ADAM17 Deficiency Protects Against Pulmonary Emphysema

Pulmonary emphysema is the major debilitating component of chronic obstructive pulmonary disease (COPD), which is a leading cause of morbidity and mortality worldwide. The ADAM17 protease mediates inflammation via ectodomain shedding of numerous pro-inflammatory cytokines, cytokine receptors and adhesion molecules, however, its role in the pathogenesis of emphysema and COPD is poorly understood. This study aims to define the role of the protease ADAM17 in the pathogenesis of pulmonary emphysema. ADAM17 protein expression and activation was investigated in lung biopsies from emphysema patients, as well as lungs of the emphysematous gp130F/F mouse model and an acute (4 day) cigarette smoke (CS)-induced lung pathology model. The Adam17ex/ex mice, which display significantly reduced global ADAM17 expression, were coupled with emphysema-prone gp130F/F mice to produce gp130F/F:Adam17ex/ex. Both Adam17ex/ex and WT mice were subjected to acute CS exposure. Histological, immunohistochemical, immunofluorescence and molecular analyses, as well as lung function tests, were performed to assess pulmonary emphysema, inflammation and alveolar cell apoptosis. ADAM17 was hyperphosphorylated in the lungs of emphysema patients, and also emphysematous gp130F/F and CS-exposed mice. ADAM17 deficiency ameliorated the development of pulmonary emphysema in gp130F/F mice by suppressing elevated alveolar cell apoptosis. In addition, genetic blockade of ADAM17 protected mice from CS-induced pulmonary inflammation and alveolar cell apoptosis. Our study places the protease ADAM17 as a central molecular switch implicated in the development of pulmonary emphysema, which paves the way for using ADAM17 inhibitors as potential therapeutic agents to treat COPD and emphysema.