Integration of Leukotriene and Prostaglandin Receptor Signaling in Mast cell Activation and Pulmonary Inflammation during Asthma

白三烯和前列腺素受体信号在哮喘期间肥大细胞激活和肺部炎症中的整合

• 批准号: 10328546
• 负责人: Sailaja Paruchuri
• 金额: $ 35.58万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-20 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328546
• 关键词: Accounting; Adenosine Diphosphate; Affect; Agonist; Allergens; Allergic Disease; Allergic inflammation; Anti-Inflammatory Agents; Asthma; Binding; Blood Vessels; Bronchoconstrictor Agents; CCL4 gene; Cell physiology; Cells; Chemosensitization; Collaborations; Combined Modality Therapy; Complex; Cyclic GMP; Cytoplasmic Granules; Development; Dimerization; Dinoprostone; Disease; Dose; Effector Cell; Eicosanoids; Emergency department visit; Extravasation; FOS gene; Fluorescence; Future; G-Protein-Coupled Receptors; GPR17 gene; GTP-Binding Protein alpha Subunits, Gs; Generations; Goblet Cells; Human; Immune; Immune response; Immunologics; Individual; Infectious Agent; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intranasal Administration; Laboratories; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotriene Receptor; Ligands; Lipids; Macrophage Inflammatory Proteins; Mediating; Mediator of activation protein; Metaplastic Cell; Mucositis; Mus; Outcome; PPAR gamma; PTGS2 gene; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Peripheral; Peroxisome Proliferators; Pharmaceutical Preparations; Physiologic pulse; Physiological; Physiology; Play; Positioning Attribute; Production; Prostaglandin D2; Prostaglandin Receptor; Prostaglandins; Pulmonary Inflammation; Receptor Signaling; Role; Sampling; Signal Transduction; Site; Source; Spectrum Analysis; Steroids; Testing; Therapeutic; Transcript; Translations; United States; Up-Regulation; Urine; airway hyperresponsiveness; antagonist; asthma model; asthmatic patient; base; biophysical techniques; chemokine; clinical efficacy; clopidogrel; combat; cysteinyl leukotriene receptor; cysteinyl-leukotriene; in vivo; mast cell; novel; preference; pyroglyphid; receptor; recruit; release of sequestered calcium ion into cytoplasm; response; synergism; transcription factor; treatment strategy

Project Summary Mast cells (MCs) are effector cells in asthma and their activation causes secretion of cysteinyl leukotrienes (cys-LTs) and prostaglandins (PGs). MCs not only secrete these mediators, but they also possess receptors for them, to perceive their signals. Cys-LTs are potent bronchoconstrictors, powerful inducers of vascular leakage, potentiators of airway hyper-responsiveness and play an important role in asthma and other inflammatory disorders. Cys-LTs mainly act through two G-protein-coupled receptors (GPCR), CysLT1R and CysLT2R. Another GPCR, GPR17 is activated by LTD4. Both CysLT2R and GPR17 negatively regulate CysLT1R function. LTE4, the most abundant and stable of the cys-LTs, is a weak, partial agonist for the CysLT1R and CysLT2R. However, LTE4 induces unique responses in vivo that cannot be recapitulated by LTC4 or LTD4. In MC, LTE4 is more potent than LTD4 and relays signals through peroxisome proliferator activating receptor (PPAR)-γ and P2Y12R. Recently, GPR99 was identified as another CysLTR with a preference for LTE4. Understanding how all these cys-LT receptors (CysLTR) interact with each other in response to multiple ligands is critical, especially considering their role in airway physiology. Further, cys-LTs together with PGE2 synergistically potentiate calcium flux, c- Fos, COX-2, PGD2 and Macrophage Inflammatory Protein-1β (MIP-1β; CCL4)) generation in MCs. Interestingly, LTD4-PGE2 synergism is blocked only by combined treatment of CysLT1R antagonist (MK571/ singulair) and EP3 antagonist (L-798), suggesting the need for a combination of CysLT1R antagonists and EP3R antagonists to treat inflammation in asthma. LTD4+PGE2 synergism also potentiates pulmonary inflammation in der f sensitized mice (recruitment of immune cells, goblet cell metaplasia, up-regulation of inflammatory transcripts). Similar to LTD4, LTE4 synergizes with PGE2 but it differs from LTD4 via signals involving PPARγ. Based on these observations, we hypothesize that cys- LTs induce complex interactions between cys-LT-responsive receptors to profoundly influence the downstream signaling by switching anti-inflammatory PGE2 signaling to pro-inflammatory, upregulating COX-2 and PGD2 production in MC impacting Th2 inflammation and asthma. We will test this hypothesis in the following specific aims: 1) To determine the interplay between the known (CysLT1R and CysLT2R) and putative (GPR99, P2Y12R and PPARɣ) CysLTRs in response to cys-LTs, influencing MC function, 2) To uncover the mechanism by which cys-LT-PGE2 synergism induces PGD2 production and MC activation and 3) To determine the physiological significance of cys-LT+PGE2 interactions and MC in pulmonary inflammation in vivo. We will analyze pathologic, physiologic, and immunologic signatures of the immune response and evaluate the contribution of MCs. These studies will carry substantial pathogenic and therapeutic implications for asthma and allergic diseases as well as provide the basis for development and translation of future therapeutic molecules that regulate inflammation.

项目摘要 肥大细胞（MC）是哮喘中的效应细胞，其激活导致胱天稳定素的分泌 白细胞（CYS-LTS）和前列腺素（PGS）。 MC不仅分泌这些调解人，而且还 为他们拥有接收器，以感知其信号。 CYS-LT是潜在的支气管收集器，有力的 血管泄漏的诱导者，气道超反应性的潜在主义者，并在 哮喘和其他炎症性疾病。 CYS-LTS主要通过两个G蛋白偶联受体起作用 （GPCR），cyslt1r和cyslt2r。另一个GPCR GPR17被LTD4激活。 cyslt2r和 GPR17负调控Cyslt1r函数。 LTE4是CYS-LTS中最丰富和稳定的 Cyslt1r和Cyslt2r的弱，部分激动剂。但是，LTE4在体内诱导独特的响应 LTC4或LTD4不能概括这一点。在MC中，LTE4比LTD4更有潜力，并继电器信号 通过过氧化物体增殖物激活受体（PPAR）-γ和P2Y12R。最近，GPR99是 被识别为另一个偏爱LTE4的cysltr。了解所有这些CYS-LT接收器 （cysltr）响应多种配体而彼此相互作用至关重要，尤其是考虑到它们 在气道生理中的作用。此外，cys-lts与PGE2合成钙通量，c- FOS，COX-2，PGD2和巨噬细胞炎性蛋白1β（MIP-1β； CCL4））在MC中产生。 有趣的是，LTD4-PGE2协同作用仅通过CYSLT1R拮抗剂的联合处理而阻止 （MK571/ Singulair）和EP3拮抗剂（L-798），表明需要组合Cyslt1R 拮抗剂和EP3R拮抗剂治疗哮喘注射剂。 LTD4+PGE2的协同作用 增强der f感应小鼠的肺部炎症（免疫细胞，杯状细胞募集 化生，炎症转录的上调）。与LTD4相似，LTE4与PGE2协同作用 LTD4通过涉及PPARγ的信号的差异。基于这些观察结果，我们假设Cys- LTS引起CYS-LT响应受体之间的复杂相互作用，以深刻影响 通过将抗炎PGE2信号转换为促炎，上调，下游信号传导 MC中的COX-2和PGD2产生影响Th2注射和哮喘。我们将检验这个假设 在以下特定目的中：1）确定已知（Cyslt1r和Cyslt2r）之间的相互作用 和推定（GPR99，P2Y12R和PPARɣ）cysltrs响应Cys-LT，影响MC函数，2） 揭示CYS-LT-PGE2协同作用诱导PGD2产生和MC的机制 激活和3）确定Cys-LT+PGE2相互作用和MC的物理意义 体内肺部炎症。我们将分析病理，生理和免疫学特征 免疫反应并评估MC的贡献。这些研究将携带大量 对哮喘和过敏性疾病的致病性和治疗意义，并为 调节炎症的未来治疗分子的开发和翻译。