Abstract
RATIONALE: In chronic obstructive pulmonary disease (COPD), neutrophil (PMN)-derived neutrophil elastase positive (NE+) extracellular vesicles (EVs) induce many of the pathologic features of the disorder, including emphysema. Chronic PMN inflammation is a hallmark of COPD, however the mechanisms driving chronic recruitment of PMNs into the lung are poorly understood. OBJECTIVE: In this study, we tested the hypothesis that PMN-derived, NE + EVs can spawn additional NE + EVs and promote chronic PMN inflammation. METHODS: NE + and NE- EVs were generated in vitro upon stimulation of isolated human neutrophils with fMLF or the matrikine Proline-Glycine-Proline (PGP). Smoke EVs were isolated from mice exposed to cigarette smoke. EVs were transferred into naïve mice and mouse PMN EVs were isolated 7 days later. Serial transfers of mouse EVs into naïve recipients were performed to determine the self-propagating nature of NE + EVs. MEASUREMENTS AND MAIN RESULTS: Activated human PMN-derived (ie, CD66b+/NE+) EVs, but not NE- EVs, elicited the de novo generation of murine PMN-derived Ly6G+/NE + EVs in recipient mouse airways. These Ly6G+/NE + EVs serially propagated emphysema and de novo NE + EV production in multiple passages between new naïve recipients. This process is driven by such mouse NE + EVs apparently generating PGP that causes both PMN influx into the airways and activation of the newly arrived PMNs to release yet more NE + EVs. Likewise, smoke-elicited EVs were able to serially propagate emphysema. CONCLUSION: These findings have far reaching implications for our understanding of COPD, chronic inflammation, and EVs as self-propagating agents in smokers and COPD patients.