EFFECT OF EXOSOMES DERIVED FROM BONE MARROW MESENCHYMAL STEM CELLS ON PROGRAMMED CELL DEATH IN BLAST-INDUCED LUNG INJURY IN RATS

ABSTRACT Blast lung injuries (BLIs) are frequent because of industrial accidents and terrorist groups. Bone marrow mesenchymal stem cells (BMSCs) and exosomes derived from BMSCs (BMSCs-Exo) have become a hot topic in modern biology because of their significance in damage healing, immune regulation, and gene therapy. The aim of this study is to investigate the effect of BMSCs and BMSCs-Exo on BLI in rats caused by gas explosion. Here, BMSCs and BMSCs-Exo were transplanted into BLI rats via tail vein and then evaluated pathological alterations, oxidative stress, apoptosis, autophagy, and pyroptosis in the lung tissue. Through histopathology and changes in malondialdehyde (MDA) and superoxide dismutase (SOD) contents, we discovered that oxidative stress and inflammatory infiltration in the lungs were significantly reduced by BMSCs and BMSCs-Exo. After treatment with BMSCs and BMSCs-Exo, apoptosis-related proteins, such as cleaved caspase-3 and Bax, were significantly decreased, and the ratio of Bcl-2/Bax was significantly increased; the level of pyroptosis-associated proteins, including NLRP3, GSDMD-N, cleaved caspase-1, IL-1β, and IL-18, were decreased; autophagy-related proteins, beclin-1 and LC3, were downregulated while P62 was upregulated; the number of autophagosomes was decreased. In summary, BMSCs and BMSCs-Exo attenuate BLI caused by gas explosion, which may be associated with apoptosis, aberrant autophagy, and pyroptosis.

[1]  S. Yao,et al.  [Role of pyroptosis pathway related molecules in acute lung injury induced by gas explosion in rats]. , 2022, Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases.

[2]  Jing Li,et al.  How to analyse the injury based on 24Model: a case study of coal mine gas explosion injury , 2021, Injury Prevention.

[3]  S. Yao,et al.  [Changes and significance of autophagy in rat lung injury induced by gas explosion]. , 2021, Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases.

[4]  Yang Wang,et al.  BMSC-Derived Exosomes Ameliorate LPS-Induced Acute Lung Injury by miR-384-5p-Controlled Alveolar Macrophage Autophagy , 2021, Oxidative medicine and cellular longevity.

[5]  Xiaowen He,et al.  BMSC-derived exosomes ameliorate sulfur mustard-induced acute lung injury by regulating the GPRC5A–YAP axis , 2021, Acta Pharmacologica Sinica.

[6]  Ping Chen,et al.  Exosomal miR-22-3p from human umbilical cord blood-derived mesenchymal stem cells protects against lipopolysaccharid-induced acute lung injury. , 2021, Life sciences.

[7]  L. Ning,et al.  Cytosolic DNA‐STING‐NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide , 2020, Clinical and translational medicine.

[8]  J. Qu,et al.  [Effect of adipose-derived mesenchymal stem cells and liraglutide on acute lung injury]. , 2020, Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases.

[9]  Q. Shu,et al.  Mesenchymal Stem Cell–Derived Extracellular Vesicles Alleviate Acute Lung Injury Via Transfer of miR-27a-3p* , 2020, Critical care medicine.

[10]  A. Malik,et al.  IL-1β Suppression of VE-cadherin transcription underlies sepsis-induced inflammatory lung injury. , 2020, The Journal of clinical investigation.

[11]  Yunen Liu,et al.  Tanshinone IIA alleviates blast-induced inflammation, oxidative stress and apoptosis in mice partly by inhibiting the PI3K/Akt/FoxO1 signaling pathway. , 2020, Free radical biology & medicine.

[12]  L. Antounians,et al.  Systematic review of extracellular vesicle-based treatments for lung injury: are EVs a potential therapy for COVID-19? , 2020, Journal of extracellular vesicles.

[13]  Jianying Li,et al.  Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice , 2019, Theranostics.

[14]  Qin Han,et al.  The synergistic effect of electroacupuncture and bone mesenchymal stem cell transplantation on repairing thin endometrial injury in rats , 2019, Stem Cell Research & Therapy.

[15]  Min Zhao,et al.  The protective effects of bone mesenchymal stem cells on paraquat-induced acute lung injury via the muc5b and ERK/MAPK signaling pathways. , 2019, American journal of translational research.

[16]  M. D'Arcy.  Cell death: a review of the major forms of apoptosis, necrosis and autophagy , 2019, Cell biology international.

[17]  D. Richardson,et al.  The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis , 2019, Oxidative medicine and cellular longevity.

[18]  Zan Huang,et al.  Mitochondrial ROS promote macrophage pyroptosis by inducing GSDMD oxidation , 2019, Journal of molecular cell biology.

[19]  Patty J. Lee,et al.  Cell Death in the Lung: The Apoptosis-Necroptosis Axis. , 2019, Annual review of physiology.

[20]  Guodong Song,et al.  N-Acetylcysteine enhances the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation in rats with severe acute pancreatitis. , 2019, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[21]  M. Dehghan,et al.  Intrapulmonary autologous transplant of bone marrow-derived mesenchymal stromal cells improves lipopolysaccharide-induced acute respiratory distress syndrome in rabbit , 2018, Critical Care.

[22]  Xiao-Lin Qi,et al.  Apoptotic mechanisms in rabbits with blast-induced acute lung injury 1. , 2018, Acta cirurgica brasileira.

[23]  Zhilong Jiang,et al.  Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury , 2018, Molecular medicine reports.

[24]  I. Dikic,et al.  Mechanism and medical implications of mammalian autophagy , 2018, Nature reviews. Molecular cell biology.

[25]  Y. Liu,et al.  Chitosan oligosaccharide ameliorates acute lung injury induced by blast injury through the DDAH1/ADMA pathway , 2018, PloS one.

[26]  M. Marazzi,et al.  Mesenchymal stem/stromal cell extracellular vesicles: From active principle to next generation drug delivery system. , 2017, Journal of controlled release : official journal of the Controlled Release Society.

[27]  J. Wightman.  Pathophysiology of Primary Blast Injury. , 2017, Annals of emergency medicine.

[28]  G. Núñez,et al.  Mechanism and Regulation of NLRP3 Inflammasome Activation. , 2016, Trends in biochemical sciences.

[29]  Rachel T. Uren,et al.  Disordered clusters of Bak dimers rupture mitochondria during apoptosis , 2016, bioRxiv.

[30]  R. Lockey,et al.  The role of the NLRP3 inflammasome in pulmonary diseases , 2015, Therapeutic advances in respiratory disease.

[31]  S. Kourembanas,et al.  MSC microvesicles for the treatment of lung disease: a new paradigm for cell-free therapy. , 2014, Antioxidants & redox signaling.

[32]  P. Liu,et al.  Therapeutic action of bone marrow-derived stem cells against acute kidney injury. , 2014, Life sciences.

[33]  Chang‐gui Wu,et al.  Bone Marrow Mesenchymal Stem Cells Ameliorates Seawater-Exposure-Induced Acute Lung Injury by Inhibiting Autophagy in Lung Tissue , 2014, Pathology research international.

[34]  Jiqi Yan,et al.  Complement C5a exacerbates acute lung injury induced through autophagy-mediated alveolar macrophage apoptosis , 2014, Cell Death and Disease.

[35]  D. Vaux,et al.  Prosurvival Bcl-2 family members affect autophagy only indirectly, by inhibiting Bax and Bak , 2014, Proceedings of the National Academy of Sciences.

[36]  D. Klionsky,et al.  The variability of autophagy and cell death susceptibility , 2013, Autophagy.

[37]  Imre Mäger,et al.  Extracellular vesicles: biology and emerging therapeutic opportunities , 2013, Nature Reviews Drug Discovery.

[38]  J. Dubuisson,et al.  Inflammasome Components Coordinate Autophagy and Pyroptosis as Macrophage Responses to Infection , 2013, mBio.

[39]  Ming-jun Wang,et al.  [The epidemiological features of blast injury of lungs caused by gas explosion]. , 2012, Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases.

[40]  B. Thébaud,et al.  Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. , 2012, Stem cells and development.

[41]  Y. Kuan,et al.  Luteolin attenuates the pulmonary inflammatory response involves abilities of antioxidation and inhibition of MAPK and NFκB pathways in mice with endotoxin-induced acute lung injury. , 2011, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[42]  S. Ryter,et al.  Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. , 2011, Nature immunology.

[43]  J. Smith,et al.  The epidemiology of blast lung injury during recent military conflicts: a retrospective database review of cases presenting to deployed military hospitals, 2003–2009 , 2011, Philosophical Transactions of the Royal Society B: Biological Sciences.

[44]  Daniel J Klionsky,et al.  Mammalian autophagy: core molecular machinery and signaling regulation. , 2010, Current opinion in cell biology.

[45]  F. Dilworth,et al.  Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks , 2010, Proceedings of the National Academy of Sciences.

[46]  Arthur S Slutsky,et al.  Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury , 2008, Cell.

[47]  M. Rojas,et al.  Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[48]  Cristina Muñoz-Pinedo,et al.  Different mitochondrial intermembrane space proteins are released during apoptosis in a manner that is coordinately initiated but can vary in duration. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[49]  R. Hunt,et al.  Blast Lung Injury , 2006, Prehospital Emergency Care.

[50]  William P Schecter,et al.  Blast lung injury: clinical manifestations, treatment, and outcome. , 2005, American journal of surgery.

[51]  R A Knight,et al.  Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009 , 2005, Cell Death and Differentiation.

[52]  E. E. Turk,et al.  Histologic, immunohistochemical, and ultrastructural findings in human blast lung injury. , 2003, American journal of respiratory and critical care medicine.

[53]  Naftali Kaminski,et al.  Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[54]  P. Krammer,et al.  Tumor Immunology , 2018, Medical Immunology.

[55]  J. Connett,et al.  Prolonged partial liquid ventilation using conventional and high-frequency ventilatory techniques: gas exchange and lung pathology in an animal model of respiratory distress syndrome. , 1997, Critical care medicine.

[56]  Y. Tyurina,et al.  Antioxidant depletion, lipid peroxidation, and impairment of calcium transport induced by air-blast overpressure in rat lungs. , 1996, Experimental lung research.

[57]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[58]  R A Knight,et al.  Classification of cell death: recommendations of the Nomenclature Committee on Cell Death , 2005, Cell Death and Differentiation.

[59]  C. Leeuwenburgh,et al.  Aging and lifelong calorie restriction result in adaptations of skeletal muscle apoptosis repressor, apoptosis-inducing factor, X-linked inhibitor of apoptosis, caspase-3, and caspase-12. , 2004, Free radical biology & medicine.