Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Haikou, People's Republic of China.
Department of Pulmonary and Critical Care Medicine, Affiliated Hainan Hospital of Hainan Medical University, Haikou, People's Republic of China.
Sci Rep. 2023 May 19;13(1):8098. doi: 10.1038/s41598-023-35214-4.
Steroid-resistant asthma is a troublesome clinical problem in public health. The pathogenesis of steroid-resistant asthma is complex and remains to be explored. In our work, the online Gene Expression Omnibus microarray dataset GSE7368 was used to explore differentially expressed genes (DEGs) between steroid-resistant asthma patients and steroid-sensitive asthma patients. Tissue-specific gene expression of DEGs was analyzed using BioGPS. The enrichment analyses were performed using GO, KEGG, and GSEA analysis. The protein-protein interaction network and key gene cluster were constructed using STRING, Cytoscape, MCODE, and Cytohubba. A steroid-resistant neutrophilic asthma mouse model was established using lipopolysaccharide (LPS) and ovalbumin (OVA). An LPS-stimulated J744A.1 macrophage model was prepared to validate the underlying mechanism of the interesting DEG gene using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 66 DEGs were identified, most of which were present in the hematologic/immune system. Enrichment analysis displayed that the enriched pathways were the IL-17 signaling pathway, MAPK signal pathway, Toll-like receptor signaling pathway, and so on. DUSP2, as one of the top upregulated DEGs, has not been clearly demonstrated in steroid-resistant asthma. In our study, we observed that the salubrinal administration (DUSP2 inhibitor) reversed neutrophilic airway inflammation and cytokine responses (IL-17A, TNF-α) in a steroid-resistant asthma mouse model. We also found that salubrinal treatment reduced inflammatory cytokines (CXCL10 and IL-1β) in LPS-stimulated J744A.1 macrophages. DUSP2 may be a candidate target for the therapy of steroid-resistant asthma.
类固醇抵抗性哮喘是公共卫生领域一个棘手的临床问题。类固醇抵抗性哮喘的发病机制复杂，仍有待探索。在我们的工作中，使用在线基因表达综合数据库 microarray 数据集 GSE7368 来探讨类固醇抵抗性哮喘患者和类固醇敏感性哮喘患者之间的差异表达基因（DEGs）。使用 BioGPS 分析 DEGs 的组织特异性基因表达。使用 GO、KEGG 和 GSEA 分析进行富集分析。使用 STRING、Cytoscape、MCODE 和 Cytohubba 构建蛋白质-蛋白质相互作用网络和关键基因簇。使用脂多糖（LPS）和卵清蛋白（OVA）建立类固醇抵抗性嗜中性粒细胞性哮喘小鼠模型。制备 LPS 刺激的 J744A.1 巨噬细胞模型，使用定量逆转录-聚合酶链反应（qRT-PCR）验证感兴趣的 DEG 基因的潜在机制。鉴定出 66 个差异表达基因，其中大多数存在于血液/免疫系统中。富集分析显示，富集途径为 IL-17 信号通路、MAPK 信号通路、Toll 样受体信号通路等。DUSP2 作为上调的顶级 DEG 之一，在类固醇抵抗性哮喘中尚未得到明确证实。在我们的研究中，我们观察到 salubrinal 给药（DUSP2 抑制剂）逆转了类固醇抵抗性哮喘小鼠模型中的嗜中性气道炎症和细胞因子反应（IL-17A、TNF-α）。我们还发现，salubrinal 处理减少了 LPS 刺激的 J744A.1 巨噬细胞中的炎性细胞因子（CXCL10 和 IL-1β）。DUSP2 可能是治疗类固醇抵抗性哮喘的候选靶点。
