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Elucidating the role of ADAM33 in airway inflammation and remodelling in asthma

Elucidating the role of ADAM33 in airway inflammation and remodelling in asthma
Elucidating the role of ADAM33 in airway inflammation and remodelling in asthma

Asthma is a heterogeneous chronic inflammatory disease characterised by recurrent, reversible airflow obstruction, bronchial hyperresponsiveness (BHR) and airway remodelling. Impaired lung function in childhood asthma has been associated with polymorphisms in ADAM33. Soluble ADAM33 (sADAM33) is increased in bronchial lavage fluid (BALF) from asthmatics and is inversely correlated with FEV1. sADAM33 is induced by TGF-β present in asthmatic lungs, and promotes angiogenesis. ADAM33 expression is developmentally regulated and is influenced by maternal allergy via IL-13. This thesis will examine the hypothesis that alteration in the expression of ADAM33 will influence lung structure, affecting vessel and smooth muscle formation and these subsequent changes will impact on pulmonary function in airway inflammation.

 

In DOX inducible Il-13 transgenic mice, significant neutrophilic inflammation and goblet cell metaplasia were observed. BHR was induced after methacholine challenge and IHC showed increased bronchial smooth muscle. Similarly, in human embryonic and juvenile mouse lungs, IL-13 suppressed Adam33 mRNA but not Acta2. ADAM33 was identified in BALF of the overexpressing mice. ADAM33 enzymatic activity was also significantly increased. In the ADAM33 transgenic model, induction of ADAM33 resulted in enzymatically active sADAM33 in BALF. ADAM33 significantly increased the expression of fibrotic markers suggesting regulation of pulmonary myogenesis, fibrogenesis, and angiogenesis. Consistent with this, immunofluorescence revealed airway remodelling with increased smooth muscle, collagen deposition and vessel formation in ADAM33 mice. In contrast, inflammatory cell counts in BALF, expression of inflammatory mediators and mucus related genes were not altered by ADAM33. In Adam33 -/- challenged with HDM, there was less BHR and eosinophilic and neutrophilic inflammation compared to Adam33 +/+. HDM caused suppression of Adam33 mRNA as well as ectodomain shedding of ADAM33 protein in BALF of wildtype mice that was absent in Adam33 -/-.


The study provides novel data showing expression of sADAM33 in airways to induce myogenesis, fibrogenesis and angiogenesis, consistent with a process causing airway remodelling in the absence of inflammation.

University of Southampton
Davies, Elizabeth R.
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Davies, Elizabeth R.
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Haitchi, Hans
68dadb29-305d-4236-884f-e9c93f4d78fe

Davies, Elizabeth R. (2014) Elucidating the role of ADAM33 in airway inflammation and remodelling in asthma. University of Southampton, Doctoral Thesis, 234pp.

Record type: Thesis (Doctoral)

Abstract

Asthma is a heterogeneous chronic inflammatory disease characterised by recurrent, reversible airflow obstruction, bronchial hyperresponsiveness (BHR) and airway remodelling. Impaired lung function in childhood asthma has been associated with polymorphisms in ADAM33. Soluble ADAM33 (sADAM33) is increased in bronchial lavage fluid (BALF) from asthmatics and is inversely correlated with FEV1. sADAM33 is induced by TGF-β present in asthmatic lungs, and promotes angiogenesis. ADAM33 expression is developmentally regulated and is influenced by maternal allergy via IL-13. This thesis will examine the hypothesis that alteration in the expression of ADAM33 will influence lung structure, affecting vessel and smooth muscle formation and these subsequent changes will impact on pulmonary function in airway inflammation.

 

In DOX inducible Il-13 transgenic mice, significant neutrophilic inflammation and goblet cell metaplasia were observed. BHR was induced after methacholine challenge and IHC showed increased bronchial smooth muscle. Similarly, in human embryonic and juvenile mouse lungs, IL-13 suppressed Adam33 mRNA but not Acta2. ADAM33 was identified in BALF of the overexpressing mice. ADAM33 enzymatic activity was also significantly increased. In the ADAM33 transgenic model, induction of ADAM33 resulted in enzymatically active sADAM33 in BALF. ADAM33 significantly increased the expression of fibrotic markers suggesting regulation of pulmonary myogenesis, fibrogenesis, and angiogenesis. Consistent with this, immunofluorescence revealed airway remodelling with increased smooth muscle, collagen deposition and vessel formation in ADAM33 mice. In contrast, inflammatory cell counts in BALF, expression of inflammatory mediators and mucus related genes were not altered by ADAM33. In Adam33 -/- challenged with HDM, there was less BHR and eosinophilic and neutrophilic inflammation compared to Adam33 +/+. HDM caused suppression of Adam33 mRNA as well as ectodomain shedding of ADAM33 protein in BALF of wildtype mice that was absent in Adam33 -/-.


The study provides novel data showing expression of sADAM33 in airways to induce myogenesis, fibrogenesis and angiogenesis, consistent with a process causing airway remodelling in the absence of inflammation.

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Corrected Thesis_Lizzie Davies - Version of Record
Available under License University of Southampton Thesis Licence.
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Published date: March 2014

Identifiers

Local EPrints ID: 415835
URI: https://eprints.soton.ac.uk/id/eprint/415835
PURE UUID: f4ed77f5-a10f-409b-a435-7b71770b312c
ORCID for Hans Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

Catalogue record

Date deposited: 24 Nov 2017 17:30
Last modified: 14 Mar 2019 01:45

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Contributors

Author: Elizabeth R. Davies
Thesis advisor: Hans Haitchi ORCID iD

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