Inhalation of MSC-EVs is a noninvasive strategy for ameliorating acute lung injury.

Abstract

Mesenchymal stem cell-derived small extracellular vesicles (MSC-EVs) are promising nanotherapeutic agent for pneumonia (bacterial origin, COVID-19), but the optimal administration route and potential mechanisms of action remain poorly understood. This study compared the administration of MSC-EVs via inhalation and tail vein injection for the treatment of acute lung injury (ALI) and determined the host-derived mechanisms that may contribute to the therapeutic effects of MSC-EVs in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (macrophage cell line) and animal models. Luminex liquid chip and hematoxylin and eosin (HE) staining revealed that, compared with the vehicle control, inhaled MSC-EVs outperformed those injected via the tail vein, by reducing the expression of pro-inflammatory cytokines, increasing the expression of anti-inflammatory cytokine, and decreasing pathological scores in ALI. MSC-EV administration promoted the polarization of macrophages towards a M2 phenotype in vitro and in vivo (via inhalation). RNA sequencing revealed that immune and redox mediators, including TLR4, Arg1, and HO-1, were associated with the activity MSC-EVs against ALI mice. Western blotting and immunofluorescence revealed that correlative inflammatory and oxidative mediators were involved in the therapeutic effects of MSC-EVs in LPS-stimulated cells and mice. Moreover, variable expression of Nrf2 was observed following treatment with MSC-EVs in cell and animal models, and knockdown of Nrf2 attenuated the anti-inflammatory and antioxidant activities of MSC-EVs in LPS-stimulated macrophages. Together, these data suggest that inhalation of MSC-EVs as a noninvasive strategy for attenuation of ALI, and the adaptive regulation of Nrf2 may contribute to their anti-inflammatory and anti-oxidant activity in mice.

• Authors: Ruijing Zhao, Lina Wang, Tian Wang, Panpan Xian, Hongkang Wang, Qianfa Long
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 345 Pg. 214-230 (05 2022) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 35307508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Cytokines
• Lipopolysaccharides
• NF-E2-Related Factor 2

Topics

• Acute Lung Injury (therapy)
• Animals
• Anti-Inflammatory Agents (metabolism, therapeutic use)
• Antioxidants
• COVID-19
• Cytokines (metabolism)
• Disease Models, Animal
• Extracellular Vesicles (metabolism)
• Lipopolysaccharides
• Mesenchymal Stem Cells (metabolism)
• Mice
• NF-E2-Related Factor 2 (metabolism)