Pathogenesis of airway inflammation in refractory asthma.

在重症哮喘的发病过程中，嗜酸性粒细胞和中性粒细胞都起着重要的作用。我们之前报道了严重皮质类固醇依赖性哮喘患者诱导痰中中性粒细胞和嗜酸性粒细胞浓度呈正相关。此外，我们报道，即使在没有嗜酸性粒细胞的趋化剂的情况下，IL-8刺激的中性粒细胞也能够诱导嗜酸性粒细胞跨基底膜迁移，这表明IL-8刺激的中性粒细胞导致嗜酸性粒细胞在哮喘患者的气道中积聚。在本研究中，我们进一步阐明了难治性哮喘气道炎症的发病机制。我们发现严重哮喘患者诱导痰中IL-8的浓度高于轻度哮喘患者。此外，不稳定或严重哮喘患者EBC中TXB2或LTB4浓度也升高。干扰素增强内皮细胞嗜酸性粒细胞粘附诱导活性。沙丁胺醇增加变应性哮喘患者单核细胞的IL-13并降低IFN-γ的产生。最后，包括IP-10在内的CXCR3配体增加了嗜酸性粒细胞的粘附性和超氧阴离子的产生。这些发现被认为在严重哮喘的发病机制中起重要作用。

In the pathogenesis of severe asthma, not only eosinophils but also neutrophils play important roles. We previously reported a positive correlation between the concentrations of neutrophils and eosinophils in induced sputum from patients with severe, corticosteroid-dependent asthma. Furthermore, we reported that, even in the absence of chemoattractant for eosinophils, neutrophils stimulated by IL-8 are capable of inducing the trans-basement membrane migration of eosinophils, suggesting that IL-8-stimulated neutrophils lead eosinophils to accumulate in the airways of asthmatic patients. In this study, we further elucidated the pathogenesis of airway inflammation in refractory asthma. We found that concentrations of IL-8 in induced sputa are higher in severe asthmatics than in mild asthmatics. Further, concentrations of TXB2 or LTB4 in EBC also increased in unstable or severe asthma. IFNs augment eosinophil adhesion-inducing activity of endotherial cells. Salbutamol increases IL-13 and decreases IFN-γ production by mononuclear cells from allergic asthmatics. Finally, CXCR3 ligands including IP-10 increase adhesiveness and superoxide anion production of eosinophils. These findings are thought to play important roles in the pathogenesis of severe asthma.