Pathogenic extracellular vesicles link smoking to COPD

<bold>Rationale:</bold> The role of extracellular vesicles (EVs) in lung diseases is being increasingly recognized. We have previously shown that neutrophil-derived EVs isolated from COPD patients could transfer disease to a naïve mouse. Here, we developed a mouse model to determine whether exposure to cigarette smoke (CS) could drive the generation of pathogenic EVs. <bold>Methods:</bold> EVs were isolated from the bronchoalveolar lavage fluid (BALF) of mice exposed to CS for 1 week and up to 6 months. Origin of EVs and presence of neutrophil elastase (NE) and matrix metalloproteinase 12 (MMP-12) on their surface was assessed by flow cytometry and enzymatic activity. Transfer of disease into naïve animals was performed by EV delivery into the airways with or without specific protease inhibitors. Further, EVs isolated from current smokers or never smokers BALF were transferred into naïve mice. Tissue damage for all experiments was quantified by pathological tissue scoring. <bold>Results:</bold> EVs from CS exposed mice were able to transfer disease into naïve recipients in an exposure-dependent manner, where longer exposure to CS resulted in highly pathogenic EVs compared to shorter CS exposure. Presence of NE and MMP-12 were detected on the surface of these EVs. Further, CS-derived or current smokers-derived EVs elicited rapid lung damage (1 week) in naïve animals due to an observed additive effect of NE and MMP-12. <bold>Conclusions:</bold> These result show that exposure to CS drives the generation of pathogenic EVs in mice and humans. The pathogenicity of such EVs was entirely dependent on the presence of NE and MMP-12. Further, we established a preclinical model to study the role of EVs in the development of COPD with the ability to perform future therapeutic interventions.