Abstract
Background
ADAM33, an asthma susceptibility gene associated with BHR, is a membrane-anchored protein with metalloprotease (MP) activity that can be released in a soluble form. Soluble (s)ADAM33-MP is increased in asthmatic airways and inversely correlated with FEV1.
Aims
We now investigate if human(h) sADAM33-MP causes asthma-like airway remodelling in mouse lungs and if this is reversible when ADAM33 expression is ablated.
Methods
A Doxycycline (Dox) inducible transgenic mouse expressing hsADAM33-MP in the airways was generated. Dox was administered to double- and single-transgenic control mice to induce hsADAM33 expression until 1 and 2 months post partum and lungs were harvested for mRNA, protein and immunohistochemical analyses.
Results
Induction of hsADAM33-MP for 1 and 2 months resulted in significantly increased airway α-smooth muscle actin (α-Sma), fibronectin, collagens I, III, IV, and Pecam-1 mRNAs, suggesting regulation of pulmonary myogenesis, fibrogenesis, and angiogenesis. There was no evidence for airway inflammation. In the group where Dox was stopped at 1 month and analysed at 2 months, these markers were reversed to baseline. Consistent with this, immunohistochemistry indicated reversibility of airway remodelling as a decrease in smooth muscle, collagen and vessel formation in lung sections from hsADAM33 expressing mice.
Conclusions
For the first time, this study demonstrates that expression of hsADAM33-MP in mouse airways induces airway remodelling that is both independent of inflammation and reversible when induction of hsADAM33 is arrested. These findings support the hypothesis that inhibition of hsADAM33-MP is a therapeutic target for treatment or prevention of airway remodelling in asthma.
- © 2014 ERS