背景:kallistatin在气道炎症中的作用,特别是慢性鼻窦炎伴鼻息肉(CRSwNP),尚未阐明。
目的:我们试图研究kallistatin在气道炎症中的作用。
方法:检测鼻息肉组织中Kallistatin和促炎细胞因子的表达水平。对于体内研究,我们构建了过表达kallistatin的转基因小鼠,以阐明kallistatin在气道炎症中的作用。此外,在2型炎症背景下,在kallistatin-/-大鼠体内模型中评估了气道中血浆IgE和促炎细胞因子的水平。最后,探索Notch信号通路以了解kallistatin在CRSwNP中的作用。
结果:我们显示,鼻息肉中的kallistatin表达明显高于正常鼻黏膜,并与IL-4表达相关。我们还发现过表达kallistatin的转基因小鼠的鼻粘膜表达更高水平的IL-4表达,与TH2型炎症相关。有趣的是,与野生型屋尘螨组相比,屋尘螨变应原治疗的kallistatin-/-组鼻粘膜IL-4水平较低,血浆总IgE较低.最后,我们观察到腺病毒-kallistatin转导的鼻上皮细胞中Jagged2的表达显着增加。这种升高的表达与IL-4的分泌增加相关,这归因于CD4+CD45+Notch1+T细胞群体的增加。这些发现共同可能有助于TH2型炎症的诱导。
结论:已证明Kallistatin通过增强TH2炎症参与CRSwNP的发病机制,发现这与IL-4的更多表达有关,可能通过CD4+T细胞中的Jagged2-Notch1信号传导促进。
BACKGROUND: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated.
OBJECTIVE: We sought to investigate the role of kallistatin in airway inflammation.
METHODS: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in CRSwNP.
RESULTS: We showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin-overexpressing transgenic mice expressed higher levels of IL-4 expression, associating to TH2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite allergen compared with the wild-type house dust mite group. Finally, we observed a significant increase in the expression of Jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of TH2-type inflammation.
CONCLUSIONS: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the TH2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.