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(IL)-4之间的促炎反馈反应