A disintegrin and metalloproteinase Domain-9: A novel proteinase culprit with multifarious contributions to chronic obstructive pulmonary disease

Rationale: ADAMs (proteinases with a disintegrin and a metalloproteinase domain) have not been well studied in chronic obstructive pulmonary disease (COPD). Objectives: To investigate whether ADAM9 is linked to COPD in humans and mice. Methods: ADAM9 blood and lung levels were measured in patients with COPD versus control subjects, and in air-versus cigarette smoke (CS)-exposed wild-type mice. Wild-type and Adam9 mice were exposed to air or CS for 1-6 months, and COPD-like lung pathologies were measured. Measurements and Main Results: ADAM9 staining was increased in lung epithelial cells and macrophages in smokers and even more so in patients with COPD and correlated directly with pack-year smoking history and inversely with airflow obstruction and/or FEV1 percent predicted. Bronchial epithelial cell ADAM9 mRNA levels were higher in patients with COPD than control subjects and correlated directly with pack-year smoking history. Plasma, BAL fluid, and sputum ADAM9 levels were similar in patients with COPD and control subjects. CS exposure increased Adam9 levels in wild-type murine lungs. Adam9 mice were protected from emphysema development, small-airway fibrosis, and airway mucus metaplasia. CS-exposed Adam9 mice had reduced lung macrophage counts, alveolar septal cell apoptosis, lung elastin degradation, and shedding of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor in BAL fluid samples. Recombinant ADAM9 sheds epidermal growth factor and vascular endothelial growth factor receptors from epithelial cells to reduce activation of the Akt prosurvival pathway and increase cellular apoptosis. Conclusions: ADAM9 levels are increased in COPD lungs and linked to key clinical variables. Adam9 promotes emphysema development, and large- and small-airway disease in mice. Inhibition of ADAM9 could be a therapeutic approach for multiple COPD phenotypes.