巴细胞 (ILC2) 和 2 型细胞因子 内源产生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，进一步放大 T2I 及其 后果，包括上游 BrC 扩张。该提案使用了新型转基因小鼠的组合， 离体方法和独特的模型来剖析 cysLT 串联作用的复杂途径 白三烯 E4（最稳定的 cysLT）对上皮细胞扰动的下游，激活 MC，有效引发 ILC2 激活，并诱发严重的免疫病理学。这些研究试图解释选择性 哮喘受试者对白三烯 E4 的高反应性，并通过以下方法制定治疗策略： 选择性靶向 CysLT1R 以外的受体。