Ntinopoulou Maria, Cassimos Dimitrios, Roupakia Eugenia, Kolettas Evangelos, Panopoulou Maria, Mantadakis Elpis, Konstantinidis Theocharis, Chrysanthopoulou Akrivi
Laboratory of Molecular Immunology, Department of Biological Applications and Technology, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece.
Department of Pediatrics, University General Hospital of Alexandroupolis, Democritus University of Thrace Medical School, 68100 Thrace, Greece.
Biomedicines. 2023 Jul 26;11(8):2104. doi: 10.3390/biomedicines11082104.
Childhood asthma is a chronic inflammatory airway disorder that can drive tissue remodeling. Neutrophils are amongst the most prominent inflammatory cells contributing to disease manifestations and may exert a potent role in the progression of inflammation to fibrosis. However, their role in asthma exacerbation is still understudied. Here, we investigate the association between neutrophil extracellular traps (NETs) and lung fibroblasts in childhood asthma pathophysiology using serum samples from pediatric patients during asthma exacerbation. Cell-based assays and NETs/human fetal lung fibroblast co-cultures were deployed. Increased levels of NETs and interleukin (IL)-17A were detected in the sera of children during asthma exacerbation. The in vitro stimulation of control neutrophils using the sera from pediatric patients during asthma exacerbation resulted in IL-17A-enriched NET formation. The subsequent co-incubation of lung fibroblasts with in vitro-generated IL-17A-enriched NETs led fibroblasts to acquire a pre-fibrotic phenotype, as assessed via enhanced CCN2 expression, migratory/healing capacity, and collagen release. These data uncover the important pathogenic role of the NET/IL-17A axis in asthma exacerbation, linking lung inflammation to fibroblast dysfunction and fibrosis.
儿童哮喘是一种可导致组织重塑的慢性炎症性气道疾病。中性粒细胞是导致疾病表现的最主要炎症细胞之一，可能在炎症进展为纤维化过程中发挥重要作用。然而，它们在哮喘急性加重中的作用仍未得到充分研究。在此，我们使用哮喘急性加重期儿科患者的血清样本，研究中性粒细胞胞外诱捕网（NETs）与肺成纤维细胞在儿童哮喘病理生理学中的关联。我们采用了基于细胞的检测方法以及NETs/人胎儿肺成纤维细胞共培养。在哮喘急性加重期儿童的血清中检测到NETs和白细胞介素（IL）-17A水平升高。使用哮喘急性加重期儿科患者的血清对对照中性粒细胞进行体外刺激，导致富含IL-17A的NET形成。随后，将肺成纤维细胞与体外生成的富含IL-17A的NETs共同孵育，结果显示成纤维细胞获得了纤维化前表型，这通过增强的CCN2表达、迁移/愈合能力和胶原蛋白释放得以评估。这些数据揭示了NET/IL-17A轴在哮喘急性加重中的重要致病作用，将肺部炎症与成纤维细胞功能障碍及纤维化联系起来。
