Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life
Elizabeth R. Davies, … , Jeffrey A. Whitsett, Hans Michael Haitchi
Elizabeth R. Davies, … , Jeffrey A. Whitsett, Hans Michael Haitchi
Published July 21, 2016
Citation Information: JCI Insight. 2016;1(11):e87632. https://doi.org/10.1172/jci.insight.87632.
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Research Article Pulmonology

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.

Authors

Elizabeth R. Davies, Joanne F.C. Kelly, Peter H. Howarth, David I. Wilson, Stephen T. Holgate, Donna E. Davies, Jeffrey A. Whitsett, Hans Michael Haitchi

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Figure 1

Increased soluble ADAM33 (sADAM33) enzymatic activity in bronchoalveolar lavage fluid (BALF) in human asthma and allergic mice.

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Increased soluble ADAM33 (sADAM33) enzymatic activity in bronchoalveolar...
(A) Western blotting of BALF proteins from healthy (n = 5) and asthmatic (n = 10) subjects using an antibody recognizing the metalloprotease domain of human ADAM33; representative blots are shown. (B) Combined ADAM33-immunoreactive bands (at approximately 25 kDa and between approximately 52 and 76 kDa) were analyzed by densitometry in arbitrary units (AU) (Mann Whitney test). (C) Fluorescence resonance energy transfer (FRET) peptide cleavage assay for ADAM33-specific enzymatic activity in BALF from healthy (n = 5) and asthmatic donors (n = 10), expressed as relative fluorescence units per minute (RFU/min) (Mann Whitney test). (D) Immunoblotting of BALF protein from WT mice challenged with house dust mite (HDM) extract or saline (Sal) (n = 6 per group) with an antibody against mouse ADAM33 extracellular domain. (E) Semiquantitative analysis (bands at approximately 52 and 76 kDa) by densitometry (Mann Whitney test). (F) FRET peptide cleavage assay using murine BALF from HDM-challenged mice or saline controls (n = 6 per group) (Mann Whitney test). Box plots show medians and 25th to 75th percentiles, and whiskers represent minimum and maximum values; all data points are shown. Results are from 3 independent experiments (D–F). Full unedited Western blots are available in the Supplemental Material.