Functional analysis of eosinophil infiltration mechanisms in chronic sinusitis in relation to transcription factor activation

近几十年来，副鼻窦感染的整体病理观点发生了深刻的变化和发展。通过各种细胞因子和趋化因子的释放，局部嗜酸性粒细胞募集与鼻窦疾病的程度密切相关。在本研究中，我们研究了慢性鼻窦炎嗜酸性粒细胞浸润与转录因子激活的关系机制1)我们检测了细胞因子的表达和cd4阳性细胞亚群在鼻窦粘膜的分布。低嗜酸性粒细胞患者仅显示IFN-γ mRNA表达增加。相比之下，其他患者表现出相似的细胞因子谱，GM-CSF、IL-5、eotaxin mRNA的高表达水平，CCR4阳性CD4+细胞在嗜酸性高的患者中也显著升高，导致CXCR3+/ CCR4+细胞比例降低。这些发现为慢性鼻窦炎是th2介导的疾病过程的概念提供了支持2)我们进一步研究了核因子κB （NF-κB）的激活是否发生在鼻窦粘膜，并与局部细胞因子基因表达的激活程度有关。p50亚基的细胞质和细胞核定位主要在上皮层。上皮细胞NF-κB活化程度与IL-8、IL-16和eotaxin mRNA水平呈显著相关。通过启动相关细胞因子的转录途径，这种激活似乎负责嗜酸性粒细胞的募集。3)我们在培养的窦上皮细胞中检测了TNF-α刺激引发的NF-κB激活和伴随的细胞因子表达。TNF-α治疗可使NF-κB活化程度提高2.3倍。免疫细胞化学也显示强烈的核染色，刺激后细胞质染色增加。此外，丙酸氟替卡松和白三烯拮抗剂均能有效抑制培养细胞的活化。这些结果阐明了维持窦黏膜构成性NF-κB活性的分子机制，并提供了嗜酸性粒细胞募集与慢性炎症持续之间的直接因果关系

The overall pathological view of paranasal sinus infection has profoundly changed and evolved in recent decades. A close correlation has been noted between local eosinophil recruitment and the extent of sinus disease through the release of various cytokines and chemokines. In the present study, we have investigated mechanisms of eosinophil infiltration in chronic sinusitis in relation to transcription factor activation1) 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 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 process2) We examined whether … More the activation of nuclear factor-kappa B (NF-κB) occurred in the sinus mucosa and related the degree of activation to local cytokine gene expression. Both cytoplasmic and nuclear localization of the p50 subunit was observed mainly in the epithelial layer. Significant correlations were observed between the degree of epithelial NF-κB activation and the levels of IL-8, IL-16, and eotaxin mRNA. The activation appears responsible for the recruitment of eosinophils through the initiation of the transcriptional pathway of the related cytokines3) We examined NF-κB activation and concomitant cytokine expression triggered by TNF-α stimulus in cultured sinus epithelial cells. Treatment with TNF-α augmented the degree of NF-κB activation by 2.3 folds. Immunocytochemistry also showed intense nuclear staining with increased staining in the cytoplasm occurred after stimulation. Further, both fluticasone propionate and leukotriene antagonists effectively inhibited the activation in the cultured cells. 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