Dataset Information

Bioinformatic analysis and experimental validation of the potential gene in the airway inflammation of steroid-resistant asthma.

ABSTRACT: 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.

SUBMITTER: Wei C

PROVIDER: S-EPMC10199006 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Bioinformatic analysis and experimental validation of the potential gene in the airway inflammation of steroid-resistant asthma.

Wei Chaochao C Wang Yang Y Hu Chengping C

Scientific reports 20230519 1

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 ...[more]

PMID: 37208441

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Project description:BackgroundMolecular microbiological analysis of airway samples in asthma has demonstrated an altered microbiome in comparison to healthy controls. Such changes may have relevance to treatment-resistant severe asthma, particularly those with neutrophilic airway inflammation, as bacteria might be anticipated to activate the innate immune response, a process that is poorly steroid responsive. An understanding of the relationship between airway bacterial presence and dominance in severe asthma may help direct alternative treatment approaches.ObjectiveWe aimed to use a culture independent analysis strategy to describe the presence, dominance and abundance of bacterial taxa in induced sputum from treatment resistant severe asthmatics and correlate findings with clinical characteristics and airway inflammatory markers.MethodsInduced sputum was obtained from 28 stable treatment-resistant severe asthmatics. The samples were divided for supernatant IL-8 measurement, cytospin preparation for differential cell count and Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiling for bacterial community analysis.ResultsIn 17/28 patients, the dominant species within the airway bacterial community was Moraxella catarrhalis or a member of the Haemophilus or Streptococcus genera. Colonisation with these species was associated with longer asthma disease duration (mean (SD) 31.8 years (16.7) vs 15.6 years (8.0), p = 0.008), worse post-bronchodilator percent predicted FEV1 (68.0% (24.0) vs 85.5% (19.7), p = 0.025) and higher sputum neutrophil differential cell counts (median (IQR) 80% (67-83) vs 43% (29-67), p = 0.001). Total abundance of these organisms significantly and positively correlated with sputum IL-8 concentration and neutrophil count.ConclusionsAirway colonisation with potentially pathogenic micro-organisms in asthma is associated with more severe airways obstruction and neutrophilic airway inflammation. This altered colonisation may have a role in the development of an asthma phenotype that responds less well to current asthma therapies.

Project description:BackgroundThe nature of bronchial mucosal inflammation and its physiologic and clinical significance in rhinovirus-induced asthma exacerbations is unclear. We investigated bronchial mucosal inflammatory response and its association with physiologic and clinical outcomes in an experimental model of rhinovirus-induced asthma exacerbations.MethodsWe used immunohistochemistry methods to detect phenotypes of inflammatory cells infiltrating the bronchial mucosa before and after experimental rhinovirus infection in 10 subjects with asthma and 15 normal subjects.ResultsCompared with baseline, rhinovirus infection significantly increased the number of epithelial (P = .005) and subepithelial (P = .017) neutrophils in subjects with asthma only and subepithelial CD68+ macrophages in both subjects with asthma (P = .009) and normal subjects (P = .018) but more so in those with asthma (P = .021). Numbers of CD45+, CD68+, and CD20+ cells; neutrophils; and eosinophils at day 4 postinfection were positively associated with virus load (r = 0.50-0.72, P = .016-0.03). At acute infection in subjects with asthma, CD4+ cells correlated with chest symptom scores (r = 0.69, P = .029), the fall in the 10% fall in FEV1 (PC10) correlated with neutrophils (r = -0.89, P = .029), the PC10 correlated inversely with CD4+ (r = -0.67, P = .023) and CD8+ cells (r = -0.65, P = .03), the 20% fall in FEV1 was inversely associated with CD20+ cells (r = -0.65, P = .03), and higher epithelial CD8+ cell counts were significantly associated with a greater maximum fall in FEV1 (r = -0.72, P = .03), whereas higher subepithelial mast cell counts were significantly associated with a lower maximum percent fall in peak expiratory flow (r = 0.8, P = .024).ConclusionsIn subjects with asthma, rhinovirus infection induces bronchial mucosal neutrophilia and more severe monocyte/macrophage infiltration than in normal subjects. Airway neutrophils, eosinophils, and T and B lymphocytes during infection are related to virus load and physiologic and clinical severity, whereas mast cells are related to greater lung function.

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Dataset Information

Bioinformatic analysis and experimental validation of the potential gene in the airway inflammation of steroid-resistant asthma.

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Bioinformatic analysis and experimental validation of the potential gene in the airway inflammation of steroid-resistant asthma.

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