Control of Pulmonary Inflammation by Leukotriene E4

白三烯 E4 控制肺部炎症

• 批准号: 10666460
• 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/10666460
• 关键词: Agonist; Arachidonate 5-Lipoxygenase; Asthma; Automobile Driving; Basophils; Blood Platelets; Bronchial Hyperreactivity; Brush Cell; Cells; Clinical; Complex; Cyclooxygenase Inhibitors; Development; Epithelial Cells; Epithelium; Functional disorder; Generations; Grant; Hematopoietic; Individual; Inflammation; Inflammation Mediators; Inhalation; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotriene Production; Leukotriene Receptor; Lipids; Lipoxygenase Inhibitors; Lung; Lymphoid Cell; Mediating; Modeling; Mucous Membrane; Nasal Polyps; Nucleotides; P2Y2 receptor; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Production; Prostaglandin D2; Pulmonary Inflammation; Reaction; Regulation; Respiratory Disease; Role; Series; Severity of illness; Signal Transduction; Smooth Muscle; System; Testing; Therapeutic; Tissues; Transgenic Mice; Urine; airway epithelium; airway inflammation; antagonist; aspirin-exacerbated respiratory disease; asthmatic; chronic rhinosinusitis; cyclooxygenase 1; cysteinyl leukotriene receptor; cysteinyl-leukotriene; cytokine; eosinophil; immunopathology; improved; individual variation; inhibitor; 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/摘要 这项持续支持的申请侧重于半胱氨基白三烯的作用机制 细胞角质形成蛋白(CysLts)是一类有效的脂类炎症介质，促进2型(嗜酸性)免疫病理(T2I) 这是流行和负担沉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)。该提议验证了白三烯E4(LTE4)启动呼吸道T2I的假设 通过与3型CysLT受体(CysLT3R)的结合和与P2Y2受体的核苷酸信号传导 刷状细胞(BRCs)。第二个假设是LTE4诱导的BRC激活引起第二组的激活 IL-25和IL-25协同作用产生固有淋巴样细胞(ILC2)和2型细胞因子 内源生成的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递增地激活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， 体外方法和独特的模型来剖析CysLTs串联作用的复杂途径 白三烯E4，最稳定的cysLT，激活MC，有效地诱导上皮细胞的下游扰动 ILC2激活，并诱导严重的免疫病理。这些研究试图解释选择性的 哮喘受试者对白三烯E4的高反应性，并通过 选择性靶向CysLT1R以外的受体。

项目成果

LTC4 synthase polymorphism modifies efficacy of botanical seed oil combination in asthma.

• DOI: 10.1186/2193-1801-3-661
• 发表时间: 2014
• 期刊: SpringerPlus
• 作者: Kazani S;Arm JP;Boyce J;Chhay H;Dutile S;Wechsler ME;Govindarajulu U;Ivester P;Ainsworth HC;Sergeant S;Chilton FH;Israel E
• 通讯作者: Israel E