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Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life
Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life
Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene A Disintegrin and Metalloprotease (ADAM)33, acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble (s)ADAM33 is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33 null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances post-natal airway eosinophilia and bronchial hyperresponsiveness following sub-threshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma.
2379-3708
1-16
Davies, Elizabeth R.
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Kelly, Joanne F.
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Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Wilson, David
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Holgate, Stephen
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Davies, Donna E.
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Whitsett, Jeffrey A.
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Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Davies, Elizabeth R.
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Kelly, Joanne F.
b7094829-aeb1-4bc1-b64c-7b7c716f73b5
Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Wilson, David
1500fca1-7082-4271-95f4-691f1d1252a2
Holgate, Stephen
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe

Davies, Elizabeth R., Kelly, Joanne F., Howarth, Peter H., Wilson, David, Holgate, Stephen, Davies, Donna E., Whitsett, Jeffrey A. and Haitchi, Hans Michael (2016) Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight, 1 (11), 1-16. (doi:10.1172/jci.insight.87632).

Record type: Article

Abstract

Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene A Disintegrin and Metalloprotease (ADAM)33, acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble (s)ADAM33 is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33 null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances post-natal airway eosinophilia and bronchial hyperresponsiveness following sub-threshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma.

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More information

Accepted/In Press date: 9 June 2016
e-pub ahead of print date: 21 July 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 396941
URI: https://eprints.soton.ac.uk/id/eprint/396941
ISSN: 2379-3708
PURE UUID: c79e8c02-b363-41bb-b2e0-4735cfbdeeef
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: 22 Jul 2016 08:13
Last modified: 07 Nov 2019 05:01

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