Human mesenchymal stromal cells small extracellular vesicles attenuate sepsis-induced acute lung injury in a mouse model: the role of oxidative stress and the mitogen-activated protein kinase/nuclear factor kappa B pathway

Background aims: Acute lung injury (ALI) secondary to sepsis is a complex disease associated with high morbidity and mortality. Mesenchymal stem cells (MSCs) and their conditioned medium have been demonstrated to reduce alveolar inflammation, improve lung endothelial barrier permeability and modulate oxidative stress in vivo and in vitro. Recently, MSCs have been found to release small extracellular vesicles (sEVs) that can deliver functionally active biomolecules into recipient cells. The authors' study was designed to determine whether sEVs released by MSCs would be effective in sepsis-induced ALI mice and to identify the potential mechanisms. Methods: A total of 6 h after cercal ligation and puncture, the mice received saline, sEV-depleted conditioned medium (sEVD-CM) or MSC sEVs via the tail vein. Results: The administration of MSC sEVs improved pulmonary microvascular permeability and inhibited both histopathological changes and the infiltration of polymorphonuclear neutrophils into lung tissues. In addition, the activities of antioxidant enzymes were significantly increased in the group treated with sEVs compared with the saline and sEVD-CM groups, whereas lipid peroxidation was significantly decreased. Furthermore, sEVs were found to possibly inhibit phosphorylation of the mitogen-activated protein kinase/nuclear factor kappa B (MAPK/NF-kappa B) pathway and degradation of I kappa B but increase the activities of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1. Conclusions: These findings suggest that one of the effective therapeutic mechanisms of sEVs against sepsis-induced ALI may be associated with upregulation of anti-oxidative enzymes and inhibition of MAPK/NF-kappa B activation. (C) 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.

Automated summary

The study demonstrated the therapeutic effects of MSC-derived sEVs on sepsis-induced ALI in mice, showing improvements in lung injury, reduced inflammation, and increased antioxidant enzyme activity. Additionally, sEVs may exert their effects by inhibiting phosphorylation of the MAPK/NF-kappa B pathway and I kappa B degradation, while increasing the activity of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1.