Department of Clinical and Diagnostic Science.
Department of Pathology.
Am J Respir Crit Care Med. 2023 Nov 15;208(10):1115-1125. doi: 10.1164/rccm.202303-0471OC.
Mounting evidence demonstrates a role for extracellular vesicles (EVs) in driving lung disorders, such as chronic obstructive pulmonary disease (COPD). Although cigarette smoke (CS) is the primary risk factor for COPD, a link between CS and the EVs that could lead to COPD is unknown. To ascertain whether exposure to CS elicits a proteolytic EV signature capable of driving disease pathogenesis. Protease expression and enzymatic activity were measured in EVs harvested from the BAL fluid of smoke-exposed mice and otherwise healthy human smokers. Pathogenicity of EVs was examined using pathological tissue scoring after EV transfer into naive recipient mice. The analyses revealed a unique EV profile defined by neutrophil- and macrophage-derived EVs. These EVs are characterized by abundant surface expression of neutrophil elastase (NE) and matrix metalloproteinase 12 (MMP12), respectively. CS-induced mouse or human-derived airway EVs had a robust capacity to elicit rapid lung damage in naive recipient mice, with an additive effect of NE- and MMP12-expressing EVs. These studies demonstrate the capacity of CS to drive the generation of unique EV populations containing NE and MMP12. The coordinated action of these EVs is completely sufficient to drive emphysematous disease, and their presence could operate as a prognostic indicator for COPD development. Furthermore, given the robust capacity of these EVs to elicit emphysema in naive mice, they provide a novel model to facilitate preclinical COPD research. Indeed, the development of this model has led to the discovery of a previously unrecognized CS-induced protective mechanism against EV-mediated damage.
越来越多的证据表明，细胞外囊泡（EVs）在驱动肺部疾病（如慢性阻塞性肺疾病（COPD））方面发挥着作用。虽然香烟烟雾（CS）是 COPD 的主要危险因素，但 CS 与导致 COPD 的 EV 之间的联系尚不清楚。为了确定 CS 暴露是否会引发能够驱动疾病发病机制的蛋白水解 EV 特征。从暴露于 CS 的小鼠的 BAL 液中收获的 EV 中测量蛋白酶表达和酶活性，并在其他健康的人类吸烟者中进行。通过将 EV 转移到幼稚受体小鼠中后进行病理组织评分来检查 EV 的致病性。分析显示，由中性粒细胞和巨噬细胞衍生的 EV 定义的独特 EV 谱。这些 EV 的特征是分别富含中性粒细胞弹性蛋白酶（NE）和基质金属蛋白酶 12（MMP12）的表面表达。CS 诱导的小鼠或人源性气道 EV 具有在幼稚受体小鼠中迅速引起肺损伤的强大能力，NE 和 MMP12 表达的 EV 具有附加作用。这些研究表明 CS 能够驱动包含 NE 和 MMP12 的独特 EV 群体的产生。这些 EV 的协同作用完全足以驱动肺气肿疾病，其存在可以作为 COPD 发展的预后指标。此外，鉴于这些 EV 在幼稚小鼠中引起肺气肿的强大能力，它们提供了一种新的模型来促进 COPD 的临床前研究。事实上，该模型的开发导致了发现以前未被认识到的 CS 诱导的针对 EV 介导的损伤的保护机制。
