Changes in Expression of Genes Regulating Airway Inflammation Following a High-Fat Mixed Meal in Asthmatics
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74075 | GEO | 2015/10/16
SECONDARY ACCESSION(S): PRJNA298916
REPOSITORIES: GEO
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Project description:Systemic inflammation is reported to be associated with neutrophilic airway inflammation in asthma, this study aimed to examine the molecular mechanisms of the neutrophilia that is associated with systemic inflammation, and hypothesized that asthma patients with systemic inflammation have a group of genes that are differentially expressed and are assciated with airway inflammation.
2016-01-01 | GSE43397 | GEO
Project description:Systemic inflammation is reported to be associated with neutrophilic airway inflammation in asthma, this study aimed to examine the molecular mechanisms of the neutrophilia that is associated with systemic inflammation, and hypothesized that asthma patients with systemic inflammation have a group of genes that are differentially expressed and are assciated with airway inflammation. 50 asthma patients were recruited and grouped as asthmatics with systemic inflammation (n=18) and asthamtics without systemic inflammation (n=16) accroding to the levels of serum CRP and IL-6. RNA was extracted from induced sputum and was reverse-transcribed into cDNA. Gene profiling was performed using Illumina Sentrix HumanRef-8 Version 2 Expression BeadChips, and genes that were differentially expressed between asthmatics with systemic inflammation and asthmatics without systemic inflammation were compared and valided using qPCR.
2016-07-03 | E-GEOD-43397 | biostudies-arrayexpress
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.
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Project description:The Mixed Meal Model is a physiology based mathematical model describing the post-meal interplay between glucose, insulin, triglycerides and non-esterified fatty acids (NEFA).The Mixed Meal Model can be fit to meal response data by estimating nine model parameters from measured plasma glucose, insulin, triglyceride, and NEFA trajectories. These estimated model parameters have been shown to capture features of insulin resistance, beta-cell functionality, and liver fat accumulation from the meal response data.
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Project description:Obesity is associated with severe, difficult to control asthma, and increased airway oxidative stress. Mitochondrial reactive oxygen species (mROS) are an important source of oxidative stress leading us to hypothesize that targeting mROS in obese allergic asthma might be an effective treatment strategy. Using a mouse model of house dust mite (HDM) induced allergic airway disease in mice fed a low- (LFD) or high-fat diet (HFD), and the mitochondrial antioxidant MitoQuinone (MitoQ); we investigated the effects of obesity and mROS on airway inflammation, remodelling and airway hyperreactivity (AHR). HDM induces airway inflammation, remodelling and hyperreactivity in both lean and obese mice. Obese allergic mice showed increased lung tissue eotaxin levels, airway tissue eosinophilia and AHR when compared to lean allergic mice. MitoQ reduced markers of airway inflammation, remodelling and hyperreactivity in both lean and obese allergic mice, and tissue eosinophilia in obeseHDM mice. mROS regulates cell signalling by protein oxidation of multiple downstream targets: MitoQ reduced HDM-induced cysteine-sulfenylation of several proteins including those involved in the unfolded protein response (UPR). In summary, mROS mediates the development of allergic airway disease and hence MitoQ might be effective for the treatment for asthma, and specific features of obese asthma.
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Project description:Inadequately controlled chronic airway inflammation may result in a series of irreversible changes within lung tissue, referred to as lung remodeling. The increased activation of airway fibroblasts and their differentiation towards myofibroblasts leads to the deposition of extracellular matrix (ECM) components, including collagens. The disrupted balance between the activity and concentration of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) secreted by structural lung cells and infiltrating immune cells may lead to excessive ECM remodeling. Here, we aimed to utilize HDM-induced experimental acute (mixed and neutrophilic) and chronic (neutrophilic) experimental asthma models to assess differences in lower airway remodeling. First, we confirmed increased total collagen deposition within the lung in all analyzed models. Additionally, we found an elevated frequency of IFN-producing T cells in acute neutrophilic inflammation, while an elevated frequency of IL-4 and IL-10-producing T cells was observed in mixed airway inflammation. Transcriptomic analysis revealed Th2- and Th17- -related signaling pathways, while specifically in the chronic model, we noted Th17-driven fibrosis. Moreover, transcriptomic profiling showed the dysregulation in genes associated with ECM morphology, collagens, MMPs, and TIMPs. Targeted protein analysis confirmed the increased deposition of Collagen I, III, IV, and VI. Finally, multiplexing analysis of bronchoalveolar lavage indicated an increase in MMP-2 and TIMP-4 levels among all investigated models, whereas MMP-8 and MMP-9 appeared to be increased explicitly in chronic inflammation. In summary, we confirmed that various inflammatory profiles in experimental asthma models may differentially influence the development of airway remodeling changes.
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Project description:Signalling pathways regulate all major cellular events in health and disease, including asthma development and progression. Complexity of human intracellular signalization can be explored using novel systemic approaches that exploit whole-transcriptome analysis. Cap-analysis-of-gene-expression (CAGE) is a method of choice for generating transcriptome libraries, as it interrogates only terminally capped mRNAs that have the highest probability to be translated into protein. In this study we for the first time systematically profiled differentially activated Intracellular Signalling Pathways (ISPs) in cultured primary human airway smooth muscle (ASM) cells from asthmatic (n=8) and non-asthmatic (n=6) subjects in a high-throughput assay, highlighting asthma-specific co-regulatory patterns. CAGE-libraries from primary human ASM cells were subject to massive parallel next generation sequencing, and a comprehensive analysis of ISP activation was performed using a recently developed technique OncoFinder. Analysis of 270 ISPs led to discovery of multiple pathways clearly distinguishing asthmatic from normal cells. In particular, we found 146 (p<0.05) and 103 (p<0.01) signalling pathways differentially active in asthmatic vs non-asthmatic samples. We identified seven clusters of coherently acting pathways functionally related to the disease. Pathways down-regulated in asthma mostly represented cell death-promoting pathways, whereas the up-regulated ones were mainly involved in cell growth and proliferation, inflammatory response and some specific reactions, including smooth muscle contraction and hypoxia - related signalization. Most of interactions uncovered in this study were not previously associated with asthma, suggesting that these results may be pivotal to development of novel therapeutic strategies that specifically address the ISP signature linked with asthma pathophysiology. Capped mRNA profiles of primary bronchial smooth muscle cells from 8 asthmatic and 6 healthy donors were generated by deep sequencing using Illumina HiSeq1500.
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Project description:Signalling pathways regulate all major cellular events in health and disease, including asthma development and progression. Complexity of human intracellular signalization can be explored using novel systemic approaches that exploit whole-transcriptome analysis. Cap-analysis-of-gene-expression (CAGE) is a method of choice for generating transcriptome libraries, as it interrogates only terminally capped mRNAs that have the highest probability to be translated into protein. In this study we for the first time systematically profiled differentially activated Intracellular Signalling Pathways (ISPs) in cultured primary human airway smooth muscle (ASM) cells from asthmatic (n=8) and non-asthmatic (n=6) subjects in a high-throughput assay, highlighting asthma-specific co-regulatory patterns. CAGE-libraries from primary human ASM cells were subject to massive parallel next generation sequencing, and a comprehensive analysis of ISP activation was performed using a recently developed technique OncoFinder. Analysis of 270 ISPs led to discovery of multiple pathways clearly distinguishing asthmatic from normal cells. In particular, we found 146 (p<0.05) and 103 (p<0.01) signalling pathways differentially active in asthmatic vs non-asthmatic samples. We identified seven clusters of coherently acting pathways functionally related to the disease. Pathways down-regulated in asthma mostly represented cell death-promoting pathways, whereas the up-regulated ones were mainly involved in cell growth and proliferation, inflammatory response and some specific reactions, including smooth muscle contraction and hypoxia - related signalization. Most of interactions uncovered in this study were not previously associated with asthma, suggesting that these results may be pivotal to development of novel therapeutic strategies that specifically address the ISP signature linked with asthma pathophysiology.
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