Respiratory Epithelial Gene Expression in Patients with Mild and Severe Cystic Fibrosis Lung Disease

Abstract

Despite having identical cystic fibrosis transmembrane conductance regulator genotypes, individuals with ⌬F508 homozygous cystic fibrosis (CF) demonstrate significant variability in severity of pulmonary disease. This investigation used high-density oligonucleotide microarray analysis of nasal respiratory epithelium to investigate the molecular basis of phenotypic differences in CF by (1 ) identifying differences in gene expression between ⌬F508 homozygotes in the most severe 20th percentile of lung disease by forced expiratory volume in 1 s and those in the most mild 20th percentile of lung disease and (2 ) identifying differences in gene expression between ⌬F508 homozygotes and age-matched non-CF control subjects. Microarray results from 23 participants (12 CF, 11 non-CF) met the strict quality control guidelines and were used for final data analysis. A total of 652 of the 11,867 genes identified as present in 75% of the samples were significantly differentially expressed in one of the three disease phenotypes: 30 in non-CF, 53 in mild CF, and 569 in severe CF. An analysis of genes differentially expressed by severity of CF lung disease demonstrated significant upregulation in severe CF of genes involved in protein ubiquination (P Ͻ 0.04), mitochondrial oxidoreductase activity (P Ͻ 0.01), and lipid metabolism (P Ͻ 0.03). Analysis of genes with decreased expression in patients with CF compared with control subjects demonstrated significant downregulation of genes involved in airway defense (P Ͻ 0.047) and protein metabolism (P Ͻ 0.048). This study suggests that differences in CF lung phenotype are associated with differences in expression of genes involving airway defense, protein ubiquination, and mitochondrial oxidoreductase activity and identifies specific new candidate modifiers of the CF phenotype.

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

“…Altogether, these evasion mechanisms contribute to the development of RSV-associated diseases. Interestingly, DUOX2 expression is decreased in patients with cystic fibrosis (CF) [35]. Thus, our data shed lights on a potential mechanism for the increased susceptibility of CF patients to respiratory virus infections [36].…”

Long noncoding RNA are aberrantly expressed in vivo in the cystic fibrosis bronchial epithelium

“…Other studies have profiled mRNA expression within the context of CF. At least three studies have profiled mRNA expression in the CF nasal epithelium (Ogilvie et al, 2011, Wright et al, 2006, Clarke et al, 2013.…”

“…Differences between studies may be partly explained by different experimental procedures employed. These differences include genotype of the cells used, statistical or normalisation approaches and tissue type; such as bronchial and nasal brushings (Ogilvie et al, 2011, Wright et al, 2006, Clarke et al, 2013, isogenic bronchial cells (Virella-Lowell et al, 2000), primary tracheal and bronchial cell cultures (Zabner et al, 2005) and foetal tracheal cells (Verhaeghe et al, 2007). It remains to be determined what direct contribution mutant CFTR makes to an altered CF transcriptome, and it is highly likely that other factors such as infection and inflammation are major contributors to this altered expression of both lncRNAs and protein coding transcripts.…”

NOX Enzymes and Pulmonary Disease

“…Cystic fibrosis airway biopsy samples exhibit decreased DUOX2 expression, suggesting that the enhanced susceptibility to infections in cystic fibrosis may be linked to impaired DUOX-mediated host defense (146). In support of NOX-…”