Source: International Congress 2014 – COPD: points to ponder
Disease area: Airway diseases

Abstract

BackgroundADAM33Â, an asthma susceptibility gene associated with BHRÂ, 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.AimsWe 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.MethodsA 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 mRNAÂ, protein and immunohistochemical analyses.ResultsInduction of hsADAM33-MP for 1 and 2 months resulted in significantly increased airway a-smooth muscle actin (a-Sma)Â, fibronectinÂ, collagens IÂ, IIIÂ, IVÂ, and Pecam-1 mRNAsÂ, suggesting regulation of pulmonary myogenesisÂ, fibrogenesisÂ, and angiogenesis. There was no evidence for airway inflammation. In the group where Dox was stopped at 1 month and analysed at 2 monthsÂ, these markers were reversed to baseline. Consistent with thisÂ, immunohistochemistry indicated reversibility of airway remodelling as a decrease in smooth muscleÂ, collagen and vessel formation in lung sections from hsADAM33 expressing mice.ConclusionsFor the first timeÂ, 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.

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E. R Davies, L. Zhang, S. T Holgate, D. E Davies, J. A. Whitsett, H. M. Haitchi (Southampton, United Kingdom; Cincinnati, United States Of America). LATE-BREAKING ABSTRACT: Airway remodelling induced by ADAM33 is reversible. Eur Respir J 2014; 44: Suppl. 58, 3625

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