Cysteinyl leukotrienes in chronic sinusitis and asthma

描述（由申请人提供）：该基金将研究白细胞介素（IL）-4（和其他细胞因子）与半胱氨酰白三烯（CysLT）之间发生的促炎反馈反应，该反应导致慢性增生性嗜酸性鼻窦炎（CHES）和阿司匹林加重呼吸道疾病（AERD）中观察到的炎症、增生和气道重塑。AERD是一种以严重持续性哮喘、侵袭性气道重塑、广泛增生性嗜酸性鼻窦炎伴鼻息肉（NP）形成和阿司匹林不耐受为特征的综合征。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受体表达的表达增加，因此，这些受试者具有组成性过度产生和对CysLT的反应性提高。CysLT通过其与两种同源受体相互作用的能力发挥作用：CysLTI和CysLT 2，这两种受体在AERD中均高度上调。我们假设CysLT通过激活嗜酸性粒细胞促进AERD的增生、纤维化和重塑。负责CysLT合成的途径和CysLT受体的表达都受到细胞因子（主要包括IL-4）的严格调节。CysLT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、粘液腺分泌以及气道平滑肌、上皮和内皮的增殖，导致纤维化。在具体目标#1中，我们将剖析CysLTI和CysLT 2受体在这些过程中的各自作用。我们的假设是，虽然CysLTI受体可能是唯一参与支气管痉挛，上调CysLT 2受体依赖性途径有更重要的重塑功能CHES/AERD。具体目标#2将研究IL-4对CysLT受体和LTC 4S表达的调节。最后，阿司匹林脱敏是AERD的有效治疗方法。因此，具体目标#3将研究阿司匹林对IL-4的拮抗作用，作为该程序疗效的治疗基础

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