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

慢性鼻窦炎分为变态反应相关和非变态反应相关，突出了细胞分布和鼻窦粘膜细胞因子表达的异质性。最近的研究表明，嗜酸性粒细胞在非传染性慢性鼻窦炎的持续性炎症中起中心作用。在本课题中，我们探讨了鼻窦炎中嗜酸性粒细胞浸润与变应性鼻炎的关系。1)我们发现变态反应素质与鼻窦CT检查和评分的鼻窦混浊程度密切相关。高嗜酸性粒细胞浸润者往往表现为弥漫性鼻窦病变，不仅局限于鼻侧壁窦口周围。2)检测鼻窦黏膜细胞因子的表达及CD4阳性细胞亚群的分布。低嗜酸性粒细胞仅表现为干扰素-γ基因表达增加。相比之下，其他患者表现出类似的…GM-CSF、IL-5、嗜酸性粒细胞趋化蛋白mRNA高表达的细胞因子谱更多。CCR4阳性的CD4+细胞在高嗜酸性粒细胞增多，导致CXCR3+/CCR4+细胞比例降低。这些发现支持慢性鼻窦炎是Th2介导的疾病过程的概念。3)我们检测了在培养的鼻窦上皮细胞中转录因子NF-κB的激活及其伴随的细胞因子的表达。经肿瘤坏死因子-α治疗后，核因子-κB的活化程度明显增强。此外，地塞米松可有效抑制培养细胞中核因子-κB的激活，并呈剂量依赖性。免疫细胞化学分析也证实了p50亚单位的细胞易位，并伴随着糖皮质激素受体的表达。这些结果阐明了维持鼻窦粘膜结构性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之间的直接因果联系。较少

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