Mechanism of eosinophil infiltration in the patients with allergic rhinitis and the interaction between inflammatory cells and epithelial cells as well as endothelial cells

嗜酸性粒细胞在变应性疾病，包括哮喘、变应性鼻炎和特应性皮炎的发展中起核心作用。体内嗜酸性粒细胞的迁移受多种细胞因子和趋化因子的调节。越来越多的证据表明，嗜酸性粒细胞趋化因子是组织嗜酸性粒细胞发展的关键介质。我们证明，eotaxin上调细胞间粘附分子-1（ICAM-1）和血管细胞（HMMEC）的表达，但不上调人脐静脉内皮细胞（HUVEC）。嗜酸性粒细胞趋化因子诱导的嗜酸性粒细胞粘附HMMEC也增加。然而，在HUVEC上，eotaxin并不诱导嗜酸性粒细胞粘附的增加。抗ICAM-1和抗VCAM-1单克隆抗体显着降低嗜酸性粒细胞趋化因子诱导的嗜酸性粒细胞粘附。这些结果表明，嗜酸性粒细胞趋化因子通过影响微血管内皮细胞上的粘附分子来调节嗜酸性粒细胞向鼻粘膜的聚集，我们还表明IL-13和IL-4在嗜酸性粒细胞趋化因子介导的鼻粘膜嗜酸性粒细胞聚集中可能是重要的。 ...更多信息 成纤维细胞是鼻粘膜中嗜酸性粒细胞趋化因子的主要细胞来源。还研究了通过CCR3的信号转导依赖于蛋白酪氨酸激酶和细胞外钙。在内皮细胞中，信号通路将不同于嗜酸性粒细胞和成纤维细胞。与内皮细胞一起培养的嗜酸性粒细胞通过用嗜酸性粒细胞趋化因子和嗜酸性粒细胞趋化因子-2刺激而显示出与单一培养不同的行为。所有鼻变态反应患者鼻灌洗液中Eotaxin水平在抗原激发后30min达到最高值，2hr后恢复至激发前水平。然而，在对照组中，抗原攻击前和抗原攻击后的嗜酸性粒细胞趋化因子水平没有显著差异。灌洗液样本中的嗜酸性粒细胞趋化因子水平与灌洗液中的嗜酸性粒细胞计数和EPX水平显著相关。PAF与嗜酸性粒细胞计数或EPX之间没有观察到相关性，IL-16与嗜酸性粒细胞计数或EPX之间也没有关系。这些结果表明，嗜酸性粒细胞趋化因子是鼻粘膜嗜酸性粒细胞炎症的重要因子之一，与其它嗜酸性粒细胞趋化因子不同，嗜酸性粒细胞趋化因子具有嗜酸性粒细胞特异性，因为它的特异性受体CCR-3在嗜酸性粒细胞上表达，而在中性粒细胞上不表达。在这项研究中，我们表明，IL-4诱导CCR-3的剂量依赖性物质。它是公认的，E-钙粘蛋白是一种有效的细胞粘附分子，在维持上皮的结构和功能的刚性不可或缺。我们证明了炎性细胞的跨上皮迁移可以直接诱导上皮E-钙粘蛋白表达的降低。此外，最显著的变化是由活化的嗜酸性粒细胞的迁移引起的，这可能是由一些独立于嗜酸性粒细胞含量的机制引起的。E-钙粘蛋白表达的降低可能引发上皮屏障的损伤，从而参与变态反应性疾病的发生。少

Eosinophil play a central role in the development of allergic diseases, including asthma, allergic rhinitis and atopic dermatitis. Eosinophil migration in vivo is regulated by many cytokines and chemokines. There is increasing evidence that eotaxin is a key mediator in the development of tissue eosinophila. We demonstrated that eotaxin upregulated the expression of intercellular dahesion molecule-1(ICAM-1) and vascular cells (HMMEC), but not human umbilical vein endothelial cells(HUVEC). The eotaxin-induced eosinophil adhesion to HMMEC was also increased. On HUVEC, however, eotaxin did not induce increases of eosinophil adhesion. Anti-ICAM-1 and anti-VCAM-1 mAbs significantly decreased eotaxin-induced eosinophil adhesion. These results suggest that eotaxin regulates eosinophil accumulation to the nasal mucosa through its effect on the adhesion molecules on microvascular endothelial cells.We also indicated that IL-13, as well as IL-4, may be important in eotaxin mediated eosinophilic in … More flammation and that fibroblasts are the major cell source for eotaxin in nasal mucosa. Signal transduction through CCR3 depends on protein tyrosin kinase and extracellular calcium was also studied. In endothelial cells, the signaling pathway will be different form eosinophil and fibroblast. Eosinophils cultured with endothilial cells show different behavior from single culture by stimulus with eotaxin and eotaxin-2. This indicates there exists a certain established system seems to cause the signal transfer between eosinophils and endothelial cells.In all patients with nasal allergy, eotaxin levels in nasal lavage fluids reached to the maximum value 30 min after antigen challenge and returned to the pre-challenge values 2hr after nasal antigen challenge. In the control group, however, no significant differences were noted in the eotaxin level between before antigen challenge and after antigen challenge. The levels of eotaxin in lavage samples correlated significantly with lavage levels of eosinophil counts and EPX. No relationship was observe between PAF and eosinophil counts or EPX, nor was there a relationship between IL-16 and eosinophil counts or EPX. These results strongly suggest that eotaxin is one of the most improtant factor in eosinophilic inflammation in nasal mucosa.Unlike other eosinophil chemoattractants, eotaxin is eosinophil specific, because its specific receptor, CCR-3, is expressed on eosinophils but not on neutrophils. In this study we showed that IL-4 induces CCR-3 in dose dependent matter. It is well recognized that E-cadherin is a potent cell adhesion molecule indispensable in the maintenance of the structural and functional rigidity of the epithelium. We demonstrated that transepithelial migration of inflammatory cells can directly induce the decrease in epithelial E-cadherin expression. Furthemore, the most prominent change was induced by transmigration of activated eosinophils, which might be caused by some mechanisms independent of the eosinophil contents. The decrease in E-cadherin expression may trigger the damage of epithelial barrier, which contributes to the pathogenesis of allergic diseases. Less