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 |
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| Affiliation: | 1. Center of Pulmonary and Critical Care Medicine, Chinese People''s Liberation Army General Hospital, Chinese People''s Liberation Army Medical College, Beijing, China;2. Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China;3. Department of Hepatobiliary Surgery, Chinese People''s Liberation Army General Hospital, Chinese People''s Liberation Army Medical College, Beijing, China;4. Institute of Hepatobiliary Surgery, Chinese People''s Liberation Army General Hospital, Chinese People''s Liberation Army Medical College, Beijing, China;5. Institute of Basic Medicine Science, Chinese People''s Liberation Army General Hospital, Chinese People''s Liberation Army Medical College, Beijing, China;1. Department of Regenerative Technologies and Biofabrication, National Medical Research Radiological Center, Obninsk, Russia;2. Basel University, Basel, Switzerland;1. International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan;2. Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan;3. Clinical Immunology and Transfusion Medicine IGP, Uppsala University, Uppsala, Sweden;4. Asahi Kasei Medical Co, Ltd, Tokyo, Japan;5. International Program in Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan;1. Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, United States;2. Molecular Medicine Department of Medicine, Stanford University, CA, United States;3. School of Medicine, University of California, San Francisco, CA 94158, United States;1. Emergency Department of Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning Province 110004, China;2. Eugenom Inc., Rm 310 No. 226 North Nanjing Street, Heping District, Shenyang, Liaoning Province 110001, China |
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| Abstract: | Background aimsAcute 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.MethodsA 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.ResultsThe 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-κB) pathway and degradation of IκB but increase the activities of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1.ConclusionsThese 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-κB activation. |
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