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: 7761238
• 负责人: LARRY C BORISH
• 金额: $ 35.72万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761238
• 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

这笔赠款将研究白细胞介素 (IL)-4 之间产生的促炎反馈反应 （和其他细胞因子）和半胱氨酰白三烯 (CysLT) 会导致炎症、增生和 在慢性增生性嗜酸性粒细胞性鼻窦炎（CHES）和阿司匹林恶化的情况下观察到气道重塑 呼吸道疾病（AERD）。 AERD 是一种以严重持续性哮喘、侵袭性哮喘为特征的综合征 气道重塑、广泛增生性嗜酸性鼻窦炎伴鼻息肉 (NP) 形成，以及 对阿司匹林不耐受。嗜酸性粒细胞对于与哮喘和 CHES 相关的纤维化过程至关重要。 阿司匹林不耐受反映白三烯 C4 合酶 (LTC4S) 和 CysLT 受体表达增加 表达，因此，这些受试者具有本构性过剩和更高的反应能力 至 CysLT。 CysLT 通过与两种同源受体相互作用的能力发挥作用：CysLTI 和 CysLT2 两者在 AERD 中均高度上调。我们假设 CysLT 有助于 通过嗜酸性粒细胞的激活来实现 AERD 的增生、纤维化和重塑。两条路 负责 CysLT 合成，CysLT 受体的表达受到细胞因子的严格调控， 主要包括 IL-4。 CysLT 和 IL-4 之间的促炎反馈可促进嗜酸性粒细胞 介导炎症、粘液腺分泌以及气道平滑肌、上皮细胞的增殖， 和内皮细胞，导致纤维化。在具体目标 1 中，我们将剖析 CysLTI 的个人角色和 CysLT2 受体参与这些过程。我们的假设是，虽然 CysLTI 受体可能是独特的 参与支气管痉挛，CysLT2受体依赖性途径的上调更为重要 CHES/AERD 中的重构功能。具体目标#2 将研究 CysLT 受体的调节和 IL-4 表达 LTC4S。最后，阿司匹林脱敏是治疗 AERD 的有效方法。所以 具体目标#3将研究阿司匹林拮抗IL-4的作用，作为疗效的治疗基础 这个程序的