Abstract
BackgroundNeutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA.MethodsAsthmatics (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.ResultsNA 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.ConclusionsIL-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).
Highlights
Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids
Subjects characteristics Baseline characteristics of the subjects were summarized in Table 1. 28 healthy controls and 115 asthmatics were enrolled with induced sputum samples
Sputum profile of asthmatic patients The eosinophilic group had higher baseline sputum cell IL-5 mRNA expression compared to neutrophilic (p = 0.004) and pauci-granulocytic groups (p < 0.001) (Additional file 1: Figure S1b)
Summary
Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA. Eosinophil cell count could be a very good marker to predict therapy response in type-2 asthma, it is not clear which innate biomarkers could predict the poor improvement in non-type-2 asthma patients. A recent study shows both leucine-rich repeat-containing family protein 3 inflammasome activation and IL-1β gene expression increase in neutrophilic asthma [2]. Respiratory symptoms and lung function tests are very important for asthma patient evaluation. According to GINA2020, lung function should be evaluated regularly for asthma patients [3]. Low forced expiratory volume in one second (FEV1) is a strong independent predictor for acute exacerbations [4, 5] and lung function decline [6]. Since the correlation between lung function and symptoms is weak, it is suggested to monitor lung function in addition to symptoms when evaluating the efficiency of asthma therapy [7]
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