Adam8 limits emphysema development in smoke-exposed mice: A new player in the pathogenesis of COPD

Abstract

Abstract Background A disintegrin and metalloproteinase-8 (ADAM8) is expressed by lung cells implicated COPD pathogenesis. It’s not known whether ADAM8 contributes to COPD pathogenesis. Methods ADAM8 expression was measured in the lungs of COPD patients and controls, and mice exposed to cigarette smoke (CS) versus air by staining lung sections for ADAM8 and markers of different lung cells. Emphysema development and small airway fibrosis were evaluated wild-type (WT), Adam8−/− and Adam8 bone marrow chimeric mice exposed to air or CS for 6 months. Lung inflammation, alveolar septal cell apoptosis, and lung oxidative stress levels were measured in WT vs. Adam8−/− mice exposed acutely to air or CS. Results Adam8 expression is reduced in alveolar macrophages and lung epithelial cells in COPD patients and CS-exposed WT mice. CS-exposed Adam8−/− mice had greater airspace enlargement, alveolar septal cell apoptosis, and oxidative stress levels (but similar small airway fibrosis) versus CS-exposed WT mice. Both leukocyte- and lung parenchymal cell-derived Adam8 mediate Adam8’s protective activities in the lung. CS-exposed Adam8−/− mice had greater lung macrophage counts than WT mice. ADAM8 does not degrade mediators of inflammation or regulate monocyte adhesion or migration. Adam8−/− alveolar macrophages were protected from CS-induced activation of the intrinsic apoptosis pathway. Conclusions ADAM8 protects against CS-induced emphysema development by reducing lung inflammation by increasing macrophage apoptosis and reducing alveolar septal cell death. However, ADAM8’s expression is reduced in COPD lungs. ADAM8 may be a therapeutic target for COPD.