ADAM17 Deficiency Protects against Pulmonary Emphysema

• Published in: American journal of respiratory cell and molecular biology Vol. 64; no. 2; pp. 183 - 195
• Main Authors: Saad, Mohamed I, McLeod, Louise, Hodges, Christopher, Vlahos, Ross, Rose-John, Stefan, Ruwanpura, Saleela, Jenkins, Brendan J
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.02.2021
• Subjects: ADAM17 Protein - deficiency; ADAM17 Protein - metabolism; Animals; Apoptosis - physiology; Chronic obstructive pulmonary disease; Cytokines - metabolism; Emphysema; Humans; Lung - metabolism; Lung diseases; Mice; Nicotiana - adverse effects; Obstructive lung disease; Pathogenesis; Pneumonia - metabolism; Proteases; Proteinase; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Emphysema - metabolism; Smoking - adverse effects; Studies; cigarette smoking; apoptosis; ADAM17; inflammation; emphysema
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/RCMB.2020-0214OC

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 (A disintegrin and metalloproteinase 17) protease mediates inflammation via ectodomain shedding of numerous proinflammatory 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 patients with emphysema, as well as lungs of the emphysematous mouse model and an acute (4 d) cigarette smoke (CS)-induced lung pathology model. The mice, which display significantly reduced global ADAM17 expression, were coupled with emphysema-prone mice to produce : . Both and wild-type 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 patients with emphysema and also in emphysematous and CS-exposed mice. ADAM17 deficiency ameliorated the development of pulmonary emphysema in 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.