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Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by IL-13

Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by IL-13
Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by IL-13
Effective treatment for severe corticosteroid refractory asthma is a significant unmet clinical need. It affects only a small percent of the asthmatic population but accounts for a disproportionate use of healthcare resources. The aim was to study IL-13 transgenic mice to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms.

IL-13 expression in the lungs was induced using Doxycycline in Ccsp-rtTA/Otet-Il-13 (Ccsp/Il-13) mice. Where indicated, mice received intra-peritoneal injections of 3mg/kg Dexamethasone for 3-7 days. Lungs were analysed for airway hyperreactivity and inflammation.

Compared to controls, Ccsp/Il-13 mice showed significantly increased airway hyperresponsiveness (AHR) to methacholine and immunohistochemistry revealed increased bronchial smooth muscle and goblet cell metaplasia. The bronchoalveolar lavage fluid contained mixed eosinophilic and neutrophilic inflammation, but neutrophils predominated. Characteristic Th2-responsive genes as well as genes associated with Th17 responses were significantly elevated. Treatment with steroids did not abrogate AHR, even though eosinophilia and the ‘Th2’ gene signature were significantly reduced. Neutrophils and the ‘Th17’ signature remained elevated.

Although IL-13 promotes eosinophilic airways disease, it can also drive corticosteroid refractory inflammation characterised by persistent neutrophilia, Th17 cytokines and maintenance of AHR. The Ccsp/Il-13 mouse may be a useful model for dissecting the molecular pathways and mechanisms associated with predominant neutrophilic, corticosteroid refractory airway disease.
Corticosteroid resistance, Neutrophilic, airway inflammation, airway hyperresponsiveness, IL-13
111 PA973
Davies, Elizabeth R
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Davies, Donna E
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Davies, Elizabeth R
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Kelly, Joanne, Freda Carmichael
5950d431-bc7e-4bad-817b-77446fc7332e
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Davies, Donna E
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe

Davies, Elizabeth R, Kelly, Joanne, Freda Carmichael, Whitsett, Jeffrey A., Davies, Donna E and Haitchi, Hans Michael (2018) Corticosteroid-resistant neutrophilic airway inflammation and hyperresponsiveness caused by IL-13. European Respiratory Society (ERS) International Congress 2018, , Paris, France. 15 - 19 Sep 2018. 111 PA973 .

Record type: Conference or Workshop Item (Poster)

Abstract

Effective treatment for severe corticosteroid refractory asthma is a significant unmet clinical need. It affects only a small percent of the asthmatic population but accounts for a disproportionate use of healthcare resources. The aim was to study IL-13 transgenic mice to test the hypothesis that a subset of IL-13 mediated airway responses are corticosteroid-unresponsive and contribute to ongoing airways symptoms.

IL-13 expression in the lungs was induced using Doxycycline in Ccsp-rtTA/Otet-Il-13 (Ccsp/Il-13) mice. Where indicated, mice received intra-peritoneal injections of 3mg/kg Dexamethasone for 3-7 days. Lungs were analysed for airway hyperreactivity and inflammation.

Compared to controls, Ccsp/Il-13 mice showed significantly increased airway hyperresponsiveness (AHR) to methacholine and immunohistochemistry revealed increased bronchial smooth muscle and goblet cell metaplasia. The bronchoalveolar lavage fluid contained mixed eosinophilic and neutrophilic inflammation, but neutrophils predominated. Characteristic Th2-responsive genes as well as genes associated with Th17 responses were significantly elevated. Treatment with steroids did not abrogate AHR, even though eosinophilia and the ‘Th2’ gene signature were significantly reduced. Neutrophils and the ‘Th17’ signature remained elevated.

Although IL-13 promotes eosinophilic airways disease, it can also drive corticosteroid refractory inflammation characterised by persistent neutrophilia, Th17 cytokines and maintenance of AHR. The Ccsp/Il-13 mouse may be a useful model for dissecting the molecular pathways and mechanisms associated with predominant neutrophilic, corticosteroid refractory airway disease.

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More information

Published date: 16 September 2018
Venue - Dates: European Respiratory Society (ERS) International Congress 2018, , Paris, France, 2018-09-15 - 2018-09-19
Keywords: Corticosteroid resistance, Neutrophilic, airway inflammation, airway hyperresponsiveness, IL-13

Identifiers

Local EPrints ID: 428127
URI: http://eprints.soton.ac.uk/id/eprint/428127
PURE UUID: f0904e0d-48ff-429b-adb5-989ca35f4640
ORCID for Elizabeth R Davies: ORCID iD orcid.org/0000-0002-8629-8324
ORCID for Donna E Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

Catalogue record

Date deposited: 12 Feb 2019 17:30
Last modified: 10 Nov 2021 03:25

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Contributors

Author: Joanne, Freda Carmichael Kelly
Author: Jeffrey A. Whitsett
Author: Donna E Davies ORCID iD

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