Cysteinyl leukotrienes in chronic sinusitis and asthma

这笔赠款将研究白介素4与白介素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(CysLts)，导致炎症、增生和 慢性增生性嗜酸性鼻窦炎(CHS)和阿司匹林加重时的气道重塑 呼吸道疾病(AERD)。AERD是一种以严重的持续性哮喘为特征的综合征，具有攻击性 呼吸道重塑，广泛增生性嗜酸性鼻窦炎并鼻息肉(NP)形成，以及 对阿司匹林不耐受。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。 阿司匹林耐受反映白三烯C4合成酶和CysLT受体表达增加 因此，这些受试者具有结构性的生产过剩和高度的反应性 敬CysLts。CysLTs通过与两种同源受体相互作用发挥作用 CysLT2基因在AERD中高表达。我们假设CysLts对 通过激活嗜酸性粒细胞，AERD的增殖、纤维化和重塑。这两条路径 负责CysLT的合成和CysLT受体的表达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- 介导炎症、粘液腺分泌和呼吸道平滑肌、上皮细胞增殖， 和内皮，导致纤维化。在具体目标#1中，我们将剖析CysLTI和 CysLT2受体在这些过程中的作用。我们的假设是，尽管CysLTI受体可能是唯一的 参与支气管痉挛的CysLT2受体依赖通路的上调更重要 CHES/AERD的重塑功能。特定目标#2将研究CysLT受体和 IL-4诱导表达LTC4S。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，作为疗效的治疗基础 这一过程的

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