Expression profiling of genes related to asthma exacerbations

Abstract

Summary Background Asthma is a chronic airway inflammatory disease; however, the molecular mechanisms that underlie asthma exacerbation are only partially understood. Objective To identify gene expression signatures that reflect the acute exacerbation of asthma, we examined the differential expression of genes during asthma exacerbation and stable condition by using microarray analysis. Methods The subjects were mite‐sensitive asthmatic children and non‐asthmatic control children. The children were divided into four groups (AE: asthma exacerbation, n=12; SA: stable asthma, n=11; IC: infected control, n=6; and NC: non‐infected control, n=5). Total RNA was extracted from peripheral blood mononuclear cells and subjected to microarray analysis with Illumina Human Ref8 BeadChip arrays. Welch's t‐test was performed to identify genes whose expression was altered during asthma exacerbation. Quantitative real‐time RT‐PCR was performed on samples collected from 43 asthmatic children and 11 control children to verify the microarray results. Results The expression of 137/16 genes was significantly up/down‐regulated during asthma exacerbation assessed by microarray analysis. Of the genes, 62 were also differentially expressed during upper respiratory infection. Many of the asthma exacerbation related genes were involved in defence responses and responses to external stimuli, but these associations disappeared after excluding the infection‐related genes. Quantitative real‐time RT‐PCR confirmed that the genes related (S100A8 and GAS6) and unrelated to infections (CD200 and RBP7) were differentially expressed during asthma exacerbation (P<0.01). Conclusions Previously unidentified immune responses during asthma exacerbation may provide further clarification of the molecular mechanisms underlying asthma.

Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma

“…This cluster also has the lowest baseline lung function, the highest bronchodilator reversibility, the highest FE NO levels, and the highest doses of ICS: all characteristics that are associated with near-fatal asthma (35). Given that the adults and children in TEA cluster 1 are linked by a common transcriptomic signature in the airway that is associated with epithelial cell differentiation (EXOSC9 and SNAPC5), neurohumoral hemostasis (NRCAM and PCLO), and histamine synthesis (DNAH17 and DEFB1), it is plausible that these genes contribute to a greater risk of severe bronchospasm and near-fatal asthma associated with this cluster (26)(27)(28)(29)(30). TEA cluster 2 is the least common TEA cluster in both cohorts (19% of YCAAD and 12% of Asthma BRIDGE) and has the most within-cluster heterogeneity, compared with the other TEA clusters (color heterogeneity seen in Figure 3).…”

“…Two DEGs (EXOSC9 and SNAPC5) that code for proteins involved in RNA processing were down-regulated compared with control subjects with no asthma (27). Three DEGs (NRCAM, PCLO, and SLC4A4) that are associated with neuron function were significantly increased in TEA cluster 1 compared with control subjects with no asthma (28)(29)(30). In TEA cluster 3, all of the 27 DEGs are upregulated compared with control subjects.…”

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

“…Three studies of small or modest size have profiled gene expression during acute exacerbation in blood or nasal cells, reporting up-regulation of similar pathways related to innate and adaptive immune responses (3)(4)(5). However, these studies focused on expression changes during acute exacerbations and provided no information regarding expression across the broad range of asthma control states that precede exacerbation.…”

“…Using clinical phenotype data available in Asthma BRIDGE and in CAMP, we developed two composite scores summarizing self-reported asthma control in the preceding 6 months (chronic, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] and 7 days (acute, 0-28), respectively, each modeled on the ACT questionnaire (11), where higher scores indicate worse asthma control. Based on the medians of the corresponding phenotypic distributions, optimal chronic asthma control was defined as a score less than or equal to six in BRIDGE WB and moderately suboptimal asthma control was defined as a score less than or equal to 11 in BRIDGE CD4 ( Figure 2).…”

Serum S100A8 and S100A9 Enhance Innate Immune Responses in the Pathogenesis of Baker's Asthma

“…S100A8 and S100A9 have recently been implicated in the pathogenesis of asthma, although their roles are unclear [5,13,15]. The expression of S100A9 in peripheral blood mononuclear cells is elevated during asthma exacerbations [16], and sputum levels of S100A9 were increased in patients with severe neutrophilic asthma [8]. Based on these findings, we aimed to further elucidate the associations and roles of S100A8 and S100A9 proteins in innate immune responses in the pathogenesis of baker's asthma.…”