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 gp130^F/F mouse model and an acute (4 d) cigarette smoke (CS)–induced lung pathology model. The Adam17^ex/ex mice, which display significantly reduced global ADAM17 expression, were coupled with emphysema-prone gp130^F/F mice to produce gp130^F/F:Adam17^ex/ex. Both Adam17^ex/ex 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 gp130^F/F and CS-exposed mice. ADAM17 deficiency ameliorated the development of pulmonary emphysema in gp130^F/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.

肺气肿是慢性阻塞性肺病 (COPD) 的主要使人衰弱的因素，而慢性阻塞性肺病是全世界发病和死亡的主要原因。 ADAM17（解整合素和金属蛋白酶 17）蛋白酶通过胞外域释放大量促炎细胞因子、细胞因子受体和粘附分子来介导炎症；然而，其在肺气肿和慢性阻塞性肺病发病机制中的作用尚不清楚。本研究旨在明确蛋白酶 ADAM17 在肺气肿发病机制中的作用。在肺气肿患者的肺活检、肺气肿gp130 ^F/F小鼠模型和急性（4 天）香烟烟雾 (CS) 诱导的肺病理模型的肺中研究了 ADAM17 蛋白的表达和激活。 Adam17 ^ex/ex小鼠整体 ADAM17 表达显着降低，与易发生肺气肿的gp130 ^F/F小鼠偶联，产生gp130 ^F/F ： Adam17 ^ex/ex 。 Adam17 ^ex/ex和野生型小鼠均受到急性 CS 暴露。进行组织学、免疫组织化学、免疫荧光和分子分析以及肺功能测试来评估肺气肿、炎症和肺泡细胞凋亡。 ADAM17 在肺气肿患者的肺部以及肺气肿gp130 ^F/F和 CS 暴露小鼠的肺部过度磷酸化。 ADAM17 缺陷通过抑制肺泡细胞凋亡增加来改善gp130 ^F/F小鼠肺气肿的发展。 此外，ADAM17 的基因阻断可以保护小鼠免受 CS 诱导的肺部炎症和肺泡细胞凋亡的影响。我们的研究将蛋白酶 ADAM17 作为与肺气肿发生有关的中心分子开关，这为使用 ADAM17 抑制剂作为治疗 COPD 和肺气肿的潜在治疗药物铺平了道路。