Airway epithelial barrier, mucins and inflammasome in distinct eosinophilic, neutrophilic and mixed inflammatory phenotypes of asthma
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ABSTRACT:
PROVIDER: PRJNA427213 | ENA |
REPOSITORIES: ENA
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Project description:Asthma is a complex, chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Distinct inflammatory phenotypes of eosinophilic, mixed, neutrophilic and paucigranulocytic asthma are identified in patients, but most in vivo mouse models, studying asthma mechanisms, mimic only eosinophilic phenotype in humans. The detailed unbiased in vivo studies on molecular responses among different kinds of inflammation in asthma models are lacking. Therefore, we developed mouse models representing three different inflammatory phenotypes of airway inflammation, namely eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitisation. We used microarrays to determine the global gene expression in the lungs of mice with eosinophilic, mixed and neutrophilic inflammatory phenotypes to uncover underlying differences in clinical presentation and to find novel molecular targets and pathways, which might reflect different molecular mechanisms of the disease. By whole genome transcriptome profiling, we found that airway tight junction (TJ) molecules, mucins and inflammasome-related genes are differentially expressed in distinct phenotypes of allergic airway inflammation. Next, detailed analysis of several molecules from these families by quantitative RT-PCR, western blot and confocal microscopy revealed that (i) Zo-1 and Cldn18 were downregulated in all phenotypes, while Cldn4 upregulation was characteristic for neutrophilic airway inflammation; (ii) mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic asthma, and (iii) upregulation of inflammasome-related molecules such as Nlrp3, Nlrc4, Casp-1 and IL-1b was characteristic for neutrophilic asthma. Finally, we showed that inflammasome/Th-17/neutrophilic axis cytokines, namely IL-1b and IL-17 impaired epithelial barrier function and increased mucins expressions in primary human bronchial epithelial cells from normal and asthmatic donors. Our findings suggest that differential expression of TJs, mucins and inflammasome-related molecules in distinct asthma phenotypes could be mechanistically linked and might further reflect the differences observed in the clinic.
2018-10-03 | GSE108417 | GEO
Project description:lncRNA expression analysis in patients with eosinophilic and neutrophilic asthma
| PRJNA480892 | ENA
Project description:Long non-coding RNA (lncRNA) are known to be important in many diseases. There has been some reports that lncRNA take part in the pathogenesis of systemic inflammation of asthma. lncRNA regulates gene transcription, protein expression and epigenetic regulation. However, the lncRNAs associated with differently airway phenotype such as eosinophilic and neutrophilic asthma remains unknown. We aimed at identifying the differences in circulating lncRNA signature in Eos and Neu samples. lncRNA expression were studied between blood samples from Eos patients, Neu patients and healthy individuals (Control). Bioinformatic analysis was used to describe relevant biological pathways. Using quantitative real-time PCR, lncRNA expression was measured. Comparing with Control samples, Eos sample has 190 own lncRNA and Neu sample has 166 own lncRNA(difference ≥ 2-fold). KEGG pathway annotation data and GO terms revealed that several lncRNAs are possibly associated with respective phenotype. lncRNA was identifying to differ significantly between Eos and Neu samples by using qRT-PCR. The results show us that lncRNA may be involved in different phenotypes of asthma. Whether we can recognize different phenotypes of asthma through these lncRNA (as biomarkers) needs further study.
2019-04-09 | GSE117038 | GEO
Project description:This study identifies differentially expression genes in the sputum of people with eosinophilic, neutrophilic and paucigranulocytic asthma. A selection of markers identified using this microarray were further validated using qPCR on a wider sample set. Gene expression profiles were generated from induced sputum samples from 47 asthma patients and were grouped by the inflammatory phenotype assigned using sputum cell counts into neutrophilic asthma (n=12), eosinophilic asthma (n=17) and paucigranulocytic asthma (n=18). RNA was extracted, amplified and hybridised to Illumina Sentrix HumanRef-8 Version 2 Expression BeadChips, and genes that were differentially expressed between asthma inflammatory phenotypes were compared.
2014-03-25 | E-GEOD-45111 | biostudies-arrayexpress
Project description:Many neutrophilic asthma patients do not respond to current medications, highlighting the need for novel therapeutic targets. Here, we investigated the role of intraflagellar transport (IFT) complex protein IFT20 in neutrophilic asthma. Mice lacking CD4+ T cell-specific IFT20 displayed reduced protease-induced neutrophilic asthma inflammation. Thus, IFT20 may represent a promising therapeutic target for treatment of patients with neutrophilic asthma.
2022-07-31 | GSE179622 | GEO
Project description:Severe asthma is a complex disease with different inflammatory phenotypes. Transcriptomic profiling has contributed to understanding the pathogenesis of asthma, especially type-2 inflammation; however, there is still poor understanding of non-eosinophilic asthma, and consequently there are limited treatment options. The aim of this study was to determine transcriptomic profiles in endobronchial biopsies of adults with severe asthma and different inflammatory phenotypes (neutrophilic, eosinophilic and paucigranulocytic) compared with healthy controls.
2021-07-31 | GSE143303 | GEO
Project description:This study identifies differentially expression genes in the sputum of people with eosinophilic, neutrophilic and paucigranulocytic asthma. A selection of markers identified using this microarray were further validated using qPCR on a wider sample set.
2014-03-25 | GSE45111 | GEO
Project description:BACKGROUND:Improvements in asthma diagnosis and management require deeper understanding of the heterogeneity of the complex airway inflammation. We hypothesise that differences in the two major inflammatory phenotypes of asthma; eosinophilic and neutrophilic asthma, will be reflected in the lung protein expression profile of murine asthma models and can be delineated using proteomics of bronchoalveolar lavage (BAL). METHODS:BAL from mice challenged with ovalbumin (OVA/OVA) alone (standard model of asthma, here considered eosinophilic) or OVA in combination with endotoxin (OVA/LPS, model of neutrophilic asthma) was analysed using liquid chromatography coupled to high resolution mass spectrometry, and compared with steroid-treated animals and healthy controls. In addition, conventional inflammatory markers were analysed using multiplexed ELISA (Bio-Plex™ assay). Multivariate statistics was performed on integrative proteomic fingerprints using principal component analysis. Proteomic data were complemented with lung mechanics and BAL cell counts. RESULTS:Several of the analysed proteins displayed significant differences between the controls and either or both of the two models reflecting eosinophilic and neutrophilic asthma. Most of the proteins found with mass spectrometry analysis displayed a considerable increase in neutrophilic asthma compared with the other groups. Conversely, the larger number of the inflammatory markers analysed with Bio-Plex™ analysis were found to be increased in the eosinophilic model. In addition, major inflammation markers were correlated to peripheral airway closure, while commonly used asthma biomarkers only reflect central inflammation. CONCLUSION:Our data suggest that the commercial markers we are currently relying on to diagnose asthma subtypes are not giving us comprehensive or specific enough information. The analysed protein profiles allowed to discriminate the two models and may add useful information for characterization of different asthma phenotypes.
| S-EPMC4137270 | biostudies-literature
Project description:This project used a state-of-the-art, multi-omics approach to improve our understanding of the aetiopathogenesis of a highly prevalent, performance-limiting disorder of racehorses; mild to moderate equine asthma (MMEA). This advanced knowledge is a prerequisite to improving prophylactic, management and therapeutic options for this condition. Although a number of risk factors for MMEA have been identified, incomplete understanding of the precise aetiopathogenesis of this syndrome means that options for intervention are currently limited. This study aimed to apply a multi-omic approach, reveal key inflammatory pathways involved in inflammatory cell recruitment to the lower airways and highlight pathways specific to different MMEA inflammatory cell profiles (MMEA endotypes). Thus, we compared BALF cell gene and protein expression data from horses with normal bronchoalveolar lavage fluid (BALF) cytology (n = 8) with those isolated from horses with neutrophilic (n = 4), mastocytic (n = 8), mixed neutrophilic/mastocytic (n=4) and mixed eosinophilic/mastocytic (n=3) inflammation. Analyses on transcriptomic and proteomic data derived from BALF cells from horses with neutrophilic cytology showed enrichment in classical inflammatory pathways, while horses with mastocytic cytology showed enrichment in pathways involved in hypersensitivity reactions related to non-classical inflammation that could mimic a Th2 immune response. The mixed eosinophilic/mastocytic group also presented with a non-classical inflammatory profile while, the mixed neutrophilic/mastocytic group revealed profiles consistent with both neutrophilic inflammation and hypersensitivity. Our adopted multi-omics approach (both gene and protein expression) has enabled a more holistic assessment of the immunological status of the lower airways associated with the different cytological profiles of equine asthma.
2024-12-05 | GSE277308 | GEO
Project description:Neutrophilic asthma is associated with disease severity and corticosteroid insensitivity. Novel therapies are required to manage this life-threatening asthma phenotype. Programmed cell death protein-1 (PD-1) is a key homeostatic modulator of the immune response for T cell effector functions. Our study was conducted to assess the therapeutic potential of a novel human PD-1 agonist in a humanized mouse model in which the PD-1 extracellular domain is entirely humanized. Using single-cell RNA sequencing, we demonstrated that PD-1 agonist treatment alleviates lung inflammation via the reprogramming of pulmonary effector T cells.
2022-08-07 | GSE210349 | GEO