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Altered epithelial gene expression in peripheral airways of severe asthma

Altered epithelial gene expression in peripheral airways of severe asthma
Altered epithelial gene expression in peripheral airways of severe asthma

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.

1932-6203
Singhania, Akul
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Rupani, Hitasha
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Jayasekera, Nivenka
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Lumb, Simon
73cfade0-96c0-4a26-9448-44373a84a99f
Hales, Paul
c7728e29-1f0c-4a80-afb2-327aeb42c65c
Gozzard, Neil
d6dccab8-d170-4280-9289-82acabebc156
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Singhania, Akul
322f628d-5374-49ec-b7d7-13bb3885d636
Rupani, Hitasha
cbc7068a-4279-4c8e-b83f-353210711062
Jayasekera, Nivenka
2dd458a6-97a3-4c79-b922-2e91c8fc8117
Lumb, Simon
73cfade0-96c0-4a26-9448-44373a84a99f
Hales, Paul
c7728e29-1f0c-4a80-afb2-327aeb42c65c
Gozzard, Neil
d6dccab8-d170-4280-9289-82acabebc156
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21

Singhania, Akul, Rupani, Hitasha, Jayasekera, Nivenka, Lumb, Simon, Hales, Paul, Gozzard, Neil, Davies, Donna E., Woelk, Christopher H. and Howarth, Peter H. (2017) Altered epithelial gene expression in peripheral airways of severe asthma. PLoS ONE, 12 (1), [e0168680]. (doi:10.1371/journal.pone.0168680).

Record type: Article

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.

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More information

Published date: 3 January 2017
Additional Information: Funding Information: Gene array analysis was funded by UCB Celtech as part of an academic collaboration with The University of Southampton. This commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials. Publisher Copyright: © 2017 Singhania et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Identifiers

Local EPrints ID: 475280
URI: http://eprints.soton.ac.uk/id/eprint/475280
ISSN: 1932-6203
PURE UUID: 14a599ed-30d5-4a39-a776-2312f1b582fa
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991

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Date deposited: 14 Mar 2023 18:01
Last modified: 06 Jun 2024 01:32

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Contributors

Author: Akul Singhania
Author: Hitasha Rupani
Author: Nivenka Jayasekera
Author: Simon Lumb
Author: Paul Hales
Author: Neil Gozzard
Author: Donna E. Davies ORCID iD
Author: Christopher H. Woelk

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