Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life
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
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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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 3

Human soluble ADAM33 (sADAM33) causes airway “remodeling” in developing lungs.

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Human soluble ADAM33 (sADAM33) causes airway “remodeling” in developing ...
(A–J) Reverse-transcription quantitative PCR (RT-qPCR) for remodeling and inflammatory gene expression in whole-lung lobe lysates from double-transgenic (DTg) Ccsp/ADAM33 or single-transgenic (STg) littermate control mice at embryonic day 17.5 (ED17.5) (n = 12/12) and 10 days postpartum (PD10) (n = 8/10) and 28 days postpartum (PD28) (n = 12/12) in which transgene expression was induced by feeding mice doxycycline during pregnancy and up to 4 weeks after birth: (A) Acta2, (B) Col1a1, (C) Col3a1, (D) Fn1 (E) Pecam1 (F) Ccl11, (G) Il5, (H) Il13, (I) Cxcl1, and (J) Muc5ac (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. Representative immunofluorescence staining for ACTA2/αSMA (green), PECAM1 (red), and nuclei (blue) in lungs from (K and M) STg littermate control or (L and N) DTg Ccsp/Adam33 mice after ADAM33 transgene expression for 4 weeks postpartum. White rectangles in K and L are shown at higher magnification in M and N. Aw, airway; Ve, vessel. Representative immunohistochemistry staining for ACTA2/αSMA (brown) in sections of human embryonic lung explants cultures from 8 to 10 weeks after conception (n = 3) in the presence of (O and Q) recombinant inactive mutant (E346A) ADAM33-Pro-metalloprotease (ADAM33-Pro-MP) and (P and R) enzymatically active ADAM33-Pro-MP. Black rectangles in O and P are shown at higher magnification in Q and R. Scale bar: 100 μm. Results are representative of 3 independent experiments.