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DsRNA-induced changes in gene expression profiles of primary nasal and bronchial epithelial cells from patients with asthma, rhinitis and controls.

ABSTRACT: BACKGROUND: Rhinovirus infections are the most common cause of asthma exacerbations. The complex responses by airway epithelium to rhinovirus can be captured by gene expression profiling. We hypothesized that: a) upper and lower airway epithelium exhibit differential responses to double-stranded RNA (dsRNA), and b) that this is modulated by the presence of asthma and allergic rhinitis. OBJECTIVES: Identification of dsRNA-induced gene expression profiles of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles. METHODS: This study had a cross-sectional design including 18 subjects: 6 patients with allergic asthma with concomitant rhinitis, 6 patients with allergic rhinitis, and 6 healthy controls. Comparing 6 subjects per group, the estimated false discovery rate was approximately 5%. RNA was extracted from isolated and cultured primary epithelial cells from nasal biopsies and bronchial brushings stimulated with dsRNA (poly(I:C)), and analyzed by microarray (Affymetrix U133+ PM Genechip Array). Data were analysed using R and the Bioconductor Limma package. Overrepresentation of gene ontology groups were captured by GeneSpring GX12. RESULTS: In total, 17 subjects completed the study successfully (6 allergic asthma with rhinitis, 5 allergic rhinitis, 6 healthy controls). dsRNA-stimulated upper and lower airway epithelium from asthma patients demonstrated significantly fewer induced genes, exhibiting reduced down-regulation of mitochondrial genes. The majority of genes related to viral responses appeared to be similarly induced in upper and lower airways in all groups. However, the induction of several interferon-related genes (IRF3, IFNAR1, IFNB1, IFNGR1, IL28B) was impaired in patients with asthma. CONCLUSIONS: dsRNA differentially changes transcriptional profiles of primary nasal and bronchial epithelial cells from patients with allergic rhinitis with or without asthma and controls. Our data suggest that respiratory viruses affect mitochondrial genes, and we identified disease-specific genes that provide potential targets for drug development.

SUBMITTER: Wagener AH

PROVIDER: S-EPMC3916078 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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dsRNA-induced changes in gene expression profiles of primary nasal and bronchial epithelial cells from patients with asthma, rhinitis and controls.

Wagener Ariane H AH Zwinderman Aeilko H AH Luiten Silvia S Fokkens Wytske J WJ Bel Elisabeth H EH Sterk Peter J PJ van Drunen Cornelis M CM

Respiratory research 20140129

<h4>Background</h4>Rhinovirus infections are the most common cause of asthma exacerbations. The complex responses by airway epithelium to rhinovirus can be captured by gene expression profiling. We hypothesized that: a) upper and lower airway epithelium exhibit differential responses to double-stranded RNA (dsRNA), and b) that this is modulated by the presence of asthma and allergic rhinitis.<h4>Objectives</h4>Identification of dsRNA-induced gene expression profiles of primary nasal and bronchia ...[more]

PMID: 24475887

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Project description:BackgroundThe link between upper and lower airways in patients with both asthma and allergic rhinitis is still poorly understood. As the biological complexity of these disorders can be captured by gene expression profiling we hypothesized that the clinical expression of rhinitis and/or asthma is related to differential gene expression between upper and lower airways epithelium.ObjectiveDefining gene expression profiles of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles.MethodsThis cross-sectional study included 18 subjects (6 allergic asthma and allergic rhinitis; 6 allergic rhinitis; 6 healthy controls). The estimated false discovery rate comparing 6 subjects per group was approximately 5%. RNA was extracted from isolated and cultured epithelial cells from bronchial brushings and nasal biopsies, and analyzed by microarray (Affymetrix U133+ PM Genechip Array). Data were analysed using R and Bioconductor Limma package. For gene ontology GeneSpring GX12 was used.ResultsThe study was successfully completed by 17 subjects (6 allergic asthma and allergic rhinitis; 5 allergic rhinitis; 6 healthy controls). Using correction for multiple testing, 1988 genes were differentially expressed between healthy lower and upper airway epithelium, whereas in allergic rhinitis with or without asthma this was only 40 and 301 genes, respectively. Genes influenced by allergic rhinitis with or without asthma were linked to lung development, remodeling, regulation of peptidases and normal epithelial barrier functions.ConclusionsDifferences in epithelial gene expression between the upper and lower airway epithelium, as observed in healthy subjects, largely disappear in patients with allergic rhinitis with or without asthma, whilst new differences emerge. The present data identify several pathways and genes that might be potential targets for future drug development.

Project description:Perturbation of the microbiome has numerous associations with the phenotypes and progression in chronic airways disease. However, the differences in the nasal microbiome in asthma and allergic rhinitis (AR) have not been defined. We examined whether the nasal microbiome would vary among different comorbidities in asthma and AR and that those differences may be associated with the severity of asthma. Nasal lavage fluid was collected from 110 participants, including 20 healthy controls, 30 subjects with AR, 30 subjects with asthma and 30 subjects with combined asthma + AR. The Asthma Control Questionnaire (ACQ-7) was used to evaluate asthma control status. Using 16S rRNA bacterial gene sequencing, we analyzed nasal microbiome in patients with asthma, AR, combined asthma + AR, and healthy controls. Bacterial diversity was analyzed in corresponding with α diversity indices (Chao and Shannon index). Compared with healthy controls, the Chao index tended to be lower in subjects with AR (P = 0.001), asthma (P = 0.001), and combined asthma + AR (P = 0.001) when compared with healthy controls. Furthermore, the Shannon index was significantly lower in subjects with asthma (P = 0.013) and comorbid asthma with AR (P = 0.004) than the control subjects. Disparity in the structure and composition of nasal bacteria were also observed among the four groups. Furthermore, patients with combined asthma + AR and isolated asthma were divided into two groups according to the level of disease control: partially or well-controlled and uncontrolled asthma. The mean relative abundance observed in the groups mentioned the genera of Pseudoflavonifractor were dominated in patients with well and partially controlled disease, in both isolated asthma and combined asthma + AR. In subjects with uncontrolled asthma and combined asthma + AR, a lower evenness and richness (Shannon index, P = 0.040) was observed in nasal microbiome composition. Importantly, lower evenness and richness in the nasal microbiome may be associated with poor disease control in combined asthma + AR. This study showed the upper airway microbiome is associated with airway inflammation disorders and the level of asthma control.

Project description:MicroRNAs are short non-coding single stranded RNAs that regulate gene expression. While much is known about the effects of individual microRNAs, there is now growing evidence that they can work in co-operative networks. MicroRNAs are known to be dysregulated in many diseases and affect pathways involved in the pathology. We investigated dysregulation of microRNA networks using asthma as the disease model. Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness and airway remodelling. The airway epithelium is a major contributor to asthma pathology and has been shown to produce an excess of inflammatory and pro-remodelling cytokines such as TGF-β, IL-6 and IL-8 as well as deficient amounts of anti-viral interferons. After performing microRNA arrays, we found that microRNAs -18a, -27a, -128 and -155 are down-regulated in asthmatic bronchial epithelial cells, compared to cells from healthy donors. Interestingly, these microRNAs are predicted in silico to target several components of the TGF-β, IL-6, IL-8 and interferons pathways. Manipulation of the levels of individual microRNAs in bronchial epithelial cells did not have an effect on any of these pathways. Importantly, knock-down of the network of microRNAs miR-18a, -27a, -128 and -155 led to a significant increase of IL-8 and IL-6 expression. Interestingly, despite strong in silico predictions, down-regulation of the pool of microRNAs did not have an effect on the TGF-β and Interferon pathways. In conclusion, using both bioinformatics and experimental tools we found a highly relevant potential role for microRNA dysregulation in the control of IL-6 and IL-8 expression in asthma. Our results suggest that microRNAs may have different roles depending on the presence of other microRNAs. Thus, interpretation of in silico analysis of microRNA function should be confirmed experimentally in the relevant cellular context taking into account interactions with other microRNAs when studying disease.

Dataset Information

DsRNA-induced changes in gene expression profiles of primary nasal and bronchial epithelial cells from patients with asthma, rhinitis and controls.

Publications

dsRNA-induced changes in gene expression profiles of primary nasal and bronchial epithelial cells from patients with asthma, rhinitis and controls.

Similar Datasets

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