Introduction and objectives ADAM33 is an asthma susceptibility gene associated with bronchial hyperresponsiveness (BHR). It encodes a membrane-anchored protein with metalloprotease (MP) activity whose ectodomain can be shed from the cell surface as a soluble protein (sADAM33-MP). sADAM33-MP levels are increased in asthmatic airways and inversely correlated with FEV1. We have previously generated a pulmonary epithelium-specific, doxycycline (DOX)-inducible double transgenic (dTg) mouse expressing human (h)sADAM33-MP and found that the transgene caused airway remodelling in the absence of inflammation or BHR. Therefore, as asthma involves gene-environment interactions, we postulated that there is a synergistic relationship between ADAM33-remodelled airways and responses to the common aeroallergen, house dust mite (HDM).

Methods DOX was administered to dTg mice to induce hsADAM33 expression and airway remodelling for up to 6 weeks; single transgenic (sTg) littermate controls were similarly treated. Mice were then sensitised to HDM and challenged with HDM or saline. Airway resistance was measured in response to increasing concentrations of methacholine using the forced oscillation technique in anesthetised mice. Inflammatory cell counts were performed on bronchoalveolar lavage fluid (BALF) and indices of inflammation measured by RTqPCR and Luminex ELISA.

Results We first performed a concentration-response experiment with HDM extract with a standard sensitisation protocol to determine the amount of HDM extract (6.25 μg), which elicited minimal BHR and eosinophilia. This low-dose allergen challenge protocol was then applied to dTg Ccsp/ADAM33 and sTg control mice. Allergen challenge of dTg mice resulted in a significant increase in methacholine-induced airway resistance and eosinophilic airway inflammation compared to HDM-challenged sTg controls. The dTg mice also showed a significant increase in airway inflammatory mediators IL-5, IL-13 and eotaxin, in addition to markers of remodelling.

Conclusions This study demonstrates that hsADAM33-MP driven airway remodelling enhances susceptibility to HDM with increases in BHR and inflammation. These functional studies demonstrate, for the first time, a gene-environment interaction involving ADAM33 to cause remodelling and the disproportional inflammatory responses seen in the asthmatic airway. sADAM33 might be a potential target for novel disease-modifying therapies.