Molecular analysis of persistency of chronic sinus inflammation in relation to allergic diathesis.

将慢性鼻窦炎分为过敏相关性和非过敏相关性突出了窦粘膜中细胞谱和细胞因子表达的异质性。最近的研究表明，嗜酸性粒细胞在非感染性慢性鼻窦炎的持续炎症中起着重要作用。在本项目中，我们研究了嗜酸性粒细胞浸润在鼻窦炎中与变应性鼻炎的关系。1）我们发现变应性素质与鼻窦混浊程度之间存在密切关系，并通过计算机断层扫描进行评分。高嗜酸性粒细胞浸润的患者倾向于表现为弥漫性鼻窦疾病，而不仅仅局限于鼻侧壁鼻窦口周围区域。2）我们检测了鼻窦粘膜中细胞因子的表达和CD 4阳性细胞亚群的分布。低嗜酸性粒细胞数的患者仅显示IFN-γ mRNA表达增加。相比之下，其他患者表现出类似的 ...更多信息 GM-CSF、IL-5、嗜酸性粒细胞趋化因子mRNA的细胞因子谱具有高表达水平。CCR 4阳性CD 4+细胞在高嗜酸性粒细胞增多患者中也显著较高，导致CXCR 3 +/CCR 4+细胞比率降低。这些发现为慢性鼻窦炎是Th 2介导的疾病过程的概念提供了支持。3）我们检测了培养的鼻窦上皮细胞中TNF-α刺激触发的转录因子NF-κB激活和伴随的细胞因子表达。TNF-α处理显著增加NF-κB活化程度。地塞米松预处理能有效抑制NF-κB的活化，并呈剂量依赖性。免疫细胞化学分析也证实了p50亚基的细胞易位，强烈的核染色以及伴随的糖皮质激素受体的表达。这些结果阐明了维持窦粘膜组成性NF-κB活性的分子机制，并将提供嗜酸性粒细胞募集与慢性炎症持续性之间的直接因果关系。少

The division of chronic sinusitis into allergy-associated and non-allergy associated highlights heterogenecity in the celluar profile and the cytokine expression involved in the sinus mucosa. Recent studies have implicated eosinophils as a central player in the persistent inflammation occurring in non-infectious chronic sinusitis. In the present project, we have investigated mechanisms of eosinophil infiltration in sinusitis in relation to allergic rhinitis.1)We found intimate relation between allergic diathesis and the degree of sinus opacification examined and scored by computed tomography. Patients with high eosinophil infiltration tended to show diffuse sinus diseases not only restricted to the region around the sinus ostia in the lateral nasal wall.2)We examined cytokine expression and the distribution of CD4-positive cell subsets in the sinus mucosa. The patients with low eosinophilia only showed an increase in IFN-γ mRNA expression. In contrast, the other patients showed similar … More cytokine profiles with high expression levels for GM-CSF, IL-5, eotaxin mRNA. CCR4-positive CD4+ cells were also significantly higher in patients with high eosinophilia, leading to decreased CXCR3+/ CCR4+ cell ratio. These findings provide support for the concept of chronic sinusitis as a Th2-mediated disease process.3)We examined transcription factor NF-κB activation and concomitant cytokine expression triggered by TNF-α stimulus in cultured sinus epithelial cells. Treatment with TNF-α significantly augmented the degree of NF-κB activation. Further, pretreatment with dexamethazone effectively inhibited the NF-κB activation dose-dependently in the cultured cells. Immunocytochemical analysis also confirmed cellular translocation of p50 subunits with intense nuclear staining as well as concomitant expression of glucocorticoid receptors. These results elucidate the molecular mechanisms responsible for the maintenance of constitutive NF-κB activity in sinus mucosa and would provide a direct causal link between the recruitment of eosinophils and persistence of chronic inflammation. Less