MSC-EVs alleviate sepsis-induced acute lung injury through inhibiting NET-triggered damage to adherens junctions of endothelial cells.

Neutrophil extracellular traps (NETs) play a crucial role in the progression of sepsis-induced acute lung injury (SI-ALI). Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) are considered to have potential therapeutic effects on SI-ALI. Nevertheless, a comprehensive understanding of the precise mechanism is currently lacking. This study intends to illustrate the therapeutic mechanisms of MSC-EVs against NET-mediated SI-ALI. In vivo and in vitro experiments demonstrate that NETs reduced the expression of VE-cadherin through calpain 1/2 activation, thereby impairing endothelial barrier function and exacerbating the pathogenesis of SI-ALI. MSC-EVs were found to alleviate SI-ALI by reducing the formation of NETs. Additionally, MSC-EVs inhibited NET generation by shifting NETosis to apoptosis through the ROS/AKT pathway. This study delineates the pathogenic role of NET-induced endothelial injury in SI-ALI and promotes MSC-EVs as a novel therapeutic approach for this disease.