期刊
JOURNAL OF CONTROLLED RELEASE
卷 345, 期 -, 页码 214-230出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2022.03.025
关键词
Small extracellular vesicles; Inhalation; Acute lung injury; Immunomodulation; Redox system
资金
- Clinical Emergency Study of MSC-EVs in the Treatment of COVID-19 [20200001YX001(1)]
- National Natural Science Foundation of China [82171353]
- Science and Technology Innovation of Shaanxi Province [2018ZDXM-SF-046]
- Major Projects of Xi'an Medical Research [201805104YX12SF38-1]
This study compared the efficacy of administering mesenchymal stem cell-derived small extracellular vesicles (MSC-EVs) via inhalation and tail vein injection for treating acute lung injury (ALI). The results showed that inhalation of MSC-EVs was more effective in reducing pro-inflammatory cytokine expression, increasing anti-inflammatory cytokine expression, and decreasing pathological scores in ALI. Additionally, MSC-EV administration promoted the polarization of macrophages towards a M2 phenotype. The study also revealed the involvement of immune and redox mediators, including TLR4, Arg1, and HO-1, in the therapeutic effects of MSC-EVs.
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.
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