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 2

Transgenic expression of human soluble ADAM33 (sADAM33) causes airway remodeling.

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Transgenic expression of human soluble ADAM33 (sADAM33) causes airway re...
(A) Human ADAM33 mRNA in single-transgenic (STg) littermate control and double-transgenic (DTg) Ccsp/ADAM33 mouse lungs. (B and C) Representative immunofluorescence staining images for human ADAM33 (red), ACTA2/αSMA (green), and nuclei (blue) in lungs from (B) STg littermate control and (C) DTg Ccsp/ADAM33 mice. Scale bar: 50 μm. (D) Western blotting for human ADAM33 in BALF from DTg Ccsp/ADAM33 or STg control mice. (E) Fluorescence resonance energy transfer (FRET) peptide cleavage assay for ADAM33 enzymatic activity in bronchoalveolar lavage fluid (BALF) from DTg Ccsp/ADAM33 (red) mice, STg (blue) mice, or saline controls (black). Representative traces are shown. (F–O) Relative mRNA expression in whole-lung lobe lysates from adult DTg Ccsp/ADAM33 mice (gray bars) after induction of human ADAM33 for 4 (n = 13) or 8 weeks (n = 16) versus STg littermate controls (white bars) (n = 16 or n = 12, respectively): (F) Ccl11, (G) Il5, (H) Il13, (I) Cxcl1, (J) Muc5ac, (K) Acta2, (L) Col1a1, (M) Col3a1, (N) Fn1, and (O) Pecam1 (2-way ANOVA, Tukey’s multiple comparison 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 (F–O). Representative immunofluorescence staining for ACTA2/αSMA (green), PECAM1 (red), and nuclei (blue) in lungs from (P and R) STg littermate control or (Q and S) DTg Ccsp/ADAM33 mice after 8 weeks of transgene expression. White rectangles in P and Q are shown at higher magnification in R and S. Aw, airway; Ve, vessel. Scale bar: 100 μm. Results are representative of 3 independent experiments (P–S). Full unedited Western blots are available in the Supplemental Material.