Interplay between LTE4/LTE4 receptors and IFN-y with mast cells and eosinophils i

LTE4/LTE4 受体和 IFN-γ 与肥大细胞和嗜酸性粒细胞之间的相互作用

• 批准号: 8259134
• 负责人: LARRY C BORISH
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259134
• 关键词: Address; Adult; Anosmia; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonate 5-Lipoxygenase; Aspirin; Asthma; CD34 gene; Carboxypeptidase; Cell Line; Cells; Chymase; Conditioned Culture Media; Cytoplasmic Granules; Development; Drug or chemical Tissue Distribution; Eosinophilia; Functional disorder; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Histamine; Histamine Release; Hour; Hyperplasia; Immune; Inflammatory; Ingestion; Interferon Receptor; Interferons; Interleukin-4; Interleukin-5; Leukotriene E4; Leukotriene Production; Leukotrienes; Life; Lipoxygenase Inhibitors; Lung; Lung diseases; Lysine; Mediating; Modeling; Molecular; Nasal Polyps; Nose; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Production; Prostaglandin D2; Proteins; Purinoceptor; Role; Secretory Vesicles; Sinusitis; Source; Surface; Symptoms; Syndrome; Tryptase; Up-Regulation; Wheezing; airway remodeling; arachidonate; base; chemokine; cysteinyl leukotriene receptor; cysteinyl-leukotriene; cytokine; eosinophil; eosinophil-activating factor; in vivo; leukotriene-C4 synthase; lipid mediator; mast cell; novel; progenitor; public health relevance; receptor; receptor expression; response; therapeutic target

DESCRIPTION (provided by applicant): These studies will focus on cellular and immune mechanisms of asthma (and sinusitis) as they pertain to aspirin-exacerbated respiratory disease (AERD). Our hypothesis is that AERD contrasts with aspirin tolerant asthma through excessive production of leukotriene E4 (LTE4) acting through specific receptors and a pro- inflammatory interplay with both interleukin (IL)-4 and interferon (IFN)-3. We also hypothesize that aspirin directly induces cellular activation in AERD. AERD is a syndrome consisting of severe persistent asthma, aggressive airway remodeling, extensive hyperplastic eosinophilic sinusitis with nasal polyp (NP) formation, anosmia, and an intolerance to aspirin characterized by symptoms ranging from nasal congestion, rhinorrhea, and wheezing to life-threatening asthma attacks. Aspirin intolerance reflects, in part, increased expression of leukotriene C4 synthase (LTC4S) and cysteinyl leukotriene (CysLT) receptor expression and, as a result, these patients have constitutive overproduction and heightened responsiveness to CysLTs (especially LTE4) with an explosive increase in CysLT production following ingestion of aspirin. We hypothesize that novel receptor(s) recognizing LTE4 are relevant to the pathophysiology of AERD. Our current studies take advantage of having generated an immortalized mast cell line ("LUVA" cells) derived from an AERD donor. These cells preserve relevant features of mast cells including possessing secretory granules containing histamine and surface expression of Fc5RI1. LUVA cells provide a novel model for investigating the previously unexplored molecular basis for direct mast cell activation by aspirin, to which they respond with release of granule contents, Ca+2 fluxes, arachidonate products, and de novo synthesized chemokines. These cells produce a secreted protein that is not any other currently characterized eosinophil-activating factor that acts to promote eosinophil hematopoiesis, survival, and LTC4S expression. We will investigate the interaction of LUVA conditioned medium (LCM) with eosinophils to further define mechanisms central to the pathophysiology of AERD. Three specific aims are proposed: Specific Aim 1 will characterize influences of LTE4 acting through LTE4-specific receptors in AERD. Specific Aim 2 will address the importance of IL-4 and IFN-3 in AERD. Although characterized by profound eosinophilia, cytokines typically associated with eosinophilia (e.g., IL-5) are only modestly and variably expressed in AERD, which instead displays a mixed Th1 (IFN-3)/Th2 (IL-4) cytokine "signature". We will focus on the relatively unexplored role of IFN-3 in promoting eosinophilia and the enhanced LTC4S expression and CysLT secretion that are central to AERD. We will investigate the ability of IFN-3 to render eosinophils responsive to LTE4. And finally, specific aim 3 will characterize LUVA cells and their activation in response to aspirin. In addition, we will define the factor secreted by LUVA cells that enhances eosinophil hematopoiesis and upregulation of LTC4S. PUBLIC HEALTH RELEVANCE: Aspirin-exacerbated respiratory disease (AERD) comprises 5-20% of adult asthmatics and is over-represented among severe asthmatics. Many features of AERD are poorly understood, including the basis for the pathognomonic upregulation of leukotriene production and responsiveness and the mechanism for the cellular activation that occurs after aspirin ingestion. We propose that these leukotrienes act through receptors unique to AERD and they interact with a previously unexplored mast cell-derived protein and IFN-3, features that may prove to be targets for therapeutic modulation.

描述（由申请人提供）：这些研究将集中于与阿司匹林糖尿病呼吸道疾病（AERD）有关的哮喘（和鼻窦炎）的细胞和免疫机制。我们的假设是，通过过度产生白细胞E4（LTE4），通过特定受体作用的白细胞E4（LTE4）与阿司匹林耐受性哮喘形成鲜明对比，并与interleukin（IL）-4和Interferon（INFERON）（IFN）（IFN）-3作用着炎性相互作用。我们还假设阿司匹林直接诱导AERD中的细胞活化。 AIRD是一种综合征，由严重的持续性哮喘，侵略性气道重塑，广泛的增生性嗜酸性鼻窦炎和鼻息肉（NP）形成，厌食以及阿司匹林的耐受性，其症状为特征，其特征在于鼻腔充满，rhinorrhea，以及鼻鼻，鼻式和生命的攻击。阿司匹林的不耐症部分反映了白三烯C4合酶（LTC4S）和白细胞三烯（CYSLT）受体表达的表达增加，结果，这些患者的组成型过度生产过度生产并增强了对Cyslts（尤其是LTE4）（尤其是LTE4）（尤其是LTE4）（尤其是LTE4），其爆炸性促进了Cyslt的生产效率促进性属性的促进性。我们假设识别LTE4的新型受体与AERD的病理生理有关。我们目前的研究利用了来自AIRD供体的永生肥大细胞系（“ LUVA”细胞）。这些细胞保留了肥大细胞的相关特征，包括拥有含有组胺的分泌颗粒和FC5RI1的表面表达。 LUVA细胞提供了一种新型模型，用于研究阿司匹林直接肥大细胞激活的先前未开发的分子基础，它们会随着颗粒含量的释放，Ca+2通量，蛛网氧化盐产物和从头合成的趋化因子的释放而做出反应。这些细胞产生一种分泌的蛋白质，该蛋白质当前没有任何其他表征的嗜酸性粒细胞激活因子，该因子可促进嗜酸性粒细胞造血，生存和LTC4S表达。我们将研究LUVA条件培养基（LCM）与嗜酸性粒细胞的相互作用，以进一步定义AERD病理生理学中心的机制。提出了三个特定的目标：具体目标1将表征LTE4通过AERD中LTE4特异性受体作用的影响。具体目标2将解决AERD中IL-4和IFN-3的重要性。尽管具有深度嗜酸性粒细胞的特征，但通常与嗜酸性粒细胞相关的细胞因子（例如IL-5）仅适度且可变地在AERD中表达，而AERD则表现出混合的Th1（IFN-3）/Th2（yil-4）细胞因子“ signature”。我们将重点关注IFN-3在促进嗜酸性粒细胞和增强的LTC4表达和CYSLT分泌方面的相对未开发的作用。我们将研究IFN-3使嗜酸性粒细胞对LTE4有反应的能力。最后，特定的目标3将表征LUVA细胞及其对阿司匹林的激活。此外，我们将定义LUVA细胞分泌的因素，从而增强嗜酸性粒细胞造血和LTC4的上调。 公共卫生相关性：阿司匹林发育的呼吸道疾病（AERD）占成人哮喘患者的5-20％，并且在严重的哮喘患者中被过度代表。 AERD的许多特征知之甚少，包括白细胞产生和反应性的病理上调的基础，以及阿司匹林摄入后发生的细胞激活机制。我们建议这些白细胞通过AERD独有的受体起作用，并与以前未开发的肥大细胞衍生的蛋白质和IFN-3相互作用，这些特征可能被证明是治疗性调节的靶标。