In asthma, the airway epithelium has an impaired capacity to differentiate and plays a key role in the development of airway inflammation and remodeling through mediator release. The study objective was to investigate the release of (IL)-1 family members from primary airway epithelial-cells during differentiation, and how they affect primary airway fibroblast (PAF)-induced inflammation, extracellular matrix (ECM) production, and collagen I remodeling. The release of IL-1α/β and IL-33 during airway epithelial differentiation was assessed over 20-days using air-liquid interface cultures. The effect of IL-1 family cytokines on airway fibroblasts grown on collagen-coated well-plates and 3-dimensional collagen gels was assessed by measurement of inflammatory mediators and ECM proteins by ELISA and western blot, as well as collagen fiber formation using non-linear optical microscopy after 24-hours. The production of IL-1α is elevated in undifferentiated asthmatic-PAECs compared to controls. IL-1α/β induced fibroblast pro-inflammatory responses (CXCL8/IL-8, IL-6, TSLP, GM-CSF) and suppressed ECM-production (collagen, fibronectin, periostin) and the cell’s ability to repair and remodel fibrillar collagen I via LOX, LOXL1 and LOXL2 activity, as confirmed by inhibition with β-aminopropionitrile. These data support a role for epithelial-derived-IL-1 in the dysregulated repair of the asthmatic-EMTU and provides new insights into the contribution of airway fibroblasts in inflammation and airway remodeling in asthma.

在哮喘中，气道上皮的分化能力受损，在气道炎症的发展和通过介质释放的重塑中起关键作用。研究目的是研究分化期间主要气道上皮细胞的（IL）-1家族成员释放，以及它们如何影响主要气道成纤维细胞（PAF）诱导的炎症，细胞外基质（ECM）产生和胶原I重塑。使用气液界面培养法评估了20天内气道上皮分化过程中IL-1α/β和IL-33的释放。通过ELISA和Western blot检测炎症介质和ECM蛋白，评估了IL-1家族细胞因子对胶原包被的多孔板和3维胶原凝胶上生长的气道成纤维细胞的影响，以及24小时后使用非线性光学显微镜观察胶原纤维的形成。与对照组相比，未分化的哮喘PAECs中IL-1α的产生增加。IL-1α/β诱导成纤维细胞促炎反应（CXCL8 / IL-8，IL-6，TSLP，GM-CSF）并抑制ECM产生（胶原蛋白，纤连蛋白，骨膜素）以及细胞修复和重塑纤维状胶原的能力I通过LOX，LOXL1和LOXL2活性，如通过β-氨基丙腈的抑制所证实的。这些数据支持上皮来源的IL-1在哮喘性EMTU失调修复中的作用，并为气道成纤维细胞在哮喘炎症和气道重塑中的作用提供了新的见解。IL-1α/β诱导成纤维细胞促炎反应（CXCL8 / IL-8，IL-6，TSLP，GM-CSF）并抑制ECM产生（胶原蛋白，纤连蛋白，骨膜素）以及细胞修复和重塑纤维状胶原的能力I通过LOX，LOXL1和LOXL2活性，如通过β-氨基丙腈的抑制所证实的。这些数据支持上皮来源的IL-1在哮喘性EMTU失调修复中的作用，并为气道成纤维细胞在哮喘炎症和气道重塑中的作用提供了新的见解。IL-1α/β诱导成纤维细胞促炎反应（CXCL8 / IL-8，IL-6，TSLP，GM-CSF）并抑制ECM产生（胶原蛋白，纤连蛋白，骨膜素）以及细胞修复和重塑纤维状胶原的能力I通过LOX，LOXL1和LOXL2活性，如通过β-氨基丙腈的抑制所证实的。这些数据支持上皮来源的IL-1在哮喘性EMTU失调修复中的作用，并为气道成纤维细胞在哮喘炎症和气道重塑中的作用提供了新的见解。