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Shi Q, Liu H, Wang H, Tang L, Di Q, Wang D. MFGE8 regulates the EndoMT of HLMECs through the BMP signaling pathway and fibrosis in acute lung injury. Respir Res 2025; 26:142. [PMID: 40223052 DOI: 10.1186/s12931-025-03215-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND To investigate the effects and mechanisms of MFGE8 on LPS-induced endothelial-to-mesenchymal transition (EndoMT) and pulmonary fibrosis in human lung microvascular endothelial cells (HLMECs) and a mouse model of acute lung injury. METHODS Serum MFGE8 levels were compared between ARDS patients and controls. In vitro, HLMECs were treated with LPS, siRNA targeting MFGE8, and recombinant human MFGE8 (rhMFGE8).HLMEC morphology, invasion, migration, and EndoMT markers (CD31, ɑ-SMA) were evaluated. BMP/Smad1/5-Smad4 signaling and Snail expression were assessed via immunofluorescence, western blotting, and qRT-PCR. In vivo, rhMFGE8 effects on pulmonary fibrosis and EndoMT were analyzed in a mouse model of acute lung injury. RESULTS MFGE8 levels were significantly reduced in ARDS patients, with higher levels correlating to better survival. In vitro, rhMFGE8 improved HLMEC morphology, reduced invasion and migration, and attenuated LPS-induced EndoMT by increasing CD31 and decreasing α-SMA. MFGE8 knockdown increased BMP/Smad1/5-Smad4 signaling and Snail expression, while rhMFGE8 inhibited these effects. In vivo, rhMFGE8 ameliorated pulmonary fibrosis and EndoMT in mice. CONCLUSIONS MFGE8 regulates LPS-induced EndoMT in HLMECs via the BMP/Smad1/5-Smad4 pathway and protects against pulmonary fibrosis in acute lung injury, suggesting it as a therapeutic target for ALI and ARDS.
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Affiliation(s)
- Qingqiang Shi
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Huang Liu
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Hanghang Wang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Ling Tang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Qi Di
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Daoxin Wang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Ma W, Tang S, Yao P, Zhou T, Niu Q, Liu P, Tang S, Chen Y, Gan L, Cao Y. Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies. Signal Transduct Target Ther 2025; 10:75. [PMID: 40050633 PMCID: PMC11885678 DOI: 10.1038/s41392-025-02127-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 12/27/2024] [Accepted: 12/27/2024] [Indexed: 03/09/2025] Open
Abstract
In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause of morbidity and mortality in critically ill patients. ARDS is characterized by acute hypoxaemic respiratory failure with diffuse pulmonary inflammation and bilateral edema due to excessive alveolocapillary permeability in patients with non-cardiogenic pulmonary diseases. Over the past seven decades, our understanding of the pathology and clinical characteristics of ARDS has evolved significantly, yet it remains an area of active research and discovery. ARDS is highly heterogeneous, including diverse pathological causes, clinical presentations, and treatment responses, presenting a significant challenge for clinicians and researchers. In this review, we comprehensively discuss the latest advancements in ARDS research, focusing on its heterogeneity, pathophysiological mechanisms, and emerging therapeutic approaches, such as cellular therapy, immunotherapy, and targeted therapy. Moreover, we also examine the pathological characteristics of COVID-19-related ARDS and discuss the corresponding therapeutic approaches. In the face of challenges posed by ARDS heterogeneity, recent advancements offer hope for improved patient outcomes. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.
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Affiliation(s)
- Wen Ma
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China
| | - Songling Tang
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Yao
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tingyuan Zhou
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China
| | - Qingsheng Niu
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Liu
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Shiyuan Tang
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Chen
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Gan
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Yu Cao
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China.
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Feng Y, Tang M, Li H, Yao S, Li B. Mouse mesenchymal stem cell-derived exosomal miR-205-5p modulates LPS-induced macrophage polarization and alleviates lung injury by regulating the USP7/FOXM1 axis. Drug Deliv Transl Res 2025:10.1007/s13346-025-01813-z. [PMID: 40000557 DOI: 10.1007/s13346-025-01813-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 02/27/2025]
Abstract
Exosomal microRNAs produced from mesenchymal stem cells (MSCs) are crucial in the management of acute lung injury (ALI). In this work, mMSCs separated from bone marrow were used to extract exosomes (MSC-Exos). MSC-Exos treatment attenuated pathological changes and scores, and edema in ALI mice. Also, MSC-Exos administration modulated the concentrations of inflammatory factors as well as the macrophage polarization both in vivo and in vitro. Upregulation of miR-205-5p in MSC-Exos regulated the macrophage polarization and the contents of inflammatory factors in animal and cell models. MiR-205-5p targeted USP7, and negatively modulated the expression of USP7. USP7 interacted with FOXM1, and reduced the ubiquitination degradation of FOXM1. MSC-derived exosomal miR-205-5p modulated ubiquitination of FOXM1 by targeting USP7. The ameliorative effect of MSC-Exos on the macrophage polarization and the inflammatory factors release was reversed with the overexpression of USP7 in animal and cell models. Collectively, MSC-derived exosomal miR-205-5p regulated lipopolysaccharide (LPS)-induced macrophage polarization and alleviated lung injury by the USP7/FOXM1 axis, which developed a potential target for the treatment of ALI.
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Affiliation(s)
- Yinglu Feng
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Min Tang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Haopeng Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
| | - Bo Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
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Zhang S, Zhao X, Lv Y, Niu J, Wei X, Luo Z, Wang X, Chen XL. Exosomes of different cellular origins: prospects and challenges in the treatment of acute lung injury after burns. J Mater Chem B 2025; 13:1531-1547. [PMID: 39704476 DOI: 10.1039/d4tb02351j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2024]
Abstract
Acute lung injury (ALI) is a critical clinical disease caused by direct factors (inhalation injury, gastroesophageal reflux, etc.) or indirect factors (including infection, sepsis, burn, shock, trauma, acute pancreatitis, fat embolism, drug overdose, etc.). ALI is characterized mainly by diffuse interstitial and alveolar edema caused by an uncontrolled inflammatory response and damage to the alveoli-capillary barrier and has very high morbidity and mortality rates. Currently, there is no effective treatment strategy other than mechanical ventilation, fluid management or other supportive treatments. Exosomes are nanovesicle-like vesicles with double-membrane structures detached from the cell membrane or secreted by cells. These vesicles can be used as drug carriers because of their unique biological properties, such as anti-inflammatory, anti-apoptotic, pro-cell growth and immunomodulatory functions, and have been applied in the treatment of ALI in recent years. In this study, the mechanism and pathophysiological characteristics of ALI were first systematically described. The different cellular sources and characteristics of exosomes are summarized, and their functions and value as drug carriers in the treatment of ALI are discussed, as are the challenges that may be faced in the treatment of ALI with exosomes.
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Affiliation(s)
- Shuo Zhang
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Xinyu Zhao
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Yang Lv
- Plastic Surgery Department, The Second Affiliated Hospital of Anhui Medical University, 230061, P. R. China
| | - Jianguo Niu
- School of Biomedical Engineering, Anhui Medical University, Hefei 230022, China.
| | - Xiaolong Wei
- School of Biomedical Engineering, Anhui Medical University, Hefei 230022, China.
| | - Zhiwen Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P. R. China.
| | - Xianwen Wang
- School of Biomedical Engineering, Anhui Medical University, Hefei 230022, China.
| | - Xu-Lin Chen
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
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Lv K, Liang Q. Macrophages in sepsis-induced acute lung injury: exosomal modulation and therapeutic potential. Front Immunol 2025; 15:1518008. [PMID: 39840035 PMCID: PMC11746006 DOI: 10.3389/fimmu.2024.1518008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 12/16/2024] [Indexed: 01/23/2025] Open
Abstract
Sepsis-induced acute lung injury (ALI) remains a leading cause of mortality in critically ill patients. Macrophages, key modulators of immune responses, play a dual role in both promoting and resolving inflammation. Exosomes, small extracellular vesicles released by various cells, carry bioactive molecules that influence macrophage polarization and immune responses. Emerging researchers have identified exosomes as crucial mediators that modulate macrophage activity during sepsis-induced ALI. This review explores the role of exosomes in modulating macrophage functions, focusing on the cellular interactions within the lung microenvironment and their potential as therapeutic targets. It highlights the regulation of macrophages by exosomes derived from pathogenic germs, neutrophils, alveolar epithelial cells, and mesenchymal stromal cells. By understanding these mechanisms, it aims to uncover innovative therapeutic strategies for sepsis-induced ALI.
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Affiliation(s)
- Kaiying Lv
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Qun Liang
- Department of Critical Care Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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Wu A, Zhang A, Wang T, Chen J, Shi J. Inhibition of miR-9-3p facilitates ferroptosis by activating SAT1/p53 pathway in lung adenocarcinoma. Transl Lung Cancer Res 2024; 13:3426-3442. [PMID: 39830759 PMCID: PMC11736596 DOI: 10.21037/tlcr-24-762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 11/26/2024] [Indexed: 01/22/2025]
Abstract
Background Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and accounts for about 40% of all lung cancer cases. This research aims to investigate the effects of miR-9-3p on ferroptosis in LUAD cells and to elucidate its regulatory mechanisms. Studies have shown that LUAD is related to ferroptosis, and specific microRNAs (miRNA) are also related to ferroptosis. However, further research is needed to elucidate the mechanisms by which miR-9-3p induces ferroptosis in LUAD. Methods Our study comprehensively analyzed multiple databases to investigate miR-9-3p expression in LUAD tissues. Quantitative polymerase chain reaction (qPCR) was utilized to detect miR-9-3p levels in LUAD cells and tissues, examining its prognostic significance. Reactive oxygen species (ROS) and superoxide dismutase (SOD) assays assessed the impact of miR-9-3p on lipid peroxidation in LUAD cells. Dual-luciferase reporter assays were conducted to evaluate the binding affinity between miR-9-3p and target genes, while Western blotting and immunofluorescence were used to examine the regulation of miR-9-3p on downstream signaling pathways. Results We observed that miR-9-3p was upregulated in LUAD cells by qPCR, and the ferroptosis of LUAD cells increased upon treatment with erastin following the transfection of miR-9-3p inhibitor. Cell Counting Kit-8 (CCK-8), ROS, and SOD activity assays confirmed that inhibiting miR-9-3p enhanced lipid peroxidation in LUAD cells, contributing to higher rates of ferroptosis. Subsequent dual-luciferase reporter assays validated spermidine/spermine N1-acetyltransferase 1 (SAT1) as a target gene of miR-9-3p. Further Western blot confirmed that miR-9-3p regulated the expression of SAT1 and p53 proteins in p53 wild-type (WT) LUAD cells. Rescue experiments demonstrated that SAT1 was necessary for miR-9-3p to promote cell proliferation and suppress ferroptosis in p53 WT LUAD cells. Additionally, the effect of miR-9-3p on ferroptosis in LUAD cells was regulated by p53 signaling pathway. Conclusions Overall, these findings demonstrate that miR-9-3p negatively regulates ferroptosis in LUAD cells through SAT1 and p53 signaling pathway, suggesting that miR-9-3p plays a crucial role in LUAD pathogenesis and targeting this miRNA with an inhibitor exhibits promising potential for the treatment of LUAD.
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Affiliation(s)
- Anqi Wu
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Anping Zhang
- Department of Cardiac Surgery, The Second Affiliated Hospital of Nantong University, Nantong, China
| | - Tianyi Wang
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Jianle Chen
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, China
- Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, China
| | - Jiahai Shi
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, China
- Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, China
- School of Public Health, Nantong University, Nantong, China
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Ye C, Yang X, Zhu L, Chang G, Hu Y, Wang W. Macrophage-derived exosomal miR-2137 regulates pyroptosis in LPS-induced acute lung injury. Int Immunopharmacol 2024; 143:113549. [PMID: 39550844 DOI: 10.1016/j.intimp.2024.113549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 10/16/2024] [Accepted: 10/29/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND Alveolar macrophages (AMs) play a predominant role in acute lung injury (ALI). However, the role of macrophage-derived exosomal miRNAs in lipopolysaccharide (LPS)-induced ALI has not been determined. METHODS We previously reported that exosomes in the bronchoalveolar lavage fluid (BALF) of mice with ALI were derived predominantly from macrophages. Exosomal small RNA sequencing was conducted to identify the miRNA profiles. Exosomes derived from LPS-induced macrophages (LPS-exos) were intravenously administered to C57BL/6J mice, after which lung injury and pyroptosis were assessed. LPS-exos were cultured with alveolar epithelial cells (AECs) to further validate the results of the animal studies. RESULTS LPS-exos promoted lung inflammation and pyroptosis in vivo and in vitro. MiR-2137 was significantly upregulated in both LPS-exos and in MLE-12 cells. LPS-exos reduced cell viability, promoted the expression of LDH and inflammatory cytokines, and exacerbated vacuolization in MLE-12 cells. The administration of miR-2137 mimics and LPS-treated exosomes further strengthened these effects and enhanced pyroptosis mediated by NLRP3, Caspase1, ASC, and GSDMD. MiR-2137 mediated the effects of LPS-exos by targeting Wnt9a in AECs. In addition, the miR-2137 inhibitor markedly decreased the severity of LPS-exo-induced histological lesions, inflammation and pyroptosis in the lung. CONCLUSION Exosomal miR-2137 derived from AMs contributes to LPS-induced ALI by inducing AEC pyroptosis through the targeting of Wnt9a to activate the Wnt signaling pathway. This study revealed that AMs and AECs interact in ALI, providing novel strategies for ALI treatment.
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Affiliation(s)
- Cong Ye
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Xiaodong Yang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Lin Zhu
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guilin Chang
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu Hu
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Weixi Wang
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China.
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Liu QK, Xiang GH, Liu WL, Dong JY, Wen YQ, Hao H. Efficacy and safety of several common drugs in the treatment of acute respiratory distress syndrome: A systematic review and network meta-analysis. Medicine (Baltimore) 2024; 103:e40472. [PMID: 39809198 PMCID: PMC11596352 DOI: 10.1097/md.0000000000040472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 10/24/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND This study aimed to compare the effectiveness and safety of neuromuscular blockers, mesenchymal stem cells (MSC), and inhaled pulmonary vasodilators (IV) for acute respiratory distress syndrome through a network meta-analysis of randomized controlled trials (RCTs). METHODS We searched Chinese and English databases, including China National Knowledge Infrastructure, The Cochrane Library, PubMed, and EMbase, with no time restrictions. We conducted a network meta-analysis and reported the results according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We included 27 clinical RCTs, all of which were two-arm trials, totaling 3492 patients. We selected 28-day mortality as the primary outcome measure, whereas 90-day mortality, ventilator-free days, and oxygenation served as secondary outcome measures for analysis and comparison. RESULTS We selected 3 treatment modalities and evaluated their clinical trials in comparison with the standard control group. For the 28-day in-hospital mortality, we included 21 RCTs, involving 2789 patients. Compared to standard treatment, neuromuscular blockers were associated with reduced 28-day hospital mortality (odds ratios [OR] 0.52, 95% confidence intervals [CI] (0.31, 0.88)), while IV and MSC were not associated with reduced hospital mortality (OR 0.89, 95% CI (0.50, 1.55); OR 0.90, 95% CI (0.49, 1.66)). In terms of 90-day mortality, days free of mechanical ventilation, and improvement in oxygenation, there were no significant differences compared to standard treatment with neuromuscular blockers, MSC, and IV. CONCLUSION Neuromuscular blockers significantly reduced the 28-day mortality rate in acute respiratory distress syndrome patients. However, in terms of 90-day mortality, ventilator-free days, oxygenation improvement, IV, MSC, and neuromuscular blockers did not significantly improve.
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Affiliation(s)
- Qing-Kuo Liu
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Guo-Han Xiang
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Wen-Li Liu
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Jin-Yan Dong
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yu-Qi Wen
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Hao Hao
- Intensive Care Unit, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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Tian L, Jin J, Lu Q, Zhang H, Tian S, Lai F, Liu C, Liang Y, Lu Y, Zhao Y, Yao S, Ren W. Bidirectional modulation of extracellular vesicle-autophagy axis in acute lung injury: Molecular mechanisms and therapeutic implications. Biomed Pharmacother 2024; 180:117566. [PMID: 39423751 DOI: 10.1016/j.biopha.2024.117566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/09/2024] [Indexed: 10/21/2024] Open
Abstract
Acute lung injury (ALI), a multifactorial pathological condition, manifests through heightened inflammatory responses, compromised lung epithelial-endothelial barrier function, and oxidative stress, potentially culminating in respiratory failure and mortality. This study explores the intricate interplay between two crucial cellular mechanisms-extracellular vesicles (EVs) and autophagy-in the context of ALI pathogenesis and potential therapeutic interventions.EVs, bioactive membrane-bound structures secreted by cells, serve as versatile carriers of molecular cargo, facilitating intercellular communication and significantly influencing disease progression. Concurrently, autophagy, an essential intracellular degradation process, maintains cellular homeostasis and has emerged as a promising therapeutic target in ALI and acute respiratory distress syndrome.Our research unveils a fascinating "EV-Autophagy dual-drive pathway," characterized by reciprocal regulation between these two processes. EVs modulate autophagy activation and inhibition, while autophagy influences EV production, creating a dynamic feedback loop. This study posits that precise manipulation of this pathway could revolutionize ALI treatment strategies.By elucidating the mechanisms underlying this cellular crosstalk, we open new avenues for targeted therapies. The potential for engineered EVs to fine-tune autophagy in ALI treatment is explored, alongside innovative concepts such as EV-based vaccines for ALI prevention and management. This research not only deepens our understanding of ALI pathophysiology but also paves the way for novel, more effective therapeutic approaches in critical care medicine.
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Affiliation(s)
- Linqiang Tian
- Henan Medical Key Laboratory for Research of Trauma and Orthopedics, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province 453003, China; Clinical Medical Center of Tissue Egineering and Regeneration, Xinxiang Medical University, Xinxiang, Henan Province 453003, China
| | - Jie Jin
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China
| | - Qianying Lu
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China
| | - Huajing Zhang
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China
| | - Sijia Tian
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China
| | - Feng Lai
- Henan Medical Key Laboratory for Research of Trauma and Orthopedics, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province 453003, China
| | - Chuanchuan Liu
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China
| | - Yangfan Liang
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China
| | - Yujia Lu
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China
| | - Yanmei Zhao
- School of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; Key Laboratory for Disaster Medicine Technology, Tianjin 300072, China.
| | - Sanqiao Yao
- Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan Province 453003, China; School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province 453003, China.
| | - Wenjie Ren
- Henan Medical Key Laboratory for Research of Trauma and Orthopedics, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province 453003, China; Clinical Medical Center of Tissue Egineering and Regeneration, Xinxiang Medical University, Xinxiang, Henan Province 453003, China; Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan Province 453003, China.
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10
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Shen Y, He Y, Pan Y, Liu L, Liu Y, Jia J. Role and mechanisms of autophagy, ferroptosis, and pyroptosis in sepsis-induced acute lung injury. Front Pharmacol 2024; 15:1415145. [PMID: 39161900 PMCID: PMC11330786 DOI: 10.3389/fphar.2024.1415145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 07/25/2024] [Indexed: 08/21/2024] Open
Abstract
Sepsis-induced acute lung injury (ALI) is a major cause of death among patients with sepsis in intensive care units. By analyzing a model of sepsis-induced ALI using lipopolysaccharide (LPS) and cecal ligation and puncture (CLP), treatment methods and strategies to protect against ALI were discussed, which could provide an experimental basis for the clinical treatment of sepsis-induced ALI. Recent studies have found that an imbalance in autophagy, ferroptosis, and pyroptosis is a key mechanism that triggers sepsis-induced ALI, and regulating these death mechanisms can improve lung injuries caused by LPS or CLP. This article summarized and reviewed the mechanisms and regulatory networks of autophagy, ferroptosis, and pyroptosis and their important roles in the process of LPS/CLP-induced ALI in sepsis, discusses the possible targeted drugs of the above mechanisms and their effects, describes their dilemma and prospects, and provides new perspectives for the future treatment of sepsis-induced ALI.
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Affiliation(s)
- Yao Shen
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Yingying He
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Ying Pan
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Li Liu
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Yulin Liu
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Jing Jia
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, China
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Lin KC, Fang WF, Yeh JN, Chiang JY, Chiang HJ, Shao PL, Sung PH, Yip HK. Outcomes of combined mitochondria and mesenchymal stem cells-derived exosome therapy in rat acute respiratory distress syndrome and sepsis. World J Stem Cells 2024; 16:690-707. [PMID: 38948095 PMCID: PMC11212548 DOI: 10.4252/wjsc.v16.i6.690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/08/2024] [Accepted: 05/09/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND The treatment of acute respiratory distress syndrome (ARDS) complicated by sepsis syndrome (SS) remains challenging. AIM To investigate whether combined adipose-derived mesenchymal-stem-cells (ADMSCs)-derived exosome (EXAD) and exogenous mitochondria (mitoEx) protect the lung from ARDS complicated by SS. METHODS In vitro study, including L2 cells treated with lipopolysaccharide (LPS) and in vivo study including male-adult-SD rats categorized into groups 1 (sham-operated-control), 2 (ARDS-SS), 3 (ARDS-SS + EXAD), 4 (ARDS-SS + mitoEx), and 5 (ARDS-SS + EXAD + mitoEx), were included in the present study. RESULTS In vitro study showed an abundance of mitoEx found in recipient-L2 cells, resulting in significantly higher mitochondrial-cytochrome-C, adenosine triphosphate and relative mitochondrial DNA levels (P < 0.001). The protein levels of inflammation [interleukin (IL)-1β/tumor necrosis factor (TNF)-α/nuclear factor-κB/toll-like receptor (TLR)-4/matrix-metalloproteinase (MMP)-9/oxidative-stress (NOX-1/NOX-2)/apoptosis (cleaved-caspase3/cleaved-poly (ADP-ribose) polymerase)] were significantly attenuated in lipopolysaccharide (LPS)-treated L2 cells with EXAD treatment than without EXAD treatment, whereas the protein expressions of cellular junctions [occluding/β-catenin/zonula occludens (ZO)-1/E-cadherin] exhibited an opposite pattern of inflammation (all P < 0.001). Animals were euthanized by 72 h post-48 h-ARDS induction, and lung tissues were harvested. By 72 h, flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflammatory cells (Ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+) and albumin were lowest in group 1, highest in group 2, and significantly higher in groups 3 and 4 than in group 5 (all P < 0.0001), whereas arterial oxygen-saturation (SaO2%) displayed an opposite pattern of albumin among the groups. Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers (CD68+/γ-H2AX) displayed an identical pattern of SaO2% among the groups (all P < 0.0001). The protein expressions of inflammatory (TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress (NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged (cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic (beclin-1/Atg-5/ratio of LC3B-II/LC3B-I) biomarkers exhibited a similar manner, whereas antioxidants [nuclear respiratory factor (Nrf)-1/Nrf-2]/cellular junctions (ZO-1/E-cadherin)/mitochondrial electron transport chain (complex I-V) exhibited an opposite manner of albumin among the groups (all P < 0.0001). CONCLUSION Combined EXAD-mitoEx therapy was better than merely one for protecting the lung against ARDS-SS induced injury.
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Affiliation(s)
- Kun-Chen Lin
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Wen-Feng Fang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Jui-Ning Yeh
- Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hsin-Ju Chiang
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Pei-Lin Shao
- Department of Nursing, Asia University, Taichung 41354, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Hon-Kan Yip
- Department of Nursing, Asia University, Taichung 41354, Taiwan
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
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12
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Lin KC, Fang WF, Yeh JN, Chiang JY, Chiang HJ, Shao PL, Sung PH, Yip HK. Outcomes of combined mitochondria and mesenchymal stem cells-derived exosome therapy in rat acute respiratory distress syndrome and sepsis. World J Stem Cells 2024; 16:689-706. [DOI: 10.4252/wjsc.v16.i6.689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/08/2024] [Accepted: 05/09/2024] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND The treatment of acute respiratory distress syndrome (ARDS) complicated by sepsis syndrome (SS) remains challenging.
AIM To investigate whether combined adipose-derived mesenchymal-stem-cells (ADMSCs)-derived exosome (EXAD) and exogenous mitochondria (mitoEx) protect the lung from ARDS complicated by SS.
METHODS In vitro study, including L2 cells treated with lipopolysaccharide (LPS) and in vivo study including male-adult-SD rats categorized into groups 1 (sham-operated-control), 2 (ARDS-SS), 3 (ARDS-SS + EXAD), 4 (ARDS-SS + mitoEx), and 5 (ARDS-SS + EXAD + mitoEx), were included in the present study.
RESULTS In vitro study showed an abundance of mitoEx found in recipient-L2 cells, resulting in significantly higher mitochondrial-cytochrome-C, adenosine triphosphate and relative mitochondrial DNA levels (P < 0.001). The protein levels of inflammation [interleukin (IL)-1β/tumor necrosis factor (TNF)-α/nuclear factor-κB/toll-like receptor (TLR)-4/matrix-metalloproteinase (MMP)-9/oxidative-stress (NOX-1/NOX-2)/apoptosis (cleaved-caspase3/cleaved-poly (ADP-ribose) polymerase)] were significantly attenuated in lipopolysaccharide (LPS)-treated L2 cells with EXAD treatment than without EXAD treatment, whereas the protein expressions of cellular junctions [occluding/β-catenin/zonula occludens (ZO)-1/E-cadherin] exhibited an opposite pattern of inflammation (all P < 0.001). Animals were euthanized by 72 h post-48 h-ARDS induction, and lung tissues were harvested. By 72 h, flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflammatory cells (Ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+) and albumin were lowest in group 1, highest in group 2, and significantly higher in groups 3 and 4 than in group 5 (all P < 0.0001), whereas arterial oxygen-saturation (SaO2%) displayed an opposite pattern of albumin among the groups. Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers (CD68+/γ-H2AX) displayed an identical pattern of SaO2% among the groups (all P < 0.0001). The protein expressions of inflammatory (TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress (NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged (cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic (beclin-1/Atg-5/ratio of LC3B-II/LC3B-I) biomarkers exhibited a similar manner, whereas antioxidants [nuclear respiratory factor (Nrf)-1/Nrf-2]/cellular junctions (ZO-1/E-cadherin)/mitochondrial electron transport chain (complex I-V) exhibited an opposite manner of albumin among the groups (all P < 0.0001).
CONCLUSION Combined EXAD-mitoEx therapy was better than merely one for protecting the lung against ARDS-SS induced injury.
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Affiliation(s)
- Kun-Chen Lin
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Wen-Feng Fang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Jui-Ning Yeh
- Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, Guangdong Province, China
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hsin-Ju Chiang
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Pei-Lin Shao
- Department of Nursing, Asia University, Taichung 41354, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Hon-Kan Yip
- Department of Nursing, Asia University, Taichung 41354, Taiwan
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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Guo S, Wang D. Novel insights into the potential applications of stem cells in pulmonary hypertension therapy. Respir Res 2024; 25:237. [PMID: 38849894 PMCID: PMC11162078 DOI: 10.1186/s12931-024-02865-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 06/04/2024] [Indexed: 06/09/2024] Open
Abstract
Pulmonary hypertension (PH) refers to a group of deadly lung diseases characterized by vascular lesions in the microvasculature and a progressive increase in pulmonary vascular resistance. The prevalence of PH has increased over time. Currently, the treatment options available for PH patients have limited efficacy, and none of them can fundamentally reverse pulmonary vascular remodeling. Stem cells represent an ideal seed with proven efficacy in clinical studies focusing on liver, cardiovascular, and nerve diseases. Since the potential therapeutic effect of mesenchymal stem cells (MSCs) on PH was first reported in 2006, many studies have demonstrated the efficacy of stem cells in PH animal models and suggested that stem cells can help slow the deterioration of lung tissue. Existing PH treatment studies basically focus on the paracrine action of stem cells, including protein regulation, exosome pathway, and cell signaling; however, the specific mechanisms have not yet been clarified. Apoptotic and afunctional pulmonary microvascular endothelial cells (PMVECs) and alveolar epithelial cells (AECs) are two fundamental promoters of PH although they have not been extensively studied by researchers. This review mainly focuses on the supportive communication and interaction between PMVECs and AECs as well as the potential restorative effect of stem cells on their injury. In the future, more studies are needed to prove these effects and explore more radical cures for PH.
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Affiliation(s)
- Sijia Guo
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
| | - Dachun Wang
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- The Brown Foundation Institute of Molecular Medicine for the prevention of Human Diseases, University of Texas Medical School at Houston, Houston, TX, USA
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Ahmed SH, AlMoslemany MA, Witwer KW, Tehamy AG, El-Badri N. Stem Cell Extracellular Vesicles as Anti-SARS-CoV-2 Immunomodulatory Therapeutics: A Systematic Review of Clinical and Preclinical Studies. Stem Cell Rev Rep 2024; 20:900-930. [PMID: 38393666 PMCID: PMC11087360 DOI: 10.1007/s12015-023-10675-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2023] [Indexed: 02/25/2024]
Abstract
BACKGROUND COVID-19 rapidly escalated into a worldwide pandemic with elevated infectivity even from asymptomatic patients. Complications can lead to severe pneumonia and acute respiratory distress syndrome (ARDS), which are the main contributors to death. Because of their regenerative and immunomodulatory capacities, stem cells and their derived extracellular vesicles (EVs) are perceived as promising therapies against severe pulmonary conditions, including those associated with COVID-19. Herein, we evaluate the safety and efficacy of stem cell EVs in treating COVID-19 and complicating pneumonia, acute lung injury, and ARDS. We also cover relevant preclinical studies to recapitulate the current progress in stem cell EV-based therapy. METHODS Using PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science, we searched for all English-language published studies (2000-2023) that used stem cell EVs as a therapy for COVID-19, ARDS, or pneumonia. The risk of bias (ROB) was assessed for all studies. RESULTS Forty-eight studies met our inclusion criteria. Various-sized EVs derived from different types of stem cells were reported as a potentially safe and effective therapy to attenuate the cytokine storm induced by COVID-19. EVs alleviated inflammation and regenerated the alveolar epithelium by decreasing apoptosis, proinflammatory cytokines, neutrophil infiltration, and M2 macrophage polarization. They also prevented fibrin production and promoted the production of anti-inflammatory cytokines and endothelial cell junction proteins. CONCLUSION Similar to their parental cells, stem cell EVs mediate lung tissue regeneration by targeting multiple pathways and thus hold promise in promoting the recovery of COVID-19 patients and improving the survival rate of severely affected patients.
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Affiliation(s)
- Sarah Hamdy Ahmed
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, Giza, 6th of October City, 12582, Egypt
- Biotechnology/Biomolecular Chemistry Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Mohamed Atef AlMoslemany
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, Giza, 6th of October City, 12582, Egypt
| | - Kenneth Whitaker Witwer
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology and Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ahmed Gamal Tehamy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, Giza, 6th of October City, 12582, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, October Gardens, Giza, 6th of October City, 12582, Egypt.
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Li J, Liu K, He W, Zhang W, Li Y. Inhibition of GBP5 activates autophagy to alleviate inflammatory response in LPS-induced lung injury in mice. Exp Lung Res 2024; 50:106-117. [PMID: 38642025 DOI: 10.1080/01902148.2024.2339269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 03/29/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND Pulmonary emphysema is a condition that causes damage to the lung tissue over time. GBP5, as part of the guanylate-binding protein family, is dysregulated in mouse pulmonary emphysema. However, the role of GBP5 in lung inflammation in ARDS remains unveiled. METHODS To investigate whether GBP5 regulates lung inflammation and autophagy regulation, the study employed a mouse ARDS model and MLE-12 cell culture. Vector transfection was performed for the genetic manipulation of GBP5. Then, RT-qPCR, WB and IHC staining were conducted to assess its transcriptional and expression levels. Histological features of the lung tissue were observed through HE staining. Moreover, ELISA was conducted to evaluate the secretion of inflammatory cytokines, autophagy was assessed by immunofluorescent staining, and MPO activity was determined using a commercial kit. RESULTS Our study revealed that GBP5 expression was altered in mouse ARDS and LPS-induced MLE-12 cell models. Moreover, the suppression of GBP5 reduced lung inflammation induced by LPS in mice. Conversely, overexpression of GBP5 diminished the inhibitory impact of LPS on ARDS during autophagy, leading to increased inflammation. In the cell line of MLE-12, GBP5 exacerbates LPS-induced inflammation by blocking autophagy. CONCLUSION The study suggests that GBP5 facilitates lung inflammation and autophagy regulation. Thus, GBP5 could be a potential therapeutic approach for improving ARDS treatment outcomes, but further research is required to validate these findings.
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Affiliation(s)
- Jialin Li
- Department of Emergency, The Central Hospital of Shaoyang, Shaoyang City, Hunan Province, P.R. China
| | - Kexuan Liu
- Department of Emergency, The Central Hospital of Shaoyang, Shaoyang City, Hunan Province, P.R. China
| | - Wenjuan He
- Physiatry Department, The First People's Hospital of Chenzhou, Chenzhou City, Hunan Province, P.R. China
| | - Wencai Zhang
- Department of Critical Care Rehabilitation, The First People's Hospital of Chenzhou, Chenzhou City, Hunan Province, P.R. China
| | - Yongchao Li
- Department of Critical Care Rehabilitation, The First People's Hospital of Chenzhou, Chenzhou City, Hunan Province, P.R. China
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Kang J, Hua P, Wu X, Wang B. Exosomes: efficient macrophage-related immunomodulators in chronic lung diseases. Front Cell Dev Biol 2024; 12:1271684. [PMID: 38655063 PMCID: PMC11035777 DOI: 10.3389/fcell.2024.1271684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 03/15/2024] [Indexed: 04/26/2024] Open
Abstract
Macrophages, the predominant immune cells in the lungs, play a pivotal role in maintaining the delicate balance of the pulmonary immune microenvironment. However, in chronic inflammatory lung diseases and lung cancer, macrophage phenotypes undergo distinct transitions, with M1-predominant macrophages promoting inflammatory damage and M2-predominant macrophages fostering cancer progression. Exosomes, as critical mediators of intercellular signaling and substance exchange, participate in pathological reshaping of macrophages during development of pulmonary inflammatory diseases and lung cancer. Specifically, in inflammatory lung diseases, exosomes promote the pro-inflammatory phenotype of macrophages, suppress the anti-inflammatory phenotype, and subsequently, exosomes released by reshaped macrophages further exacerbate inflammatory damage. In cancer, exosomes promote pro-tumor tumor-associated macrophages (TAMs); inhibit anti-tumor TAMs; and exosomes released by TAMs further enhance tumor proliferation, metastasis, and resistance to chemotherapy. Simultaneously, exosomes exhibit a dual role, holding the potential to transmit immune-modulating molecules and load therapeutic agents and offering prospects for restoring immune dysregulation in macrophages during chronic inflammatory lung diseases and lung cancer. In chronic inflammatory lung diseases, this is manifested by exosomes reshaping anti-inflammatory macrophages, inhibiting pro-inflammatory macrophages, and alleviating inflammatory damage post-reshaping. In lung cancer, exosomes reshape anti-tumor macrophages, inhibit pro-tumor macrophages, and reshaped macrophages secrete exosomes that suppress lung cancer development. Looking ahead, efficient and targeted exosome-based therapies may emerge as a promising direction for treatment of pulmonary diseases.
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Affiliation(s)
- Jianxiong Kang
- Department of Thoracic Surgery at The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Peiyan Hua
- Department of Thoracic Surgery at The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaojing Wu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Bin Wang
- Department of Thoracic Surgery at The Second Hospital of Jilin University, Changchun, Jilin, China
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17
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Ye N, Shi X, Gao J, Dong R, Wang G, Wang J, Luo L, Zhang T. Exosomes from Intrahepatic Cholestasis of Pregnancy Induce Cell Apoptosis Through the miRNA-6891-5p/YWHAE Pathway. Dig Dis Sci 2024; 69:1253-1262. [PMID: 38361148 DOI: 10.1007/s10620-023-08265-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 12/21/2023] [Indexed: 02/17/2024]
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse pregnancy outcomes; however, the underlying mechanisms are not fully understood. AIMS This study aimed to determine the role of exosomal miR-6891-5p in placental trophoblast dysfunction in ICP and identify new biomarkers for ICP diagnosis. METHODS Serum samples were collected from ICP patients and healthy pregnant women, and serum exosomes were extracted and identified. Fluorescent dye labeling of exosomes and cell-verified cell phagocytosis were performed. In vitro experiments were conducted by adding taurocholic acid to simulate the ICP environment. Cell proliferation and apoptosis levels were detected using flow cytometry and the cell counting kit-8 assay. Mimics were constructed to overexpress miR-6891-5p in cells, and the binding site between miR-6891-5p and YWHAE was verified using luciferase reporter genes. RESULTS miR-6891-5p expression was significantly decreased in serum exosomes of ICP patients. Co-culturing with exosomes derived from ICP patients' serum (ICP-Exos) decreased HTR-8/SVeno cell proliferation and increased apoptosis levels. miR-6891-5p upregulation in HTR-8/SVeno cells significantly increased cell viability and reduced cell apoptosis levels, as determined by the cell counting kit-8 assay and flow cytometry. A double luciferase assay confirmed that miR-6891-5p affected the expression of the downstream YWHAE protein. CONCLUSIONS This study indicates that serum exosomes from ICP patients can impact the apoptosis of placental trophoblast HTR-8/SVeno cells through the miR-6891-5P/YWHAE pathway and can serve as specific molecular markers for ICP diagnosis.
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Affiliation(s)
- Ningzhen Ye
- Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Xinrui Shi
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Jianyi Gao
- Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Ruirui Dong
- Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Gaoying Wang
- Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Jing Wang
- Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China
| | - Liang Luo
- Wuxi No.2 People's Hospital, Jiangnan University Medical Center, Jiangnan University, Wuxi, 214001, China
| | - Ting Zhang
- Wuxi Maternity and Child Health Care Hospital, Women's Hospital of Jiangnan University, Jiangnan University, Wuxi, 214002, China.
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18
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Chen Z, Zhang J, Pan Y, Hao Z, Li S. Extracellular vesicles as carriers for noncoding RNA-based regulation of macrophage/microglia polarization: an emerging candidate regulator for lung and traumatic brain injuries. Front Immunol 2024; 15:1343364. [PMID: 38558799 PMCID: PMC10978530 DOI: 10.3389/fimmu.2024.1343364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 02/22/2024] [Indexed: 04/04/2024] Open
Abstract
Macrophage/microglia function as immune defense and homeostatic cells that originate from bone marrow progenitor cells. Macrophage/microglia activation is historically divided into proinflammatory M1 or anti-inflammatory M2 states based on intracellular dynamics and protein production. The polarization of macrophages/microglia involves a pivotal impact in modulating the development of inflammatory disorders, namely lung and traumatic brain injuries. Recent evidence indicates shared signaling pathways in lung and traumatic brain injuries, regulated through non-coding RNAs (ncRNAs) loaded into extracellular vesicles (EVs). This packaging protects ncRNAs from degradation. These vesicles are subcellular components released through a paracellular mechanism, constituting a group of nanoparticles that involve exosomes, microvesicles, and apoptotic bodies. EVs are characterized by a double-layered membrane and are abound with proteins, nucleic acids, and other bioactive compounds. ncRNAs are RNA molecules with functional roles, despite their absence of coding capacity. They actively participate in the regulation of mRNA expression and function through various mechanisms. Recent studies pointed out that selective packaging of ncRNAs into EVs plays a role in modulating distinct facets of macrophage/microglia polarization, under conditions of lung and traumatic brain injuries. This study will explore the latest findings regarding the role of EVs in the progression of lung and traumatic brain injuries, with a specific focus on the involvement of ncRNAs within these vesicles. The conclusion of this review will emphasize the clinical opportunities presented by EV-ncRNAs, underscoring their potential functions as both biomarkers and targets for therapeutic interventions.
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Affiliation(s)
- Zhihong Chen
- Department of Respiratory Medicine, The Third People’s Hospital of Longgang District, Shenzhen, China
| | - Jingang Zhang
- Department of Orthopedic, The Third People’s Hospital of Longgang District, Shenzhen, China
| | - Yongli Pan
- Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Zhongnan Hao
- Department of Neurology, University Medical Center of Göttingen, Georg-August-University of Göttingen, Göttingen, Lower Saxony, Germany
| | - Shuang Li
- Department of Respiratory Medicine, The Third People’s Hospital of Longgang District, Shenzhen, China
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Zhang X, Cheng Z, Zeng M, He Z. The efficacy of extracellular vesicles for acute lung injury in preclinical animal models: a meta-analysis. BMC Pulm Med 2024; 24:128. [PMID: 38481171 PMCID: PMC10935944 DOI: 10.1186/s12890-024-02910-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 02/15/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND With the increasing research on extracellular vesicles (EVs), EVs have received widespread attention as biodiagnostic markers and therapeutic agents for a variety of diseases. Stem cell-derived EVs have also been recognized as a new viable therapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). To assess their efficacy, we conducted a meta-analysis of existing preclinical experimental animal models of EVs for ALI treatment. METHODS The database was systematically interrogated for pertinent data encompassing the period from January 2010 to April 2022 concerning interventions involving extracellular vesicles (EVs) in animal models of acute lung injury (ALI). The lung injury score was selected as the primary outcome measure for statistical analysis. Meta-analyses were executed utilizing RevMan 5.3 and State15.1 software tools. RESULTS The meta-analyses comprised 31 studies, exclusively involving animal models of acute lung injury (ALI), categorized into two cohorts based on the presence or absence of extracellular vesicle (EV) intervention. The statistical outcomes from these two study groups revealed a significant reduction in lung injury scores with the administration of stem and progenitor cell-derived EVs (SMD = -3.63, 95% CI [-4.97, -2.30], P < 0.05). Conversely, non-stem cell-derived EVs were associated with an elevation in lung injury scores (SMD = -4.34, 95% CI [3.04, 5.63], P < 0.05). EVs originating from stem and progenitor cells demonstrated mitigating effects on alveolar neutrophil infiltration, white blood cell counts, total cell counts in bronchoalveolar lavage fluid (BALF), lung wet-to-dry weight ratios (W/D), and total protein in BALF. Furthermore, pro-inflammatory mediators exhibited down-regulation, while anti-inflammatory mediators demonstrated up-regulation. Conversely, non-stem cell-derived EVs exacerbated lung injury. CONCLUSION In preclinical animal models of acute lung injury (ALI), the administration of extracellular vesicles (EVs) originating from stem and progenitor cells demonstrably enhances pulmonary function. This ameliorative effect is attributed to the mitigation of pulmonary vascular permeability and the modulation of immune homeostasis, collectively impeding the progression of inflammation. In stark contrast, the utilization of EVs derived from non-stem progenitor cells exacerbates the extent of lung injury. These findings substantiate the potential utility of EVs as a novel therapeutic avenue for addressing acute lung injury.
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Affiliation(s)
- Xuefeng Zhang
- The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zongyong Cheng
- The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Menghao Zeng
- The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhihui He
- Department of Critical Care Medicine, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 138 Tongzibo Road, Yuelu District, Changsha, Hunan, 410013, China.
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20
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Li L, Zhang X, Chen Y. Human Umbilical Cord Mesenchymal Stem Cell Exosome-derived miR-335-5p Alleviated Lipopolysaccharide-induced Acute Lung Injury by Regulating the m6A Level of ITGβ4 Gene. Curr Med Chem 2024; 31:5448-5467. [PMID: 38310394 DOI: 10.2174/0109298673273833231220062213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/27/2023] [Accepted: 11/16/2023] [Indexed: 02/05/2024]
Abstract
BACKGROUND Acute lung injury (ALI) is a serious complication that may accompany severe pneumonia in children. Derived from human umbilical cord mesenchymal stem cell exosome (HucMSC-Exo) can contribute to the regeneration of damaged lung tissue. This study aims to investigate the impact of HucMSC-Exo on ALI and its potential mechanisms. METHODS Firstly, RT-qPCR was performed to assess the expression of miR-335-5p. Subsequently, Pearson correlation analysis was performed to examine the correlation between METTL14 and miR-335-5p, as well as the correlation between METTL14 and ITGβ4, while RNA immunoprecipitation (RIP) was used to determine the m6A modification level of ITGβ4. Additionally, molecular biology techniques were employed to evaluate the expression of glycolysis-related factors. Definitively, an LPS-induced ALI model was established to investigate the effect of miR-335-5p on mice lung tissue. RESULTS miR-335-5p was found to be highly expressed in HucMSC-Exo. Transfection with miR-335-5p mimics resulted in increased glucose uptake. Pearson correlation analysis revealed a negative correlation between METTL14 and miR-335-5p, as well as between METTL14 and ITGβ4. The m6A level of ITGβ4 was elevated in ALI. Overexpression of METTL14 was found to reduce the expression of ITGβ4 and glucose levels, while overexpression of ITGβ4 reversed the effects of METTL14 overexpression. In vivo, results demonstrated that miR-335-5p could improve the extent of lung tissue lesions and reduce glycolytic levels. CONCLUSION This study revealed the mechanism by which miR-335-5p derived from HucMSC-Exo could alleviate LPS-induced ALI by regulating the m6A modification of ITGβ4, providing a new direction for the treatment of ALI.
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Affiliation(s)
- Linrui Li
- Department of Respiratory Medicine, Hunan Children's Hospital, Changsha, 410006, China
| | - Xi Zhang
- Department of Respiratory Medicine, Hunan Children's Hospital, Changsha, 410006, China
| | - Yanping Chen
- Department of Respiratory Medicine, Hunan Children's Hospital, Changsha, 410006, China
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21
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Jin Y, Jeon H, Le Lam Nguyen T, Kim L, Heo KS. Human milk oligosaccharides 3'-sialyllactose and 6'-sialyllactose attenuate LPS-induced lung injury by inhibiting STAT1 and NF-κB signaling pathways. Arch Pharm Res 2023; 46:897-906. [PMID: 37940817 DOI: 10.1007/s12272-023-01470-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 11/01/2023] [Indexed: 11/10/2023]
Abstract
Acute lung injury (ALI) is the leading cause of respiratory diseases induced by uncontrolled inflammation and cell death. Lipopolysaccharide (LPS) is a major trigger of ALI in the progression through macrophage differentiation and the accelerated release of pro-inflammatory cytokines. The present study aimed to investigate the protective effects of human milk oligosaccharides, specifically 3'-sialyllactose (3'-SL) and 6'-sialyllactose (6'-SL), on LPS-induced ALI and elucidate their underlying signaling pathways. The inhibitory effects of 3'-SL and 6'-SL on inflammation were evaluated using LPS-treated RAW 264.7 macrophages. To establish the ALI model, mice were treated with 10 mg/kg LPS for 24 h. Histological changes in the lung tissues were assessed using hematoxylin and eosin staining and immunofluorescence. LPS causes thickening of the alveolar wall infiltration of immune cells in lung tissues and increased serum levels of TNF-α, IL-1β, and GM-CSF. However, these effects were significantly alleviated by 100 mg/kg of 3'-SL and 6'-SL. Consistent with the inhibitory effects of 3'-SL and 6'-SL on LPS-induced pro-inflammatory cytokine secretion in serum, 3'-SL and 6'-SL suppressed mRNA expression of TNF-α, IL-1β, MCP-1, iNOS, and COX2 in LPS-induced RAW 264.7 cells. Mechanistically, 3'-SL and 6'-SL abolished LPS-mediated phosphorylation of NF-κB and STAT1. Interestingly, fludarabine treatment, a STAT1 inhibitor, did not affect LPS-mediated NF-κB phosphorylation. In summary, 3'-SL and 6'-SL protect LPS-induced macrophage activation and ALI through the STAT1 and NF-κB signaling pathways.
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Affiliation(s)
- Yujin Jin
- College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, South Korea
| | - Hyesu Jeon
- College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, South Korea
| | - Thuy Le Lam Nguyen
- College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, South Korea
| | - Lila Kim
- GeneChem Inc. A-201, 187 Techno 2-ro, Daejeon, 34025, South Korea
| | - Kyung-Sun Heo
- College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, South Korea.
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22
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Yao J, Cheng M, Yang F. Calycosin Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice through the miR-375-3p/ROCK2 Axis. J INVEST SURG 2023; 36:2211166. [PMID: 37400250 DOI: 10.1080/08941939.2023.2211166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 04/15/2023] [Accepted: 04/28/2023] [Indexed: 07/05/2023]
Abstract
Objective: Septic patients are especially vulnerable to acute lung injury (ALI). Calycosin (CAL) has various promising pharmacological activities. This paper aims to expound on the role of CAL in mice with sepsis-induced ALI and the associated mechanisms.Methods: Mouse models of sepsis-induced ALI were established using lipopolysaccharide (LPS). Pulmonary histopathological changes were observed by HE staining. Cell apoptosis was assessed by TUNEL staining. Pulmonary edema was evaluated by measuring wet/dry weight. Bronchoalveolar lavage fluid (BALF) was collected to count inflammatory cells. In vitro LPS models were established using MLE-12 cells. miR-375-3p expression was determined by RT-qPCR. Cell viability and apoptosis were assessed by MTT assay and flow cytometry. Levels of inflammatory cytokines were determined by ELISA. The target relationship between miR-375-3p and ROCK2 was analyzed by the dual-luciferase assay. ROCK2 protein level was determined by Western blot.Results: miR-375-3p was weakly-expressed in mice with sepsis-induced ALI, and CAL treatment elevated miR-375-3p expression. CAL treatment mitigated pulmonary tissue damage and edema, decreased apoptosis and inflammatory cells, downregulated levels of pro-inflammatory cytokines, and upregulated levels of anti-inflammatory cytokines in mice with sepsis-induced ALI. CAL treatment increased MLE-12 cell viability and decreased apoptosis and inflammation in MLE-12 cells. Inhibition of miR-375-3p partially abrogated CAL-mediated protective action on MLE-12 cells. miR-375-3p attenuated LPS-induced MLE-12 cell injury by targeting ROCK2.Conclusion: CAL upregulates miR-375-3p to target ROCK2, thus protecting against sepsis-induced ALI in mice.
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Affiliation(s)
- Jie Yao
- Department of Intensive Care Unit, The People's Hospital of Fujian Traditional Medical University, Fuzhou, Fujian, China
| | - Mingfeng Cheng
- Department of Intensive Care Unit, The People's Hospital of Fujian Traditional Medical University, Fuzhou, Fujian, China
| | - Fan Yang
- Department of Intensive Care Unit, The People's Hospital of Fujian Traditional Medical University, Fuzhou, Fujian, China
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23
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Xu Y, Zhang C, Cai D, Zhu R, Cao Y. Exosomal miR-155-5p drives widespread macrophage M1 polarization in hypervirulent Klebsiella pneumoniae-induced acute lung injury via the MSK1/p38-MAPK axis. Cell Mol Biol Lett 2023; 28:92. [PMID: 37953267 PMCID: PMC10641976 DOI: 10.1186/s11658-023-00505-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 10/24/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Hypervirulent Klebsiella pneumoniae (hvKp) infection-induced sepsis-associated acute lung injury (ALI) has emerged as a significant clinical challenge. Increasing evidence suggests that activated inflammatory macrophages contribute to tissue damage in sepsis. However, the underlying causes of widespread macrophage activation remain unclear. METHODS BALB/c mice were intravenously injected with inactivated hvKp (iHvKp) to observe lung tissue damage, inflammation, and M1 macrophage polarization. In vitro, activated RAW264.7 macrophage-derived exosomes (iHvKp-exo) were isolated and their role in ALI formation was investigated. RT-PCR was conducted to identify changes in exosomal miRNA. Bioinformatics analysis and dual-luciferase reporter assays were performed to validate MSK1 as a direct target of miR-155-5p. Further in vivo and in vitro experiments were conducted to explore the specific mechanisms involved. RESULTS iHvKp successfully induced ALI in vivo and upregulated the expression of miR-155-5p. In vivo, injection of iHvKp-exo induced inflammatory tissue damage and macrophage M1 polarization. In vitro, iHvKp-exo was found to promote macrophage inflammatory response and M1 polarization through the activation of the p38-MAPK pathway. RT-PCR revealed exposure time-dependent increased levels of miR-155-5p in iHvKp-exo. Dual-luciferase reporter assays confirmed the functional role of miR-155-5p in mediating iHvKp-exo effects by targeting MSK1. Additionally, inhibition of miR-155-5p reduced M1 polarization of lung macrophages in vivo, resulting in decreased lung injury and inflammation induced by iHvKp-exo or iHvKp. CONCLUSIONS The aforementioned results indicate that exosomal miR-155-5p drives widespread macrophage inflammation and M1 polarization in hvKp-induced ALI through the MSK1/p38-MAPK Axis.
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Affiliation(s)
- Yihan Xu
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, People's Republic of China
| | - Chunying Zhang
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, People's Republic of China
| | - Danni Cai
- Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, People's Republic of China
| | - Rongping Zhu
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, People's Republic of China
| | - Yingping Cao
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, People's Republic of China.
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24
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Fu H, Liang X, Tan W, Hu X. Unraveling the protective mechanisms of Chuanfangyihao against acute lung injury: Insights from experimental validation. Exp Ther Med 2023; 26:535. [PMID: 37869635 PMCID: PMC10587870 DOI: 10.3892/etm.2023.12234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 08/21/2023] [Indexed: 10/24/2023] Open
Abstract
Chuanfangyihao (CFYH) is an effective treatment for acute lung injury (ALI) in clinical practice; however, its underlying mechanism of action remains unclear. Therefore, the aim of the present study was to elucidate the pharmacological mechanism of action of CFYH in ALI through experimental validation. First, a rat model of ALI was established using lipopolysaccharide (LPS). Next, the pathological changes in the lungs of the rats and the pathological damage were scored. The wet/dry weight ratios were measured, and ROS content was detected using flow cytometry. ELISA was used to examine IL-6, TNF-α, IL-1β, IL-18, and LDH levels. Immunohistochemistry was used to detect Beclin-1 and NLRP3 expression. Western blotting was performed to analyze the expression of HMGB1, RAGE, TLR4, NF-κB p65, AMPK, p-AMPK, mTOR, p-mTOR, Beclin-1, LC3-II/I, p62, Bcl-2, Bax, Caspase-3, Caspase-1, and GSDMD-NT. The mRNA levels of HMGB1, RAGE, AMPK, mTOR, and HIF-1α were determined using reverse transcription quantitative PCR. CFYH alleviated pulmonary edema and decreased the expression of IL-6, TNF-α, TLR4, NF-κB p65, HMGB1/RAGE, ROS, and HIF-1α. In addition, pretreatment with CFYH reversed ALI-induced programmed cell death. In conclusion, CFYH alleviates LPS-induced ALI, and these findings provide a preliminary clarification of the predominant mechanism of action of CFYH in ALI.
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Affiliation(s)
- Hongfang Fu
- Infectious Disease Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Xiao Liang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Wanying Tan
- Infectious Disease Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Xiaoyu Hu
- Infectious Disease Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
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25
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Liang G, Feng Y, Tang W, Yao L, Huang C, Chen Y. Proinflammatory Bone Marrow Mesenchymal Stem Cell-Derived Exosomal miR-150-3p Suppresses Proinflammatory Polarization of Alveolar Macrophages in Sepsis by Targeting Inhibin Subunit Beta A. J Interferon Cytokine Res 2023; 43:518-530. [PMID: 37819735 DOI: 10.1089/jir.2023.0068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023] Open
Abstract
Bone marrow mesenchymal stem cell (BMSC)-derived exosomes can protect lung tissues against sepsis, but its related mechanism remains elusive. BMSCs were primed with or without lipopolysaccharide (LPS) before extracting exosomes. The isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. LPS-stimulated macrophages were cocultured with exosomes for 24 h, followed by enzyme-linked immunosorbent assay, flow cytometry, and molecular experiments. Bioinformatics and luciferase assay were employed to investigate the interaction between miR-150-3p and inhibin subunit beta A (INHBA). MiR-150-3p expression was increased in exosomes in a proinflammatory environment. Exosomes suppressed proinflammatory polarization by downregulating IL-6, IL-1β, iNOS, and CD86, as well as promoted anti-inflammatory polarization by upregulating IL-10, ARG-1, and CD206 in LPS-stimulated macrophages. Such effects were more pronounced by LPS-primed exosomes, which was reversed in the absence of miR-150-3p. MiR-150-3p targeted INHBA. INHBA silencing decreased CD86 expression and increased CD206 expression in macrophages, but these effects were reversed by exosomal miR-150-3p inhibition. Proinflammatory BMSC-derived exosomal miR-150-3p suppressed proinflammatory polarization and promoted anti-inflammatory polarization of alveolar macrophages to attenuate LPS-induced sepsis by targeting INHBA.
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Affiliation(s)
- Guojin Liang
- Department of Anesthesiology, Ningbo First Hospital, Ningbo, China
| | - Yueying Feng
- Department of Pediatrics, Ningbo Women & Children's Hospital, Ningbo, China
| | - Wan Tang
- Department of Anesthesiology, Ningbo First Hospital, Ningbo, China
| | - Lifeng Yao
- Department of Anesthesiology, Ningbo First Hospital, Ningbo, China
| | - Changshun Huang
- Department of Anesthesiology, Ningbo First Hospital, Ningbo, China
| | - Yijun Chen
- Department of Anesthesiology, Ningbo First Hospital, Ningbo, China
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26
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Kosyreva A, Vishnyakova P, Tsvetkov I, Kiseleva V, Dzhalilova DS, Miroshnichenko E, Lokhonina A, Makarova O, Fatkhudinov T. Advantages and disadvantages of treatment of experimental ARDS by M2-polarized RAW 264.7 macrophages. Heliyon 2023; 9:e21880. [PMID: 38027880 PMCID: PMC10658332 DOI: 10.1016/j.heliyon.2023.e21880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 09/20/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Innate immunity reactions are core to any immunological process, including systemic inflammation and such extremes as acute respiratory distress syndrome (ARDS) and cytokine storm. Macrophages, the key cells of innate immunity, show high phenotypic plasticity: depending on microenvironmental cues, they can polarize into M1 (classically activated, pro-inflammatory) or M2 (alternatively activated, anti-inflammatory). The anti-inflammatory M2 macrophage polarization-based cell therapies constitute a novel prospective modality. Systemic administration of 'educated' macrophages is intended at their homing in lungs in order to mitigate the pro-inflammatory cytokine production and reduce the risks of 'cytokine storm' and related severe complications. Acute respiratory distress syndrome (ARDS) is the main mortality factor in pneumonia including SARS-CoV-associated cases. This study aimed to evaluate the influence of infusions of RAW 264.7 murine macrophage cell line polarized towards M2 phenotype on the development of LPS-induced ARDS in mouse model. The results indicate that the M2-polarized RAW 264.7 macrophage infusions in the studied model of ARDS promote relocation of lymphocytes from their depots in immune organs to the lungs. In addition, the treatment facilitates expression of M2-polarization markers Arg1, Vegfa and Tgfb and decreases of M1-polarization marker Cd38 in lung tissues, which can indicate the anti-inflammatory response activation. However, treatment of ARDS with M2-polarized macrophages didn't change the neutrophil numbers in the lungs. Moreover, the level of the Arg1 protein in lungs decreased throughtout the treatment with M2 macrophages, which is probably because of the pro-inflammatory microenvironment influence on the polarization of macrophages towards M1. Thus, the chemical polarization of macrophages is unstable and depends on the microenvironment. This adverse effect can be reduced through the use of primary autologous macrophages or some alternative methods of M2 polarization, notably siRNA-mediated.
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Affiliation(s)
- A.M. Kosyreva
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - P.A. Vishnyakova
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997, Moscow, Russia
| | - I.S. Tsvetkov
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - V.V. Kiseleva
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997, Moscow, Russia
| | - D. Sh. Dzhalilova
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - E.A. Miroshnichenko
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - A.V. Lokhonina
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997, Moscow, Russia
| | - O.V. Makarova
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
| | - T.H. Fatkhudinov
- Research Institute of Molecular and Cellular Medicine, Peoples' Friendship University of Russia named after Patrice Lumumba (RUDN), 6 Miklukho-Maklaya Street, 117198, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418, Moscow, Russia
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27
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Lan B, Dong X, Yang Q, Luo Y, Wen H, Chen Z, Chen H. Exosomal MicroRNAs: An Emerging Important Regulator in Acute Lung Injury. ACS OMEGA 2023; 8:35523-35537. [PMID: 37810708 PMCID: PMC10551937 DOI: 10.1021/acsomega.3c04955] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 09/11/2023] [Indexed: 10/10/2023]
Abstract
Acute lung injury (ALI) is a clinically life-threatening form of respiratory failure with a mortality of 30%-40%. Acute respiratory distress syndrome is the aggravated form of ALI. Exosomes are extracellular lipid vesicles ubiquitous in human biofluids with a diameter of 30-150 nm. They can serve as carriers to convey their internal cargo, particularly microRNA (miRNA), to the target cells involved in cellular communication. In disease states, the quantities of exosomes and the cargo generated by cells are altered. These exosomes subsequently function as autocrine or paracrine signals to nearby or distant cells, regulating various pathogenic processes. Moreover, exosomal miRNAs from multiple stem cells can provide therapeutic value for ALI by regulating different signaling pathways. In addition, changes in exosomal miRNAs of biofluids can serve as biomarkers for the early diagnosis of ALI. This study aimed to review the role of exosomal miRNAs produced by different sources participating in various pathological processes of ALI and explore their potential significance in the treatment and diagnosis.
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Affiliation(s)
- Bowen Lan
- Department
of General Surgery, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Laboratory
of Integrative Medicine, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
| | - Xuanchi Dong
- Department
of General Surgery, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Laboratory
of Integrative Medicine, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
| | - Qi Yang
- Department
of General Surgery, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Laboratory
of Integrative Medicine, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Department
of Traditional Chinese Medicine, The Second
Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Yalan Luo
- Department
of General Surgery, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Laboratory
of Integrative Medicine, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Institute
(College) of Integrative Medicine, Dalian
Medical University, Dalian 116044, China
| | - Haiyun Wen
- Department
of General Surgery, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Laboratory
of Integrative Medicine, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Institute
(College) of Integrative Medicine, Dalian
Medical University, Dalian 116044, China
| | - Zhe Chen
- Department
of General Surgery, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Laboratory
of Integrative Medicine, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
| | - Hailong Chen
- Department
of General Surgery, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Laboratory
of Integrative Medicine, The First Affiliated
Hospital of Dalian Medical University, Dalian 116000, China
- Institute
(College) of Integrative Medicine, Dalian
Medical University, Dalian 116044, China
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28
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Moosazadeh Moghaddam M, Fazel P, Fallah A, Sedighian H, Kachuei R, Behzadi E, Imani Fooladi AA. Host and Pathogen-Directed Therapies against Microbial Infections Using Exosome- and Antimicrobial Peptide-derived Stem Cells with a Special look at Pulmonary Infections and Sepsis. Stem Cell Rev Rep 2023; 19:2166-2191. [PMID: 37495772 DOI: 10.1007/s12015-023-10594-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2023] [Indexed: 07/28/2023]
Abstract
Microbial diseases are a great threat to global health and cause considerable mortality and extensive economic losses each year. The medications for treating this group of diseases (antibiotics, antiviral, antifungal drugs, etc.) directly attack the pathogenic agents by recognizing the target molecules. However, it is necessary to note that excessive use of any of these drugs can lead to an increase in microbial resistance and infectious diseases. New therapeutic methods have been studied recently using emerging drugs such as mesenchymal stem cell-derived exosomes (MSC-Exos) and antimicrobial peptides (AMPs), which act based on two completely different strategies against pathogens including Host-Directed Therapy (HDT) and Pathogen-Directed Therapy (PDT), respectively. In the PDT approach, AMPs interact directly with pathogens to interrupt their intrusion, survival, and proliferation. These drugs interact directly with the cell membrane or intracellular components of pathogens and cause the death of pathogens or inhibit their replication. The mechanism of action of MSC-Exos in HDT is based on immunomodulation and regulation, promotion of tissue regeneration, and reduced host toxicity. This review studies the potential of mesenchymal stem cell-derived exosomes/ATPs therapeutic properties against microbial infectious diseases especially pulmonary infections and sepsis.
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Affiliation(s)
- Mehrdad Moosazadeh Moghaddam
- Tissue Engineering and Regenerative Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Parvindokht Fazel
- Department of Microbiology, Fars Science and Research Branch, Islamic Azad University, Shiraz, Iran
| | - Arezoo Fallah
- Department of Bacteriology and Virology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Sedighian
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Reza Kachuei
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Elham Behzadi
- Academy of Medical Sciences of the I.R. of Iran, Tehran, Iran
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Zhuang X, Jiang Y, Yang X, Fu L, Luo L, Dong Z, Zhao J, Hei F. Advances of mesenchymal stem cells and their derived extracellular vesicles as a promising therapy for acute respiratory distress syndrome: from bench to clinic. Front Immunol 2023; 14:1244930. [PMID: 37711624 PMCID: PMC10497773 DOI: 10.3389/fimmu.2023.1244930] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury characterized by diffuse alveolar damage. The period prevalence of ARDS was 10.4% of ICU admissions in 50 countries. Although great progress has been made in supportive care, the hospital mortality rate of severe ARDS is still up to 46.1%. Moreover, up to now, there is no effective pharmacotherapy for ARDS and most clinical trials focusing on consistently effective drugs have met disappointing results. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have spawned intense interest of a wide range of researchers and clinicians due to their robust anti-inflammatory, anti-apoptotic and tissue regeneration properties. A growing body of evidence from preclinical studies confirmed the promising therapeutic potential of MSCs and their EVs in the treatment of ARDS. Based on the inspiring experimental results, clinical trials have been designed to evaluate safety and efficacy of MSCs and their EVs in ARDS patients. Moreover, trials exploring their optimal time window and regimen of drug administration are ongoing. Therefore, this review aims to present an overview of the characteristics of mesenchymal stem cells and their derived EVs, therapeutic mechanisms for ARDS and research progress that has been made over the past 5 years.
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Affiliation(s)
| | | | | | | | | | | | | | - Feilong Hei
- Department of Cardiopulmonary Bypass, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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Liu S, Fang X, Zhu R, Zhang J, Wang H, Lei J, Wang C, Wang L, Zhan L. Role of endoplasmic reticulum autophagy in acute lung injury. Front Immunol 2023; 14:1152336. [PMID: 37266445 PMCID: PMC10231642 DOI: 10.3389/fimmu.2023.1152336] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 05/03/2023] [Indexed: 06/03/2023] Open
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), the prime causes of morbidity and mortality in critically ill patients, are usually treated by general supportive treatments. Endoplasmic reticulum autophagy (ER-phagy) maintains cellular homeostasis by degrading damaged endoplasmic reticulum (ER) fragments and misfolded proteins. ER-phagy is crucial for maintaining ER homeostasis and improving the internal environment. ER-phagy has a particular role in some aspects, such as immunity, inflammation, cell death, pathogen infection, and collagen quality. In this review, we summarized the definition, epidemiology, and pathophysiology of ALI/ARDS and described the regulatory mechanisms and functions of ER-phagy as well as discussed the potential role of ER-phagy in ALI/ARDS from the perspectives of immunity, inflammation, apoptosis, pathogen infection, and fibrosis to provide a novel and effective target for improving the prognosis of ALI/ARDS.
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Affiliation(s)
- Shiping Liu
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoyu Fang
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ruiyao Zhu
- Department of Infection Prevention and Control, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jing Zhang
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Huijuan Wang
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiaxi Lei
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chaoqun Wang
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Lu Wang
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
| | - Liying Zhan
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China
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Liu Q, Ma F, Zhong Y, Wang G, Hu L, Zhang Y, Xie J. Efficacy and safety of human umbilical cord-derived mesenchymal stem cells for COVID-19 pneumonia: a meta-analysis of randomized controlled trials. Stem Cell Res Ther 2023; 14:118. [PMID: 37143167 PMCID: PMC10159228 DOI: 10.1186/s13287-023-03286-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 03/16/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Elevated levels of inflammatory factors are associated with poor prognosis in coronavirus disease-19 (COVID-19). However, mesenchymal stem cells (MSCs) have immunomodulatory functions. Accordingly, this meta-analysis aimed to determine the efficacy and safety of MSC-based therapy in patients with COVID-19 pneumonia. METHODS Online global databases were used to find relevant studies. Two independent researchers then selected and evaluated the studies for suitability while the Cochrane risk of bias tool determined the quality of all articles and Cochran's Q test and I2 index assessed the degree of heterogeneity in the principal studies. Statistical analysis was performed using Review Manager software, and the effect of each study on the overall estimate was evaluated by sensitivity analysis. RESULTS Seven studies were included in the meta-analysis, and all MSCs used in the trials were acquired from the umbilical cord. The results of these studies (n = 328) indicated that patients with COVID-19 pneumonia who received MSCs had a 0.58 risk of death compared with controls (95% CI = 0.38, 0.87; P = 0.53; I2 = 0%). In terms of inflammatory biomarkers, MSCs reduced the levels of C-reactive protein (n = 88; MD = - 32.49; 95% CI = - 48.43, - 16.56; P = 0.46; I2 = 0%) and interferon-gamma (n = 44; SMD = - 1.23; 95% CI = - 1.89, - 0.57; P = 0.37; I2 = 0%) in severe COVID-19 patients but had no significant effect on interleukin-6 (n = 185; MD = - 0.75; 95% CI = - 7.76, 6.27; P = 0.57; I2 = 0%). A summary of the data revealed no significant differences in adverse events (n = 287) or serious adverse events (n = 229) between the MSC and control groups. CONCLUSIONS Infusion of umbilical cord-derived MSCs is an effective strategy for treating patients with COVID-19 pneumonia, with no noticeable adverse effects.
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Affiliation(s)
- Qinxue Liu
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Fengjie Ma
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Yizhi Zhong
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Gaojian Wang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Li Hu
- Department of Anesthesiology, Second Affiliated Hospital of Jiaxing University, No.1518 North Huancheng Road, Nanhu District, Jiaxing, 314000, China
| | - Yaping Zhang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China
| | - Junran Xie
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No.3 East Qingchun Road, Jianggan District, Hangzhou, 310016, China.
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Liang TY, Lu LH, Tang SY, Zheng ZH, Shi K, Liu JQ. Current status and prospects of basic research and clinical application of mesenchymal stem cells in acute respiratory distress syndrome. World J Stem Cells 2023; 15:150-164. [PMID: 37180997 PMCID: PMC10173811 DOI: 10.4252/wjsc.v15.i4.150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/20/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a common and clinically devastating disease that causes respiratory failure. Morbidity and mortality of patients in intensive care units are stubbornly high, and various complications severely affect the quality of life of survivors. The pathophysiology of ARDS includes increased alveolar-capillary membrane permeability, an influx of protein-rich pulmonary edema fluid, and surfactant dysfunction leading to severe hypoxemia. At present, the main treatment for ARDS is mechanical treatment combined with diuretics to reduce pulmonary edema, which primarily improves symptoms, but the prognosis of patients with ARDS is still very poor. Mesenchymal stem cells (MSCs) are stromal cells that possess the capacity to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as the umbilical cord, endometrial polyps, menstrual blood, bone marrow, and adipose tissues. Studies have confirmed the critical healing and immunomodulatory properties of MSCs in the treatment of a variety of diseases. Recently, the potential of stem cells in treating ARDS has been explored via basic research and clinical trials. The efficacy of MSCs has been shown in a variety of in vivo models of ARDS, reducing bacterial pneumonia and ischemia-reperfusion injury while promoting the repair of ventilator-induced lung injury. This article reviews the current basic research findings and clinical applications of MSCs in the treatment of ARDS in order to emphasize the clinical prospects of MSCs.
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Affiliation(s)
- Tian-Yu Liang
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, China
| | - Li-Hai Lu
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Si-Yu Tang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Zi-Hao Zheng
- Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
| | - Kai Shi
- Department of Respiratory Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou 310015, Zhejiang Province, China
| | - Jing-Quan Liu
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, Zhejiang Province, China.
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Yang Y, Peng Y, Li Y, Shi T, Luan Y, Yin C. Role of stem cell derivatives in inflammatory diseases. Front Immunol 2023; 14:1153901. [PMID: 37006266 PMCID: PMC10062329 DOI: 10.3389/fimmu.2023.1153901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/02/2023] [Indexed: 03/16/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are pluripotent stem cells of mesodermal origin with the ability of self-renewal and multidirectional differentiation, which have all the common characteristics of stem cells and the ability to differentiate into adipocytes, osteoblasts, neuron-like cells and other cells. Stem cell derivatives are extracellular vesicles(EVs) released from mesenchymal stem cells that are involved in the process of body’s immune response, antigen presentation, cell differentiation, and anti-inflammatory. EVs are further divided into ectosomes and exosomes are widely used in degenerative diseases, cancer, and inflammatory diseases due to their parental cell characteristics. However, most diseases are closely related to inflammation, and exosomes can mitigate the damage caused by inflammation in terms of suppressing the inflammatory response, anti-apoptosis and promoting tissue repair. Stem cell-derived exosomes have become an emerging modality for cell-free therapy because of their high safety and ease of preservation and transportation through intercellular communication. In this review, we highlight the characteristics and functions of MSCs-derived exosomes and discuss the regulatory mechanisms of MSCs-derived exosomes in inflammatory diseases and their potential applications in clinical diagnosis and therapy.
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Affiliation(s)
- Yuxi Yang
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Yiqiu Peng
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Yingying Li
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Tingjuan Shi
- Department of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Yingyi Luan
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
- *Correspondence: Yingyi Luan, ; Chenghong Yin,
| | - Chenghong Yin
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, China
- *Correspondence: Yingyi Luan, ; Chenghong Yin,
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Soto-Vázquez YM, Genschmer KR. Impact of extracellular vesicles on the pathogenesis, diagnosis, and potential therapy in cardiopulmonary disease. Front Pharmacol 2023; 14:1081015. [PMID: 36891265 PMCID: PMC9986338 DOI: 10.3389/fphar.2023.1081015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/08/2023] [Indexed: 02/22/2023] Open
Abstract
Cardiopulmonary diseases span a wide breadth of conditions affecting both heart and lung, the burden of which is globally significant. Chronic pulmonary disease and cardiovascular disease are two of the leading causes of morbidity and mortality worldwide. This makes it critical to understand disease pathogenesis, thereby providing new diagnostic and therapeutic avenues to improve clinical outcomes. Extracellular vesicles provide insight into all three of these features of the disease. Extracellular vesicles are membrane-bound vesicles released by a multitude, if not all, cell types and are involved in multiple physiological and pathological processes that play an important role in intercellular communication. They can be isolated from bodily fluids, such as blood, urine, and saliva, and their contents include a variety of proteins, proteases, and microRNA. These vesicles have shown to act as effective transmitters of biological signals within the heart and lung and have roles in the pathogenesis and diagnosis of multiple cardiopulmonary diseases as well as demonstrate potential as therapeutic agents to treat said conditions. In this review article, we will discuss the role these extracellular vesicles play in the diagnosis, pathogenesis, and therapeutic possibilities of cardiovascular, pulmonary, and infection-related cardiopulmonary diseases.
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Affiliation(s)
- Yixel M Soto-Vázquez
- Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kristopher R Genschmer
- Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
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Kong X, Lu L, Lin D, Chong L, Wen S, Shi Y, Lin L, Zhou L, Zhang H, Zhang H. FGF10 ameliorates lipopolysaccharide-induced acute lung injury in mice via the BMP4-autophagy pathway. Front Pharmacol 2022; 13:1019755. [PMID: 36618911 PMCID: PMC9813441 DOI: 10.3389/fphar.2022.1019755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction: Damage to alveolar epithelial cells caused by uncontrolled inflammation is considered to be the main pathophysiological change in acute lung injury. FGF10 plays an important role as a fibroblast growth factor in lung development and lung diseases, but its protective effect against acute lung injury is unclear. Therefore, this study aimed to investigate protective effect and mechanism of FGF10 on acute lung injury in mice. Methods: ALI was induced by intratracheal injection of LPS into 57BL/6J mice. Six hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells, protein and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination and wet/dry (W/D) weight ratio analysis and blot analysis of protein expression. Results: We found that FGF10 can prevent the release of IL-6, TNF-α, and IL-1β, increase the expression of BMP4 and autophagy pathway, promote the regeneration of alveolar epithelial type Ⅱ cells, and improve acute lung injury. BMP4 gene knockdown decreased the protective effect of FGF10 on the lung tissue of mice. However, the activation of autophagy was reduced after BMP4 inhibition by Noggin. Additionally, the inhibition of autophagy by 3-MA also lowered the protective effect of FGF10 on alveolar epithelial cells induced by LPS. Conclusions: These data suggest that the protective effect of FGF10 is related to the activation of autophagy and regeneration of alveolar epithelial cells in an LPS-induced ALI model, and that the activation of autophagy may depend on the increase in BMP4 expression.
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Affiliation(s)
- Xiaoxia Kong
- School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou, Zhejiang, China,Department of Children’s Respiration, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liling Lu
- Department of Children’s Respiration, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,Department of Ultrasound, Children’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Daopeng Lin
- Department of Children’s Respiration, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,Department of Nephrology, Affiliated Cangnan Hospital, Wenzhou Medical University, Cangnan, Zhejiang, China
| | - Lei Chong
- Department of Children’s Respiration, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Shunhang Wen
- Department of Children’s Respiration, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yaokai Shi
- Department of Children’s Respiration, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lidan Lin
- School of Basic Medical Sciences, Institute of Hypoxia Research, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liqin Zhou
- Department of Pharmacy, Zhuji People’s Hospital, The Affiliated Hospital of Wenzhou Medical University, Shaoxing, Zhejiang, China
| | - Hongyu Zhang
- Department of Pharmacy, Zhuji People’s Hospital, The Affiliated Hospital of Wenzhou Medical University, Shaoxing, Zhejiang, China,School of Pharmaceutical Sciences, Cixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Hongyu Zhang, ; Hailin Zhang,
| | - Hailin Zhang
- Department of Children’s Respiration, The Second Affiliated Hospital & Yuying Children’s Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Hongyu Zhang, ; Hailin Zhang,
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Hu Q, Zhang S, Yang Y, Yao JQ, Tang WF, Lyon CJ, Hu TY, Wan MH. Extracellular vesicles in the pathogenesis and treatment of acute lung injury. Mil Med Res 2022; 9:61. [PMID: 36316787 PMCID: PMC9623953 DOI: 10.1186/s40779-022-00417-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 09/19/2022] [Indexed: 11/05/2022] Open
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common life-threatening lung diseases associated with acute and severe inflammation. Both have high mortality rates, and despite decades of research on clinical ALI/ARDS, there are no effective therapeutic strategies. Disruption of alveolar-capillary barrier integrity or activation of inflammatory responses leads to lung inflammation and injury. Recently, studies on the role of extracellular vesicles (EVs) in regulating normal and pathophysiologic cell activities, including inflammation and injury responses, have attracted attention. Injured and dysfunctional cells often secrete EVs into serum or bronchoalveolar lavage fluid with altered cargoes, which can be used to diagnose and predict the development of ALI/ARDS. EVs secreted by mesenchymal stem cells can also attenuate inflammatory reactions associated with cell dysfunction and injury to preserve or restore cell function, and thereby promote cell proliferation and tissue regeneration. This review focuses on the roles of EVs in the pathogenesis of pulmonary inflammation, particularly ALI/ARDS.
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Affiliation(s)
- Qian Hu
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Shu Zhang
- Department of Emergency Medicine, Emergency Medical Laboratory, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Yue Yang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Jia-Qi Yao
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Wen-Fu Tang
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China
| | - Christopher J Lyon
- Center of Cellular and Molecular Diagnosis, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA, 70112, USA.,Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA, 70112, USA
| | - Tony Ye Hu
- Center of Cellular and Molecular Diagnosis, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA, 70112, USA. .,Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, 1430 Tulane Ave., New Orleans, LA, 70112, USA.
| | - Mei-Hua Wan
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, 610041, China. .,West China Hospital (Airport) of Sichuan University, Chengdu, 610299, China.
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Li Y, Yu H, Lv M, Li Q, Zou K, Lv S. Combination therapy with budesonide and N-acetylcysteine ameliorates LPS-induced ALI by attenuating neutrophil recruitment through the miR-196b-5p/Socs3 molecular axis. BMC Pulm Med 2022; 22:388. [PMID: 36289489 PMCID: PMC9608916 DOI: 10.1186/s12890-022-02185-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 09/26/2022] [Indexed: 11/24/2022] Open
Abstract
Background Neutrophil infiltration accelerates the inflammatory response and is highly correlated to the development of acute lung injury (ALI). Budesonide (BUD) and N-acetylcysteine (NAC) both inhibit the inflammatory response to alleviate ALI, so we further investigated whether their combination is better for ALI. Methods In this study, we investigated the effect and mechanism of Combined BUD and NAC therapy on LPS-induced ALI. Rat ALI model and neutrophil abnormal activation model were established by lipopolysaccharide (LPS). BUD and NAC were treated alone or in combination, or cells were transfected with miR-196b-5p mimic or si-Socs3 to evaluate the efficacy and mechanism of BUD and NAC alone or in combination. Histopathological observation of lungs was performed by Hematoxylin Eosin (HE) staining. The quantity of neutrophils and inflammatory factors level in bronchoalveolar lavage fluid (BALF) were determined by Richter-Gimza complex stain and Enzyme-Linked Immunosorbnent Assay (ELISA), respectively. ReverseTranscription-PolymeraseChainReaction (RT–qPCR) was utilized to assess miR-196b-5p and inflammatory factor mRNA levels. The expression level of Socs3 was detected by immunohistochemistry or Western Blot. Results BUD and NAC combined treatment had a better effect on neutrophil recruitment and inflammatory response in LPS-induced ALI than did BUD and NAC alone. Transfection of the miR-196b-5p mimic reversed the effect of combined BUD and NAC. In conclusion, the combination of BUD and NAC is a better treatment for ALI. Conclusions Combination therapy with BUD and NAC ameliorates LPS-induced ALI by attenuating neutrophil recruitment through the miR-196b-5p/Socs3 molecular axis. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-022-02185-7.
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Affiliation(s)
- Yang Li
- Department of Rehabilitation Medicine, Qujing No.1 Hospital, Qujing, 655000 Yunnan China
| | - Huimin Yu
- Department of Rehabilitation Medicine, Qujing No.1 Hospital, Qujing, 655000 Yunnan China
| | - Meifen Lv
- Department of Rehabilitation Medicine, Qujing No.1 Hospital, Qujing, 655000 Yunnan China
| | - Qiaofen Li
- Department of Rehabilitation Medicine, Qujing No.1 Hospital, Qujing, 655000 Yunnan China
| | - Kaiwen Zou
- Department of Rehabilitation Medicine, Qujing No.1 Hospital, Qujing, 655000 Yunnan China
| | - Shaokun Lv
- Department of Rehabilitation Medicine, Qujing No.1 Hospital, Qujing, 655000 Yunnan China
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Wang X, Wu J, Xie Y, Liu Y, Feng W, Zhang L, Zhao J, Meng H, Chen B, Zhao Q, Guo R. Bone marrow mesenchymal stem cell-derived extracellular vesicles facilitate endometrial injury repair by carrying the E3 ubiquitin ligase WWP1. Biochem Cell Biol 2022; 100:357-369. [PMID: 36043683 DOI: 10.1139/bcb-2021-0543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Bone marrow mesenchymal stem cells-derived extracellular vesicles (BMSC-EVs) relieve endometrial injury. This study aimed to elucidate the BMSC-EV mechanism in alleviating endometrial injury. Endometrial injury model in vivo was induced using 95% ethanol, and endometrial epithelial cells (EECs) treated with mifepristone were applied as an endometrial injury model in vitro. After BMSCs and BMSC-EVs were isolated and identified, the BMSC-EV function was evaluated by hematoxylin-eosin and Masson staining, immunohistochemistry, quantitative real-time PCR, Cell Counting Kit-8 assay, flow cytometry, enzyme-linked immunosorbent assay, and Transwell and tubule formation assays. The BMSC-EV mechanism was assessed using Western blot, ubiquitination, and cycloheximide-chase assays. After isolation and identification, BMSC-EVs were effective in endometrial injury repair in vivo and facilitated EEC proliferation and repressed cell apoptosis in vitro; the EEC supernatants accelerated human umbilical vein endothelial cell proliferation, migration, and invasion and facilitated angiogenesis after endometrial injury in vitro. For the BMSC-EV mechanism, E3 ubiquitin ligase WWP1 in BMSC-EVs mediated the ubiquitination of peroxisome proliferator-activated receptor gamma (PPARγ), thus relieving the PPARγ inhibition on vascular endothelial growth factor expression. Furthermore, the WWP1 in BMSC-EVs alleviated endometrial injury in vitro and in vivo. BMSC-EVs facilitated endometrial injury repair by carrying WWP1.
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Affiliation(s)
- Xinxin Wang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.,Hua County People's Hospital, Anyang, Henan, China
| | - Junwei Wu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.,Hua County People's Hospital, Anyang, Henan, China.,Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ya Xie
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yanjie Liu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wei Feng
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lirong Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jing Zhao
- Hua County People's Hospital, Anyang, Henan, China
| | - Hongyu Meng
- Hua County People's Hospital, Anyang, Henan, China
| | - Baohong Chen
- Hua County People's Hospital, Anyang, Henan, China
| | - Qian Zhao
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ruixia Guo
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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39
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Liu C, Xiao K, Xie L. Progress in preclinical studies of macrophage autophagy in the regulation of ALI/ARDS. Front Immunol 2022; 13:922702. [PMID: 36059534 PMCID: PMC9433910 DOI: 10.3389/fimmu.2022.922702] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 08/03/2022] [Indexed: 12/12/2022] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a critical clinical syndrome with high morbidity and mortality that poses a major challenge in critical care medicine. The development of ALI/ARDS involves excessive inflammatory response, and macrophage autophagy plays an important role in regulating the inflammatory response in ALI/ARDS. In this paper, we review the effects of autophagy in regulating macrophage function, discuss the roles of macrophage autophagy in ALI/ARDS, and highlight drugs and other interventions that can modulate macrophage autophagy in ALI/ARDS to improve the understanding of the mechanism of macrophage autophagy in ALI/ARDS and provide new ideas and further research directions for the treatment of ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- College of Pulmonary & Critical Care Medicine, 8th Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Kun Xiao
- College of Pulmonary & Critical Care Medicine, 8th Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
| | - Lixin Xie
- School of Medicine, Nankai University, Tianjin, China
- College of Pulmonary & Critical Care Medicine, 8th Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
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40
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Qinbaohong Zhike Oral Liquid Attenuates LPS-Induced Acute Lung Injury in Immature Rats by Inhibiting OLFM4. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7272371. [PMID: 36035204 PMCID: PMC9400428 DOI: 10.1155/2022/7272371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022]
Abstract
Acute respiratory infections (ARIs) are a common public safety threat with high morbidity and mortality in pediatric patients worldwide. Qinbaohong Zhike oral liquid (QBH), a marketed traditional Chinese medicine product, has been widely used to cure respiratory diseases. QBH is reported to have antitussive, expectorant, and antiasthmatic properties. However, its treatment effect against ARIs is not elucidated. This study aimed to explore the therapeutic efficacy of QBH in the treatment of ARIs-induced pneumonia. Network pharmacology was used to predict the possible targets of QBH against ARIs. Next, the tracheal lipopolysaccharide (LPS-)-induced acute lung injury (ALI) immature rat model was constructed to evaluate the therapeutic effect of QBH. Tandem mass tag (TMT-)-based quantitative proteomics was then used to screen the in-depth disease targets of QBH. QBH exerted a protective effect against LPS-induced ALI by inhibiting pulmonary pathological damage. QBH also reduced the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and granulocyte macrophage colony-stimulating factor (GM-CSF) in the serum and IL-1β, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF in the lung tissue. Based on proteomic data, olfactomedin 4 (OLFM4) related to immunity and inflammation was selected as a potential target. Western blot analysis further confirmed the moderating effect of QBH downregulation on OLFM4 in the lung tissue. Our findings demonstrated that QBH alleviated lung tissue damage and inflammatory reaction via inhibiting OLFM4 expression in LPS-challenged immature rats. Our research indicates that QBH may have therapeutic potential for treating ARIs-related ALI in pediatric patients, which also serves as a candidate target for drug therapy of ALI by intervening OLFM-related signaling pathways.
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41
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Liu C, Xiao K, Xie L. Advances in mesenchymal stromal cell therapy for acute lung injury/acute respiratory distress syndrome. Front Cell Dev Biol 2022; 10:951764. [PMID: 36036014 PMCID: PMC9399751 DOI: 10.3389/fcell.2022.951764] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) develops rapidly and has high mortality. ALI/ARDS is mainly manifested as acute or progressive hypoxic respiratory failure. At present, there is no effective clinical intervention for the treatment of ALI/ARDS. Mesenchymal stromal cells (MSCs) show promise for ALI/ARDS treatment due to their biological characteristics, easy cultivation, low immunogenicity, and abundant sources. The therapeutic mechanisms of MSCs in diseases are related to their homing capability, multidirectional differentiation, anti-inflammatory effect, paracrine signaling, macrophage polarization, the polarization of the MSCs themselves, and MSCs-derived exosomes. In this review, we discuss the pathogenesis of ALI/ARDS along with the biological characteristics and mechanisms of MSCs in the treatment of ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Kun Xiao
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
| | - Lixin Xie
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary and Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
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42
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Liu C, Xiao K, Xie L. Advances in the use of exosomes for the treatment of ALI/ARDS. Front Immunol 2022; 13:971189. [PMID: 36016948 PMCID: PMC9396740 DOI: 10.3389/fimmu.2022.971189] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/22/2022] [Indexed: 11/16/2022] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a critical clinical syndrome with high morbidity and mortality. Currently, the primary treatment for ALI/ARDS is mainly symptomatic therapy such as mechanical ventilation and fluid management. Due to the lack of effective treatment strategies, most ALI/ARDS patients face a poor prognosis. The discovery of exosomes has created a promising prospect for the treatment of ALI/ARDS. Exosomes can exert anti-inflammatory effects, inhibit apoptosis, and promote cell regeneration. The microRNA contained in exosomes can participate in intercellular communication and play an immunomodulatory role in ALI/ARDS disease models. This review discusses the possible mechanisms of exosomes in ALI/ARDS to facilitate the development of innovative treatments for ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Kun Xiao
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Lixin Xie
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Lixin Xie,
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Liu C, Xiao K, Xie L. Advances in the Regulation of Macrophage Polarization by Mesenchymal Stem Cells and Implications for ALI/ARDS Treatment. Front Immunol 2022; 13:928134. [PMID: 35880175 PMCID: PMC9307903 DOI: 10.3389/fimmu.2022.928134] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/16/2022] [Indexed: 12/03/2022] Open
Abstract
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common condition with high mortality. ALI/ARDS is caused by multiple etiologies, and the main clinical manifestations are progressive dyspnea and intractable hypoxemia. Currently, supportive therapy is the main ALI/ARDS treatment, and there remains a lack of targeted and effective therapeutic strategies. Macrophages are important components of innate immunity. M1 macrophages are pro-inflammatory, while M2 macrophages are anti-inflammatory and promote tissue repair. Mesenchymal stem cells (MSCs) are stem cells with broad application prospects in tissue regeneration due to their multi-directional differentiation potential along with their anti-inflammatory and paracrine properties. MSCs can regulate the balance of M1/M2 macrophage polarization to improve the prognosis of ALI/ARDS. In this paper, we review the mechanisms by which MSCs regulate macrophage polarization and the signaling pathways associated with polarization. This review is expected to provide new targets for the treatment of ALI/ARDS.
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Affiliation(s)
- Chang Liu
- School of Medicine, Nankai University, Tianjin, China
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
| | - Kun Xiao
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
| | - Lixin Xie
- Center of Pulmonary & Critical Care Medicine, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Medical School of Chinese People’s Liberation Army (PLA), Beijing, China
- *Correspondence: Kun Xiao, ; Lixin Xie,
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Lee S, Ko JH, Kim SN. The Extracellular MicroRNAs on Inflammation: A Literature Review of Rodent Studies. Biomedicines 2022; 10:1601. [PMID: 35884901 PMCID: PMC9312877 DOI: 10.3390/biomedicines10071601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/03/2022] [Accepted: 07/03/2022] [Indexed: 11/17/2022] Open
Abstract
Inflammation is an indispensable biological process stimulated by infection and injuries. Inflammatory mechanisms related to extracellular vesicles (EVs), which are small membrane structures carrying various molecules, were summarized in this review. Emerging evidence from animal studies has highlighted the role of EVs in modulating inflammatory responses, by transporting various molecules involved in host defense. In this review, we have discussed the role of EV miRNAs in inflammation. Rodent studies associated with extracellular miRNAs in inflammatory diseases, published from 2012 to 2022, were explored from PUBMED, EMBASE, and MEDLINE. A total of 95 studies were reviewed. In summary, EV-associated miRNAs play a key role in various diseases, including organ injury, immune dysfunction, neurological disease, metabolic syndrome, vesicular disease, arthritis, cancer, and other inflammatory diseases. Diverse EV-associated miRNAs regulate inflammasome activation and pro- and anti-inflammatory cytokine levels by targeting genes.
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Affiliation(s)
- Seri Lee
- College of Korean Medicine, Dongguk University, Goyang 10326, Korea; (S.L.); (J.H.K.)
- Graduate School, Dongguk University, Seoul 04620, Korea
| | - Jade Heejae Ko
- College of Korean Medicine, Dongguk University, Goyang 10326, Korea; (S.L.); (J.H.K.)
| | - Seung-Nam Kim
- College of Korean Medicine, Dongguk University, Goyang 10326, Korea; (S.L.); (J.H.K.)
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45
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Wang Y, Jin X, Fan Q, Li C, Zhang M, Wang Y, Wu Q, Li J, Liu X, Wang S, Wang Y, Li L, Ling J, Li C, Wang Q, Liu Y. Deciphering the Active Compounds and Mechanisms of HSBDF for Treating ALI via Integrating Chemical Bioinformatics Analysis. Front Pharmacol 2022; 13:879268. [PMID: 35721141 PMCID: PMC9201258 DOI: 10.3389/fphar.2022.879268] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/06/2022] [Indexed: 01/08/2023] Open
Abstract
The Huashi Baidu Formula (HSBDF), a key Chinese medical drug, has a remarkable clinical efficacy in treating acute lung injury (ALI), and it has been officially approved by the National Medical Products Administration of China for drug clinical trials. Nevertheless, the regulated mechanisms of HSBDF and its active compounds in plasma against ALI were rarely studied. Based on these considerations, the key anti-inflammatory compounds of HSBDF were screened by molecular docking and binding free energy. The key compounds were further identified in plasma by LC/MS. Network pharmacology was employed to identify the potential regulatory mechanism of the key compounds in plasma. Next, the network pharmacological prediction was validated by a series of experimental assays, including CCK-8, EdU staining, test of TNF-α, IL-6, MDA, and T-SOD, and flow cytometry, to identify active compounds. Molecular dynamic simulation and binding interaction patterns were used to evaluate the stability and affinity between active compounds and target. Finally, the active compounds were subjected to predict pharmacokinetic properties. Molecular docking revealed that HSBDF had potential effects of inhibiting inflammation by acting on IL-6R and TNF-α. Piceatannol, emodin, aloe-emodin, rhein, physcion, luteolin, and quercetin were key compounds that may ameliorate ALI, and among which, there were five compounds (emodin, aloe-emodin, rhein, luteolin, and quercetin) in plasma. Network pharmacology results suggested that five key compounds in plasma likely inhibited ALI by regulating inflammation and oxidative damage. Test performed in vitro suggested that HSBDF (0.03125 mg/ml), quercetin (1.5625 μM), emodin (3.125 μM), and rhein (1.5625 μM) have anti-inflammatory function against oxidative damage and decrease apoptosis in an inflammatory environment by LPS-stimulation. In addition, active compounds (quercetin, emodin, and rhein) had good development prospects, fine affinity, and stable conformations with the target protein. In summary, this study suggested that HSBDF and its key active components in plasma (quercetin, emodin, and rhein) can decrease levels of pro-inflammatory factors (IL-6 and TNF-α), decrease expression of MDA, increase expression of T-SOD, and decrease cell apoptosis in an inflammatory environment. These data suggest that HSBDF has significant effect on anti-inflammation and anti-oxidative stress and also can decrease cell apoptosis in treating ALI. These findings provided an important strategy for developing new agents and facilitated clinical use of HSBDF against ALI.
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Affiliation(s)
- Yanru Wang
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiaojie Jin
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China.,College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Qin Fan
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Chenghao Li
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Min Zhang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yongfeng Wang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Qingfeng Wu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Jiawei Li
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiuzhu Liu
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Siyu Wang
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yu Wang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Ling Li
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jia Ling
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Chaoxin Li
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Qianqian Wang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, China
| | - Yongqi Liu
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China.,Key Laboratory of Dunhuang Medical and Transformation, Ministry of Education of The People's Republic of China, Lanzhou, China
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46
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Azhdari MH, Goodarzi N, Doroudian M, MacLoughlin R. Molecular Insight into the Therapeutic Effects of Stem Cell-Derived Exosomes in Respiratory Diseases and the Potential for Pulmonary Delivery. Int J Mol Sci 2022; 23:ijms23116273. [PMID: 35682948 PMCID: PMC9181737 DOI: 10.3390/ijms23116273] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 02/07/2023] Open
Abstract
Respiratory diseases are the cause of millions of deaths annually around the world. Despite the recent growth of our understanding of underlying mechanisms contributing to the pathogenesis of lung diseases, most therapeutic approaches are still limited to symptomatic treatments and therapies that only delay disease progression. Several clinical and preclinical studies have suggested stem cell (SC) therapy as a promising approach for treating various lung diseases. However, challenges such as the potential tumorigenicity, the low survival rate of the SCs in the recipient body, and difficulties in cell culturing and storage have limited the applicability of SC therapy. SC-derived extracellular vesicles (SC-EVs), particularly SC-derived exosomes (SC-Exos), exhibit most therapeutic properties of stem cells without their potential drawbacks. Similar to SCs, SC-Exos exhibit immunomodulatory, anti-inflammatory, and antifibrotic properties with the potential to be employed in the treatment of various inflammatory and chronic respiratory diseases. Furthermore, recent studies have demonstrated that the microRNA (miRNA) content of SC-Exos may play a crucial role in the therapeutic potential of these exosomes. Several studies have investigated the administration of SC-Exos via the pulmonary route, and techniques for SCs and SC-Exos delivery to the lungs by intratracheal instillation or inhalation have been developed. Here, we review the literature discussing the therapeutic effects of SC-Exos against respiratory diseases and advances in the pulmonary route of delivery of these exosomes to the damaged tissues.
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Affiliation(s)
- Mohammad H. Azhdari
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran 15719-14911, Iran; (M.H.A.); (N.G.)
| | - Nima Goodarzi
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran 15719-14911, Iran; (M.H.A.); (N.G.)
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran 15719-14911, Iran; (M.H.A.); (N.G.)
- Correspondence: author: (M.D.); (R.M.)
| | - Ronan MacLoughlin
- Research and Development, Science and Emerging Technologies, Aerogen Limited, IDA Business Park, H91 HE94 Galway, Ireland
- School of Pharmacy, Royal College of Surgeons, D02 YN77 Dublin, Ireland
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, D02 PN40 Dublin, Ireland
- Correspondence: author: (M.D.); (R.M.)
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Chiang MD, Chang CY, Shih HJ, Le VL, Huang YH, Huang CJ. Exosomes from Human Placenta Choriodecidual Membrane-Derived Mesenchymal Stem Cells Mitigate Endoplasmic Reticulum Stress, Inflammation, and Lung Injury in Lipopolysaccharide-Treated Obese Mice. Antioxidants (Basel) 2022; 11:antiox11040615. [PMID: 35453300 PMCID: PMC9029526 DOI: 10.3390/antiox11040615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/15/2022] [Accepted: 03/22/2022] [Indexed: 11/16/2022] Open
Abstract
Endoplasmic reticulum (ER) stress mediates the effects of obesity on aggravating sepsis-induced lung injury. We investigated whether exosomes from human placenta choriodecidual membrane-derived mesenchymal stem cells (pcMSCs) can mitigate pulmonary ER stress, lung injury, and the mechanisms of inflammation, oxidation, and apoptosis in lipopolysaccharide-treated obese mice. Diet-induced obese (DIO) mice (adult male C57BL/6J mice fed with a 12-week high-fat diet) received lipopolysaccharide (10 mg/kg, i.p.; DIOLPS group) or lipopolysaccharide plus exosomes (1 × 108 particles/mouse, i.p.; DIOLPSExo group). Our data demonstrated lower levels of ER stress (upregulation of glucose-regulated protein 78, phosphorylated eukaryotic initiation factor 2α, and C/EBP homologous protein; p = 0.038, <0.001, and <0.001, respectively), inflammation (activation of nuclear factor-kB, hypoxia-inducible factor-1α, macrophages, and NLR family pyrin domain containing 3; upregulation of tumor necrosis factor-α, interleukin-1β, and interleukin-6; p = 0.03, <0.001, <0.001, <0.001, <0.001, <0.001, and <0.001, respectively), lipid peroxidation (p < 0.001), and apoptosis (DNA fragmentation, p = 0.003) in lung tissues, as well as lower lung injury level (decreases in tidal volume, peak inspiratory flow, and end expiratory volume; increases in resistance, injury score, and tissue water content; p < 0.001, <0.001, <0.001, <0.001, <0.001, and =0.002, respectively) in the DIOLPSExo group than in the DIOLPS group. In conclusion, exosomes from human pcMSCs mitigate pulmonary ER stress, inflammation, oxidation, apoptosis, and lung injury in lipopolysaccharide-treated obese mice.
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Affiliation(s)
- Milton D. Chiang
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (M.D.C.); (V.L.L.)
| | - Chao-Yuan Chang
- Department of Medical Research, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan;
- Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Hung-Jen Shih
- Division of Urology, Department of Surgery, Changhua Christian Hospital, Changhua 500, Taiwan;
- Department of Recreation and Holistic Wellness, MinDao University, Changhua 523, Taiwan
- Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Van Long Le
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (M.D.C.); (V.L.L.)
- Department of Anesthesiology and Critical Care, Hue University of Medicine and Pharmacy, Hue City 52000, Vietnam
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
- Research Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 110, Taiwan
- International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
| | - Chun-Jen Huang
- Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: ; Tel.: +886-2-29307930 (ext. 2160); Fax: +886-2-29302448
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Huang YD, Fang Y, Ma L, Feng PJ, Li WL, Zhou YQ, Qin YH, You ZJ, Dong L. Kindlin-2 Mediates Lipopolysaccharide-Induced Acute Lung Injury Partially via Pyroptosis in Mice. Inflammation 2022; 45:1199-1208. [PMID: 35133562 DOI: 10.1007/s10753-021-01613-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/16/2021] [Accepted: 12/13/2021] [Indexed: 11/26/2022]
Abstract
Acute lung injury (ALI) is characteristic of the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of pro-inflammatory leukocytes, and intractable hypoxemia, contributing to high mortality. Kindlin-2 is involved in the process of tumor- and wound healing-associated inflammation. However, the effects of kindlin-2 on lipopolysaccharide (LPS)-induced ALI and its mechanisms remain unknown. In this study, we found that the concentration of kindlin-2 was elevated in the lungs of ALI mice. The specific deletion of kindlin-2 by kindlin-2 siRNA attenuated the severity of lung injury, which was demonstrated by the reduced number of pro-inflammatory cells in bronchoalveolar lavage fluid and lung wet/dry weight ratio, and ameliorated pathologic changes in the lungs of ALI mice. Furthermore, kindlin-2 siRNA decreased the mRNA levels of pro-inflammatory factors (IL-1β, IL-6, and TNF-α) and the protein levels of pyroptosis-related proteins. In vitro studies confirmed that LPS + ATP promoted the expressions of pro-inflammatory factors and pyroptosis-related proteins, which was prevented by kindlin-2 siRNA pretreatment in endothelial cells (ECs). In conclusion, inhibition of kindlin-2 developes protective effects against LPS-induced ALI and the cytotoxicity of ECs, which may depend on blocking pyroptosis.
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Affiliation(s)
- Yi-Dan Huang
- Department of Anesthesiology, Liuzhou Municipal People's Hospital, Liuzhou, 545006, Guangxi, China
| | - Yu Fang
- Medical Laboratory and Pathology Center, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, 410021, Hunan, China
| | - Li Ma
- Department of Anesthesiology, Liuzhou Municipal People's Hospital, Liuzhou, 545006, Guangxi, China
| | - Peng-Jiu Feng
- Department of Anesthesiology, Liuzhou Traditional Chinese Medicine Hospital, Liuzhou, 545001, Guangxi, China
| | - Wen-Long Li
- Department of Anesthesiology, Liuzhou Municipal People's Hospital, Liuzhou, 545006, Guangxi, China
| | - Yi-Qi Zhou
- Department of Anesthesiology, Liuzhou Municipal People's Hospital, Liuzhou, 545006, Guangxi, China
| | - Yuan-Hao Qin
- Department of Anesthesiology, Liuzhou Municipal People's Hospital, Liuzhou, 545006, Guangxi, China
| | - Zhi-Jian You
- Department of Anesthesiology, Liuzhou Municipal People's Hospital, Liuzhou, 545006, Guangxi, China.
| | - Liang Dong
- Department of Anesthesiology, Liuzhou Municipal People's Hospital, Liuzhou, 545006, Guangxi, China.
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