{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADAM33, a member of the disintegrin and metalloprotease (ADAM) family, is increasingly recognized as a key molecular player in airway structure and function. Predominantly expressed in mesenchymal cells such as airway fibroblasts and bronchial smooth muscle, ADAM33 is implicated in the processes of airway remodeling and bronchial hyperresponsiveness that characterize asthma and related obstructive lung diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Genetic studies have repeatedly associated polymorphisms and haplotypes of ADAM33 with susceptibility to asthma, accelerated decline in lung function, and even chronic obstructive pulmonary disease, suggesting that variants of this gene may predispose individuals to structural changes within the airway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In parallel, expression analyses in patient samples have demonstrated that ADAM33 mRNA and protein levels are elevated in severe disease and are correlated with indices of airway remodeling, including subepithelial fibrosis and smooth muscle alterations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " At the protein level, the catalytic domain of ADAM33 has been characterized structurally and functionally, revealing its ability to cleave substrates that are involved in cell–cell communication and extracellular matrix regulation; notably, the release of a soluble form of ADAM33 may promote angiogenesis and perpetuate remodeling independently of inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Although murine knockout models suggest that ADAM33 is not essential for the development of allergen-induced airway inflammation, the preponderance of human genetic and functional data supports a role for ADAM33 in the aberrant “airway–wall” remodeling that underlies chronic airway obstruction, making it a promising target for novel therapeutic approaches in asthma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Paul Van Eerdewegh, Randall D Little, Josée Dupuis, et al. 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