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: 7103793
• 负责人: LARRY C BORISH
• 金额: $ 37.98万
• 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/7103793
• 关键词: aspirin; asthma; clinical research; cytokine; eosinophil; fibrosis; hyperplasia; inflammation; lead; leukotrienes; receptor; receptor expression; role; sinusitis

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（由申请人提供）：该赠款将调查介绍反馈反应（IL）-4（IL）-4（以及其他细胞因子）和白细胞藻（Cyslts）之间会导致炎症，增生和气道重塑的炎症，增生和气道重塑，在术中观察到了炎症，增生性增生性呼吸症和呼吸道呼吸症（Chessiral e酶）（CHSE），并发生了呼吸道呼吸症（Cyslatiratiral osinbric）（Chessiric osinbiric sinositis and Sinosisis）（Cyslts）（Cyslts）。 （Aerd）。 AERD是一种综合征，其特征是严重持续性哮喘，侵略性气道重塑，广泛的增生性嗜酸性鼻窦炎，鼻息肉（NP）形成以及对阿司匹林的不耐受。嗜酸性粒细胞对于与哮喘和CHE相关的纤维化过程至关重要。阿司匹林不耐症反映了白细胞C4合酶（LTC4S）和CYSLT受体表达的表达增加，因此，这些受试者具有组成型过度生产和对CYSLT的反应性提高。 Cyslts通过与两个同源受体相互作用的能力（Cyslti和Cyslt2）在AERD中高度上调。我们假设CYSLT通过嗜酸性粒细胞的激活有助于AERD的增生，纤维化和重塑。负责CYSLT合成的途径和CYSLT受体的表达均受到细胞因子的严格调节，其中包括显着的IL-4。 CYSLT和IL-4之间的这种促炎性反馈促进了嗜酸性粒细胞介导的炎症，粘液腺体分泌以及气道平滑肌，上皮和内皮的增殖，从而导致纤维化。在特定的目标＃1中，我们将在这些过程中剖析CYSLTI和CYSLT2受体的各个角色。我们的假设是，尽管Cyslti受体可能与支气管痉挛有关，但Cyslt2受体依赖性途径的上调在CHES/AERD中具有更重要的重塑功能。特定的目标＃2将研究IL-4对CYSLT受体和LTC4表达的调节。最后，阿司匹林脱敏是对AIRD的有效治疗方法。因此，特定的目标＃3将研究阿司匹林作为该程序有效性的治疗基础IL-4拮抗作用