Studies on the Pathogenesis of Chronic Rhinosinusitis

描述(申请人提供)：慢性鼻-鼻窦炎(CRS)的发病机制以黏膜上皮细胞和T细胞活化的炎症为特征。来自我们实验室的令人兴奋的新研究表明，鼻腔上皮细胞表达B7同系物，这是一种介导T细胞激活的专门分子。我们最近的体外研究表明，选定的B7同系物被细胞因子增加，而被糖皮质激素减少。我们假设上皮细胞表面分子(B7同源物、HLA-DR、Fas、Fas配体和CD40)可以作为疾病的标志物，鼻窦疾病的恶化将与上皮性共刺激因子的增加有关。根据我们的体外研究结果，我们假设糖皮质激素治疗会抑制上皮细胞的反应。这项建议中描述的研究的主要目标是使用一系列特定的和可重复性的分析来定量共刺激分子的表达来检验这些假说。AIM 1的研究将对对照组和4组CRS患者(CRS单独、CRS伴变应性鼻炎、CRS伴哮喘和CRS同时对哮喘和阿司匹林敏感(Samter‘s Triad))鼻窦上皮细胞共刺激分子的表达进行量化。共刺激分子的表达将用Taqman聚合酶链式反应和流式细胞仪分析。这些研究将通过使用来自相同受试者的外科组织的免疫组织化学研究来加强。AIM 2的研究将确定患者在病情恶化之前、期间和之后上皮共刺激分子的表达水平，以检验疾病恶化将与共刺激分子表达变化相关的假设。我们还将检查鼻腔内糖皮质激素治疗对共刺激分子表达的体内影响。AIM 3的研究将利用培养的上皮细胞来确定可能参与CRS的刺激(细胞因子、Toll样受体配体、人鼻病毒和真菌抗原)对共刺激分子表达的影响，并探讨其作用机制。我们希望这些研究将对调节慢性鼻窦炎上皮细胞的因素有新的认识。

DESCRIPTION (provided by applicant): The pathogenesis of chronic rhinosinusitis (CRS) is characterized by mucosal inflammation with activated epithelial cells and T cells. Exciting new studies from our laboratories show that nasal epithelial cells express B7 homologs, specialized molecules that mediate T cell activation. Our recent in vitro studies show that selected B7 homologs are increased by cytokines and decreased by glucocorticoids. We hypothesize that epithelial cell surface molecules (B7 homologs, HLA-DR, Fas, Fas ligand and CD40) can serve as markers of disease and that exacerbation of sinonasal disease will be associated with increased epithelial costimulators. Based upon our in vitro findings, we hypothesize and that glucocorticoid treatment will inhibit the epithelial response. The primary goal of the studies described in this proposal is to test these hypotheses using a host of specific and reproducible assays to quantitate costimulator expression. Studies in Aim 1 will quantitate expression of costimulatory molecules on sinonasal epithelial cells from control and 4 subgroups of CRS patients with defined disease (CRS alone, CRS with allergic rhinitis, CRS with asthma and CRS with both asthma and aspirin sensitivity (Samter's triad)). Expression of costimulators will be analyzed by Taqman PCR and flow cytometry. These studies will be reinforced by studies employing immunohistochemistry of surgical tissue from the same subjects. Studies in Aim 2 will determine levels of epithelial costimulatory molecule expression in patients before, during and after exacerbations to test the hypothesis that disease exacerbation will be associated with alterations of costimulator expression. We will also examine the in vivo effect of intranasal glucocorticoid treatment on costimulator expression. Studies in Aim 3 will utilize cultured epithelial cells to determine the influence of stimuli likely to participate in CRS (cytokines, toll-like receptor ligands, human rhinovirus and fungal antigens) on costimulator expression and to probe the mechanism of the effect. It is our hope that these studies will give new insight into the factors that modulate epithelial cells in chronic rhinosinusitis.