title: Altered Epithelial Gene Expression in Peripheral Airways of Severe Asthma.
abstract: Management of severe asthma remains a challenge despite treatment with glucocorticosteroid therapy. The majority of studies investigating disease mechanisms in treatment-resistant severe asthma have previously focused on the large central airways, with very few utilizing transcriptomic approaches. The small peripheral airways, which comprise the majority of the airway surface area, remain an unexplored area in severe asthma and were targeted for global epithelial gene expression profiling in this study. Differences between central and peripheral airways were evaluated using transcriptomic analysis (Affymetrix HG U133 plus 2.0 GeneChips) of epithelial brushings obtained from severe asthma patients (N = 17) and healthy volunteers (N = 23). Results were validated in an independent cohort (N = 10) by real-time quantitative PCR. The IL-13 disease signature that is associated with an asthmatic phenotype was upregulated in severe asthmatics compared to healthy controls but was predominantly evident within the peripheral airways, as were genes related to mast cell presence. The gene expression response associated with glucocorticosteroid therapy (i.e. FKBP5) was also upregulated in severe asthmatics compared to healthy controls but, in contrast, was more pronounced in central airways. Moreover, an altered epithelial repair response (e.g. FGFBP1) was evident across both airway sites reflecting a significant aspect of disease in severe asthma unadressed by current therapies. A transcriptomic approach to understand epithelial activation in severe asthma has thus highlighted the need for better-targeted therapy to the peripheral airways in severe asthma, where the IL-13 disease signature persists despite treatment with currently available therapy.
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Akul
authors.initials: A
authors.lastname: Singhania
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Hitasha
authors.initials: H
authors.lastname: Rupani
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Nivenka
authors.initials: N
authors.lastname: Jayasekera
authors.affiliation: UCB Celltech, Slough, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Lumb
authors.affiliation: UCB Celltech, Slough, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Hales
authors.affiliation: UCB Celltech, Slough, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Gozzard
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.|Southampton NIHR Respiratory Biomedical Research Unit, Southampton Centre for Biomedical Research, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Woelk
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.|Southampton NIHR Respiratory Biomedical Research Unit, Southampton Centre for Biomedical Research, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Howarth
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D001249:Asthma / Q000378:metabolism*; D016022:Case-Control Studies; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D025341:Principal Component Analysis; D060888:Real-Time Polymerase Chain Reaction; D012137:Respiratory System / Q000378:metabolism*; D059467:Transcriptome; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D018793:Interleukin-13