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

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 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) 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 postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold 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.

SUBMITTER: Davies ER

PROVIDER: S-EPMC4968941 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Davies Elizabeth R ER Kelly Joanne F C JF Howarth Peter H PH Wilson David I DI Holgate Stephen T ST Davies Donna E DE Whitsett Jeffrey A JA Haitchi Hans Michael HM

JCI insight 20160701 11

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 33 (<i>ADAM33</i>) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in ...[more]

PMID: 27489884

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

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

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