Editors' ChoiceAsthma

Airway architect Adam33 in asthma

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Science Translational Medicine  17 Aug 2016:
Vol. 8, Issue 352, pp. 352ec130
DOI: 10.1126/scitranslmed.aah5493

In asthma, inflammation results in bronchial constriction, mucus hypersecretion, and airway remodeling. This pathology is thought to stem from a collusion of genetic predisposition and environmental factors, such as viruses or allergens, but specific airway molecules that choreograph the interaction between genes and environment remain unidentified. Genetic polymorphisms in ADAM33, a membrane-anchored protease expressed in multiple airway cell types, have been associated in population studies with asthma susceptibility and bronchial hyperresponsiveness. Davies et al. explored the pathobiology of this protein and have discovered a link between ADAM33 and allergic inflammation.

The authors first found that the expression of enzymatically active ADAM33 was increased in bronchoalveolar lavage fluid from patients with asthma and in mice sensitized and challenged with house dust mite extract, a model of allergic airway inflammation. Interestingly, inducible overexpression of soluble ADAM33 in the airway of both embryonic and adult mice increased lung expression of genes associated with asthmatic airway remodeling. Human fetal lung explants treated with recombinant ADAM33 had similar gene expression changes but not when treated with a recombinant mutant lacking protease activity.

Interestingly, ADAM33 overexpression alone did not increase inflammatory genes or cause bronchial hyperresponsiveness. However, the authors found an interaction between ADAM33 and the allergic stimulus: induction of soluble ADAM33 overexpression in the house dust mite model increased bronchial hyperresponsiveness, bronchoalveolar lavage eosinophilia, and lung expression of genes associated with T helper 2 (TH2) inflammation compared with the house dust mite model alone. Furthermore, ADAM33–/– mice in the house dust mite model were protected from airway remodeling and also had decreased bronchial hyperresponsivness, bronchoalveolar lavage eosinophil count, and lung expression of TH2 genes. Of note, airway remodeling could be reversed with cessation of transgene induction, which suggests that inhibition of ADAM33 could reverse airway pathology related to allergic inflammation.

Taken together, these studies establish that ADAM33 mediates the airway inflammatory and remodeling effects of allergen and is a potential therapeutic target for asthma. Future studies aiming for clinical translation should devise strategies for inhibition of ADAM33 in vivo and test its role in other models of asthmatic airway inflammation.

E. R. Davies et al., Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. JCI Insight 1, e87632 (2016). [Full Text]

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