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 8

Airway remodeling induced by soluble ADAM33 (sADAM33) is reversible.

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Airway remodeling induced by soluble ADAM33 (sADAM33) is reversible. (A–...
(A–J) Reverse-transcription quantitative PCR (RT-qPCR) for remodeling (n = 9/group) and inflammatory (n = 4/group) gene expression in whole-lung lobe lysates from double-transgenic (DTg) Ccsp/ADAM33 or single-transgenic (STg) littermate control mice in which transgene expression was induced by doxycycline (Dox) feeding during pregnancy and for up to 28 days (28D on Dox) or 56 days (56D on Dox) after birth or Dox feeding for 28 days after birth followed by a cessation of Dox for 28 days (28D on + 28D off Dox): (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. Results are from 3 independent experiments (A–E) and from 1 experiment (F–J). (K–N) Representative immunofluorescence staining for ACTA2/αSMA (green), PECAM1 (red), and nuclei (blue) in lungs from (K) STg littermate control or (L) DTg Ccsp/Adam33 mice in which transgene expression was induced in utero and by Dox feeding postpartum for 28 days and (N) after 56 days. (M) DTg Ccsp/Adam33 mice after ADAM33 transgene expression was induced in utero and by 28 days of Dox feeding postpartum and then 28 days off Dox. Aw, airway; Ve, vessel. Scale bar: 100 μm. Results are representative of 2 independent experiments (K–N).