A disintegrin and metalloproteinase domain-15 (ADAM15) is expressed by cells implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), but its contributions to COPD are unknown. To address this gap, ADAM15 levels were measured in samples from cigarette smoke (CS)-versus air-exposed wild-type (WT) mice. CS-induced COPD-like disease was compared in CS-exposed WT, Adam15^−/−, and Adam15 bone marrow chimeric mice. CS exposure increased Adam15 expression in lung macrophages and CD8⁺ T cells and to a lesser extent in airway epithelial cells in WT mice. CS-exposed Adam15^−/− mice had greater emphysema, small airway fibrosis, and lung inflammation (macrophages and CD8⁺ T cells) than WT mice. Adam15 bone marrow chimera studies revealed that Adam15 deficiency in leukocytes led to exaggerated pulmonary inflammation and COPD-like disease in mice. Adam15 deficiency in CD8⁺ T cells was required for the exaggerated pulmonary inflammation and COPD-like disease in CS-exposed Adam15^−/− mice (as assessed by genetically deleting CD8⁺ T cells in Adam15^−/− mice). Adam15 deficiency increased pulmonary inflammation by rendering CD8⁺ T cells and macrophages resistant to CS-induced activation of the mitochondrial apoptosis pathway by preserving mTOR signaling and intracellular Mcl-1 levels in these cells. These results strongly link ADAM15 deficiency to the pathogenesis of COPD.

去整合素和金属蛋白酶结构域 15 ( ADAM15 )由参与慢性阻塞性肺疾病 (COPD) 发病机制的细胞表达，但其对 COPD 的贡献尚不清楚。为了解决这一差距，在香烟烟雾 (CS) 与暴露于空气的野生型 (WT) 小鼠的样本中测量了 ADAM15 水平。在接触 CS 的 WT、 Adam15 ^-/-和Adam15骨髓嵌合小鼠中比较 CS 诱导的 COPD 样疾病CS 暴露增加肺巨噬细胞和 CD8 ⁺ T 细胞中的 Adam15 表达，并在较小程度上增加 WT 小鼠气道上皮细胞中的表达。CS 暴露的Adam15 ^-/-与 WT 小鼠相比，小鼠的肺气肿、小气道纤维化和肺部炎症（巨噬细胞和 CD8 ⁺ T 细胞）更严重。Adam15骨髓嵌合体研究表明，白细胞中的Adam15缺陷导致小鼠肺部炎症和 COPD 样疾病加重。暴露于 CS 的Adam15 ^-/-小鼠中严重的肺部炎症和 COPD 样疾病需要CD8 ^{+ T 细胞中的}Adam15缺陷（通过遗传删除Adam15 ^{-/-小鼠中的 CD8 +} T 细胞进行评估）。Adam15缺乏通过呈现 CD8 ⁺增加肺部炎症通过在这些细胞中保留 mTOR 信号和细胞内 Mcl-1 水平，T 细胞和巨噬细胞抵抗 CS 诱导的线粒体凋亡途径的激活。这些结果将 ADAM15 缺陷与 COPD 的发病机制密切相关。