Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA. Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-γ, IL-1β, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1β in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1β mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells. NA had increased baseline sputum cell IL-1β expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in FEV1 compared to EA. For all asthmatics, sputum IL-1β mRNA was positively correlated with protein expression. Sputum IL-1β mRNA and protein levels were negatively correlated to FEV1 improvement. After subgrouping, the correlation between IL-1β mRNA and FEV1 improvement was significant in NA but not in EA. Thickness of RBM in asthmatics was greater than that of healthy controls and positively correlated with neutrophil percentage in bronchoalveolar lavage fluid. In vitro experiments, the process of IL-1β augmenting TGF-β1-induced EMT cannot be abrogated by glucocorticoid or montelukast sodium, but can be reversed by MAPK inhibitors. IL-1β level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1β augmenting TGF-β1-induced steroid-resistant EMT through MAPK signaling pathways. Trial registration: This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: 20150406).

中文翻译：

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IL-1β 增强 TGF-β 诱导上皮细胞的上皮间质转化，并与中性粒细胞哮喘患者的肺功能改善不良有关

中性粒细胞哮喘 (NA) 对吸入皮质类固醇的反应较少。我们旨在找出 NA 治疗反应的预测因子。哮喘患者 (n = 115) 和健康对照组 (n = 28) 在为期 6 个月的标准化治疗随访期间接受了临床评估。哮喘患者按痰细胞分类计数分类。通过 RT-qPCR 测量痰细胞因子（IFN-γ、IL-1β、IL-27、FOXP3、IL-17A 和 IL-5）的 mRNA 表达。ELISA法检测痰液上清液中IL-1β蛋白。在活检样本中测量网状基底膜 (RBM)。通过A549细胞探索IL-1β介导上皮-间质转化（EMT）过程的作用和信号通路。与嗜酸性哮喘患者 (EA) 相比，NA 增加了基线痰细胞 IL-1β 表达。跟进后，与 EA 相比，NA 在 FEV1 方面的改善较小。对于所有哮喘患者，痰液 IL-1β mRNA 与蛋白表达呈正相关。痰液 IL-1β mRNA 和蛋白水平与 FEV1 改善呈负相关。亚组后，IL-1β mRNA 与 FEV1 改善之间的相关性在 NA 中显着，但在 EA 中不显着。哮喘患者的 RBM 厚度大于健康对照组，并且与支气管肺泡灌洗液中的中性粒细胞百分比呈正相关。在体外实验中，IL-1β 增强 TGF-β1 诱导的 EMT 的过程不能被糖皮质激素或孟鲁司特钠消除，但可以被 MAPK 抑制剂逆转。基线痰液中的 IL-1β 水平预示着 NA 肺功能改善不佳。潜在机制可能与 IL-1β 通过 MAPK 信号通路增强 TGF-β1 诱导的类固醇抗性 EMT 有关。试验注册：本研究经华中科技大学同济医学院同济医院伦理委员会批准（IRB ID：20150406）。