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: 7167443
• 负责人: LARRY C BORISH
• 金额: $ 36.78万
• 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/7167443
• 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; concept; cysteinyl leukotriene receptor 2; cysteinyl-leukotriene; cytokine; desensitization; eosinophil; human IRS2 protein; in vivo; leukotriene-C4 synthase; promoter; receptor; receptor expression; respiratory smooth muscle; transcription factor

DESCRIPTION (provided by applicant): 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

描述(申请人提供)：这笔赠款将研究白介素4(和其他细胞因子)和半胱氨酰白三烯(CysLTs)之间的促炎反馈反应，该反应导致慢性增生性嗜酸性鼻窦炎(CHS)和阿司匹林加重的呼吸系统疾病(AERD)观察到的炎症、增殖和呼吸道重塑。AERD是一种以严重持续性哮喘、侵袭性呼吸道重塑、广泛增生性嗜酸性鼻窦炎并鼻息肉(NP)形成和阿司匹林耐受为特征的综合征。嗜酸性粒细胞在与哮喘和CHS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合成酶(LTC4S)的表达增加和CysLT受体的表达，结果是，这些受试者有结构性的过量生产和对CysLts的高反应性。CysLts通过与两个同源受体CysLTI和CysLT2相互作用发挥作用，这两个受体在AERD中都高度上调。我们推测CysLTs通过激活嗜酸性粒细胞参与了AERD的增殖、纤维化和重塑。负责CysLT合成的途径和CysLT受体的表达都受到细胞因子的严格调控，尤其是IL-4。CysLTs和IL-4之间的这种促炎反馈促进了嗜酸性粒细胞介导的炎症、粘液腺分泌和气道平滑肌、上皮和内皮的增殖，从而导致纤维化。在特定的目标#1中，我们将剖析CysLTI和CysLT2受体在这些过程中的单独作用。我们的假设是，虽然CysLTI受体可能是唯一参与支气管痉挛的因素，但CysLT2受体依赖的通路上调在CHES/AERD中具有更重要的重塑功能。具体目标#2将研究IL-4对CysLT受体和LTC4S表达的调节。最后，阿司匹林脱敏是治疗AERD的有效方法。因此，具体目标#3将研究阿司匹林对IL-4的拮抗作用，作为这一过程疗效的治疗基础。