Cysteinyl leukotrienes in chronic sinusitis and asthma

半胱氨酰白三烯在慢性鼻窦炎和哮喘中的作用

• 批准号: 7561648
• 负责人: LARRY C BORISH
• 金额: $ 36.08万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561648
• 关键词: Address; Affinity; Agonist; Allergic; Aspirin; Asthma; Biological; Biological Assay; Bronchial Spasm; Chronic; Chronic Sinusitis; Cloning; Data; Disease; Electrophoretic Mobility Shift Assay; Endothelium; Epithelium; Feedback; Fibrosis; Genes; Genetic Transcription; Gland; Grant; Hyperplasia; Individual; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interleukins; Investigation; Knockout Mice; Leukotrienes; Lung diseases; Mediating; Molecular; Mucous body substance; Nasal Polyps; Occupations; Pathway interactions; Procedures; Process; Production; Reaction; Regulation; Reporting; Research Personnel; Role; Signaling Protein; Sinusitis; Site; Syndrome; Therapeutic; Transcriptional Regulation; Up-Regulation; Work; airway remodeling; base; cysteinyl leukotriene receptor 2; cysteinyl-leukotriene; cytokine; desensitization; effective therapy; eosinophil; human IRS2 protein; in vivo; leukotriene-C4 synthase; promoter; receptor; receptor expression; respiratory smooth muscle; transcription factor

This grant will investigate the pro-inflammatory feedback reaction that develops between interleukin (IL)-4 (and other cytokines) and cysteinyl leukotrienes (CysLTs) that leads to the inflammation, hyperplasia, and airway remodeling observed in chronic hyperplastic eosinophilic sinusitis (CHES) and asprin-exacerbated respiratory disease (AERD). AERD is a syndrome characterized by severe persistent asthma, aggressive airway remodeling, extensive hyperplastic eosinophilic sinusitis with nasal polyp (NP) formation, and intolerance to aspirin. Eosinophils are essential to the fibrotic processes associated with asthma and CHES. Aspirin intolerance reflects increased expression of leukotriene C4 synthase (LTC4S) and CysLT receptor expression and, as a result, these subjects have constitutive overproduction and heightened responsiveness to CysLTs. CysLTs function through their ability to interact with two homologous receptors: CysLTI and CysLT2 both of which are highly upregulated in AERD. We hypothesize that CysLTs contribute to the hyperplasia, fibrosis, and remodeling of AERD through their activation of eosinophils. Both the pathway responsible for CysLT synthesis and the expression of CysLT receptors are tightly regulated by cytokines, including prominently, IL-4. This pro-inflammatory feedback between CysLTs and IL-4 promotes eosinophil- mediated inflammation, mucus gland secretion, and the proliferation of airway smooth muscle, epithelium, and endothelium, leading to fibrosis. In specific aim #1 we will dissect individual roles for CysLTI and CysLT2 receptors in these processes. Our hypothesis is that whereas the CysLTI receptor may be uniquely involved in bronchospasm, the upregulation of CysLT2 receptor-dependent pathways has more important remodeling functions in CHES/AERD. Specific aim #2 will investigate the regulation of CysLT receptors and LTC4S expression by IL-4. Finally, aspirin desensitization is an effective treatment for AERD. Therefore specific aim #3 will investigate the role of IL-4 antagonism by aspirin as the therapeutic basis for the efficacy of this procedure

该基金将研究白细胞介素-4（IL-4）与炎症反应之间的促炎反馈反应。 (and其他细胞因子）和半胱氨酰白三烯（CysLT），其导致炎症、增生和 在慢性增生性嗜酸性鼻窦炎（CHES）中观察到气道重塑， 呼吸系统疾病（AERD）。AERD是一种以严重的持续性哮喘、侵袭性哮喘、呼吸道感染和哮喘发作为特征的综合征。 气道重塑，广泛增生性嗜酸性鼻窦炎伴鼻息肉（NP）形成， 阿司匹林不耐受嗜酸性粒细胞在与哮喘和CHES相关的纤维化过程中是必不可少的。 阿司匹林不耐受反映了白三烯C4合酶（LTC 4S）和CysLT受体表达增加 因此，这些受试者具有结构性过度生产和高度反应性 到CysLT CysLT通过其与两种同源受体相互作用的能力发挥作用：CysLTI和CysLTI。 CysLT 2两者在AERD中均高度上调。我们假设CysLTs有助于 增生、纤维化和通过嗜酸性粒细胞活化的AERD重塑。这两种途径 负责CysLT合成和CysLT受体的表达受到细胞因子的严格调节， 主要包括IL-4。CysLTs和IL-4之间的这种促炎反馈促进嗜酸性粒细胞- 介导的炎症，粘液腺分泌，和气道平滑肌，上皮， 和内皮细胞，导致纤维化在具体目标1中，我们将剖析CysLTI的个体作用， 这些过程中的CysLT 2受体。我们的假设是，虽然CysLTI受体可能是唯一的 在支气管痉挛中，CysLT 2受体依赖性途径的上调具有更重要的意义。 CHES/AERD中的重塑功能。具体目标#2将研究CysLT受体的调节， 通过IL-4表达LTC 4S。最后，阿司匹林脱敏是AERD的有效治疗方法。因此 具体目标#3将研究阿司匹林的IL-4拮抗作用作为疗效的治疗基础 本程序