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


OBJECTIVE
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.
Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. a.h.wagener@amc.uva.nl.
Ariane H
AH
Wagener
Aeilko H
AH
Zwinderman
Silvia
S
Luiten
Wytske J
WJ
Fokkens
Elisabeth H
EH
Bel
Peter J
PJ
Sterk
Cornelis M
CM
van Drunen
D000328:Adult; D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D061251:Primary Cell Culture; D012330:RNA, Double-Stranded / Q000096:biosynthesis* / Q000235:genetics*; D020545:Respiratory Mucosa / Q000502:physiology*; D012220:Rhinitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome / Q000502:physiology*; D055815:Young Adult
D012330:RNA, Double-Stranded