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Huang X, Xu P, Long G, Huang F, Zhang Q, Yang X, Sun H, Ji C, Liu W. Clinical significance of miR-6515-5p in predicting diagnosis and prognosis for acute respiratory distress syndrome suffering from pulmonary fibrosis. Hereditas 2025; 162:71. [PMID: 40287741 PMCID: PMC12034141 DOI: 10.1186/s41065-025-00436-1] [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: 03/17/2025] [Accepted: 04/14/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND The high mortality rate of ARDS is closely related to pulmonary fibrosis (PLF), and the degree of pulmonary fibrosis affects the prognosis of ARDS. Numerous studies indicated the abnormal expression of miRNAs in the pathogenesis of various lung diseases, such as ARDS and PLF. This study aimed to explore the expression of serum miR-6515-5p and its clinical performance in ARDS complicated with PLF. METHODS RT-qPCR analysis was employed to measure miR-6515-5p levels within the serum specimens from ARDS patients who either had PLF or did not. Receiver Operating Characteristics (ROC) curve was conducted to evaluate the diagnostic value of miR-6515-5p. To analyze the risk factors linked with the development of PLF in ARDS patients, logistic regression analysis was conducted. Kaplan-Meier curve was conducted to assess the prognostic value of miR-6515-5p in predicting the outcome of ARDS patients with PLF. Multivariate COX regression analysis was performed to identify the PLF-related risk factors associated with outcomes. RESULTS Serum miR-6515-5p was downregulated in ARDS patients, especially in patients suffering from PLF. miR-6515-5p expression can distinguish ARDS patients from healthy individuals and related to the occurrence of PLF. Most patients with low miR-6515-5p expression had low FVC and DLCO, as well as high Murray score and APACHE II score. Moreover, miR-6515-5p expression has a certain high value in differentiating ARDS patients with PLF from those without PLF. In addition, miR-6515-5p may be a prognostic marker in ARDS patients suffering from PLF. CONCLUSIONS These data identified the abnormal expression of miR-6515-5p in ARDS and PLF, and implied a potential clinical early diagnostic and prognostic marker in ARDS suffering from PLF.
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Affiliation(s)
- Xueqin Huang
- Department of Respiratory Medicine, 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Cangshan Campus, Fuzhou, 350007, Fujian Province, China
| | - Peng Xu
- Department of Emergency, Wuhan Brain Hospital, General Hospital of the YANGTZE River Shipping, Wuhan, Hubei, China
| | - Guangwen Long
- Department of Emergency, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, 550002, Guizhou, China.
| | - Feihong Huang
- Department of Emergency, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, 550002, Guizhou, China
| | - Qian Zhang
- Department of Emergency, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, 550002, Guizhou, China
| | - Xiulin Yang
- Department of Emergency, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, 550002, Guizhou, China
| | - Hongpeng Sun
- Department of Emergency, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, 550002, Guizhou, China
| | - Chunling Ji
- Department of Emergency, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, 550002, Guizhou, China
| | - Wang Liu
- Department of Integrated Section, Wushan Hospital Hangzhou First People's Hospital (Hangzhou Cancer Hospital), No.34, Yanguan Lane, Zhongshan South Road, Shangcheng District, Hangzhou, 310002, Zhejiang Province, China.
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Hernandez-Gonzalez F, Pietrocola F, Cameli P, Bargagli E, Prieto-González S, Cruz T, Mendoza N, Rojas M, Serrano M, Agustí A, Faner R, Gómez-Puerta JA, Sellares J. Exploring the Interplay between Cellular Senescence, Immunity, and Fibrosing Interstitial Lung Diseases: Challenges and Opportunities. Int J Mol Sci 2024; 25:7554. [PMID: 39062798 PMCID: PMC11276754 DOI: 10.3390/ijms25147554] [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: 05/26/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs.
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Affiliation(s)
- Fernanda Hernandez-Gonzalez
- Department of Respiratory Medicine, Respiratory Institute, Hospital Clinic Barcelona, 08036 Barcelona, Spain; (A.A.); (J.S.)
- Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-G.); (T.C.); (N.M.); (R.F.)
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
| | - Federico Pietrocola
- Department of Cell and Molecular Biology, Karolinska Institutet, 17165 Solna, Sweden;
| | - Paolo Cameli
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences & Neuro-Sciences, University of Siena, 53100 Siena, Italy; (P.C.); (E.B.)
| | - Elena Bargagli
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences & Neuro-Sciences, University of Siena, 53100 Siena, Italy; (P.C.); (E.B.)
| | - Sergio Prieto-González
- Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-G.); (T.C.); (N.M.); (R.F.)
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
- Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic Barcelona, 08036 Barcelona, Spain
| | - Tamara Cruz
- Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-G.); (T.C.); (N.M.); (R.F.)
- Centro Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain
| | - Nuria Mendoza
- Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-G.); (T.C.); (N.M.); (R.F.)
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
- Centro Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain
| | - Mauricio Rojas
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Manuel Serrano
- Cambridge Institute of Science, Altos Labs, Cambridge CB21 6GP, UK;
| | - Alvar Agustí
- Department of Respiratory Medicine, Respiratory Institute, Hospital Clinic Barcelona, 08036 Barcelona, Spain; (A.A.); (J.S.)
- Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-G.); (T.C.); (N.M.); (R.F.)
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
- Centro Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain
| | - Rosa Faner
- Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-G.); (T.C.); (N.M.); (R.F.)
- Centro Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain
- Biomedicine Department, University of Barcelona, 08036 Barcelona, Spain
| | - Jose A. Gómez-Puerta
- Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-G.); (T.C.); (N.M.); (R.F.)
- Rheumatology Department, Hospital Clinic Barcelona, 08036 Barcelona, Spain
| | - Jacobo Sellares
- Department of Respiratory Medicine, Respiratory Institute, Hospital Clinic Barcelona, 08036 Barcelona, Spain; (A.A.); (J.S.)
- Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (S.P.-G.); (T.C.); (N.M.); (R.F.)
- Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain
- Centro Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), 08036 Barcelona, Spain
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Shakour N, Karami S, Iranshahi M, Butler AE, Sahebkar A. Antifibrotic effects of sodium-glucose cotransporter-2 inhibitors: A comprehensive review. Diabetes Metab Syndr 2024; 18:102934. [PMID: 38154403 DOI: 10.1016/j.dsx.2023.102934] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 11/25/2023] [Accepted: 12/20/2023] [Indexed: 12/30/2023]
Abstract
BACKGROUND AND AIMS Scar tissue accumulation in organs is the underlying cause of many fibrotic diseases. Due to the extensive array of organs affected, the long-term nature of fibrotic processes and the large number of people who suffer from the negative impact of these diseases, they constitute a serious health problem for modern medicine and a huge economic burden on society. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of anti-diabetic pharmaceuticals that offer additional benefits over and above their glucose-lowering properties; these medications modulate a variety of diseases, including fibrosis. Herein, we have collated and analyzed all available research on SGLT2is and their effects on organ fibrosis, together with providing a proposed explanation as to the underlying mechanisms. METHODS PubMed, ScienceDirect, Google Scholar and Scopus were searched spanning the period from 2012 until April 2023 to find relevant articles describing the antifibrotic effects of SGLT2is. RESULTS The majority of reports have shown that SGLT2is are protective against lung, liver, heart and kidney fibrosis as well as arterial stiffness. According to the results of clinical trials and animal studies, many SGLT2 inhibitors are promising candidates for the treatment of fibrosis. Recent studies have demonstrated that SGLT2is affect an array of cellular processes, including hypoxia, inflammation, oxidative stress, the renin-angiotensin system and metabolic activities, all of which have been linked to fibrosis. CONCLUSION Extensive evidence indicates that SGLT2is are promising treatments for fibrosis, demonstrating protective effects in various organs and influencing key cellular processes linked to fibrosis.
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Affiliation(s)
- Neda Shakour
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shima Karami
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Adliya, Bahrain
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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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, Huang H, Li Y. Roles of exosomes and exosome-derived miRNAs in pulmonary fibrosis. Front Pharmacol 2022; 13:928933. [PMID: 36034858 PMCID: PMC9403513 DOI: 10.3389/fphar.2022.928933] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 07/15/2022] [Indexed: 11/13/2022] Open
Abstract
Pulmonary fibrosis is a chronic, progressive fibrosing interstitial lung disease of unknown etiology that leads rapidly to death. It is characterized by the replacement of healthy tissue through an altered extracellular matrix and damage to the alveolar structure. New pharmacological treatments and biomarkers are needed for pulmonary fibrosis to ensure better outcomes and earlier diagnosis of patients. Exosomes are nanoscale vesicles released by nearly all cell types that play a central role as mediators of cell-to-cell communication. Moreover, exosomes are emerging as a crucial factor in antigen presentation, immune response, immunomodulation, inflammation, and cellular phenotypic transformation and have also shown promising therapeutic potential in pulmonary fibrosis. This review summarizes current knowledge of exosomes that may promote pulmonary fibrosis and be utilized for diagnostics and prognostics. In addition, the utilization of exosomes and their cargo miRNAs as novel therapeutics and their potential mechanisms are also discussed. This review aims to elucidate the role of exosomes in the pathogenesis of pulmonary fibrosis and paves the way for developing novel therapeutics for pulmonary fibrosis. Further in-depth research and clinical trials on this topic are encouraged in the future.
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Affiliation(s)
- Yongfeng Yang
- Precision Medicine Key Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hong Huang
- Precision Medicine Key Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Key Laboratory of Transplantation Engineering and Immunology, Institute of Clinical Pathology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Li
- Precision Medicine Key Laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- *Correspondence: Yi Li,
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Mei Q, Liu Z, Zuo H, Yang Z, Qu J. Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis. Front Pharmacol 2022; 12:797292. [PMID: 35126134 PMCID: PMC8807692 DOI: 10.3389/fphar.2021.797292] [Citation(s) in RCA: 142] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/29/2021] [Indexed: 12/15/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal fibrotic lung disease that occurs primarily in middle-aged and elderly adults. It is a major cause of morbidity and mortality. With an increase in life expectancy, the economic burden of IPF is expected to continuously rise in the near future. Although the exact pathophysiological mechanisms underlying IPF remain not known. Significant progress has been made in our understanding of the pathogenesis of this devastating disease in last decade. The current paradigm assumes that IPF results from sustained or repetitive lung epithelial injury and subsequent activation of fibroblasts and myofibroblast differentiation. Persistent myofibroblast phenotype contributes to excessive deposition of the extracellular matrix (ECM) and aberrant lung repair, leading to tissue scar formation, distortion of the alveolar structure, and irreversible loss of lung function. Treatments of patients with IPF by pirfenidone and nintedanib have shown significant reduction of lung function decline and slowing of disease progression in patients with IPF. However, these drugs do not cure the disease. In this review, we discuss recent advances on the pathogenesis of IPF and highlight the development of novel therapeutic strategies against the disease.
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Affiliation(s)
| | | | | | | | - Jing Qu
- *Correspondence: Zhenhua Yang, ; Jing Qu,
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Proteome Characterization of BALF Extracellular Vesicles in Idiopathic Pulmonary Fibrosis: Unveiling Undercover Molecular Pathways. Int J Mol Sci 2021; 22:ijms22115696. [PMID: 34071777 PMCID: PMC8199247 DOI: 10.3390/ijms22115696] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/24/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
In the longtime challenge of identifying specific, easily detectable and reliable biomarkers of IPF, BALF proteomics is providing interesting new insights into its pathogenesis. To the best of our knowledge, the present study is the first shotgun proteomic investigation of EVs isolated from BALF of IPF patients. Our main aim was to characterize the proteome of the vesicular component of BALF and to explore its individual impact on the pathogenesis of IPF. To this purpose, ultracentrifugation was chosen as the EVs isolation technique, and their purification was assessed by TEM, 2DE and LC-MS/MS. Our 2DE data and scatter plots showed considerable differences between the proteome of EVs and that of whole BALF and of its fluid component. Analysis of protein content and protein functions evidenced that EV proteins are predominantly involved in cytoskeleton remodeling, adenosine signaling, adrenergic signaling, C-peptide signaling and lipid metabolism. Our findings may suggest a wider system involvement in the disease pathogenesis and support the importance of pre-fractioning of complex samples, such as BALF, in order to let low-abundant proteins-mediated pathways emerge.
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Yamada M. Extracellular vesicles: Their emerging roles in the pathogenesis of respiratory diseases. Respir Investig 2021; 59:302-311. [PMID: 33753011 DOI: 10.1016/j.resinv.2021.02.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 06/12/2023]
Abstract
Alveoli are the basic structure of the lungs, consisting of various types of parenchymal and bone marrow-derived cells including alveolar macrophages. These various types of cells have several important functions; thus, communication between these cells plays an important role in homeostasis as well as in the pathophysiology of diseases in the lungs. For a better understanding of the pathophysiology of lung diseases, researchers have isolated each type of lung cell to investigate the changes in their gene expressions, including their humoral factor or adhesion molecules, to reveal the intercellular communication among these cells. In particular, investigations during the past decade have focused on extracellular vesicles, which are lipid bilayer delimited vesicles released from a cell that can move among various cells and transfer substances, including microRNAs, mRNAs and proteins, thus, functioning as intercellular messengers. Extracellular vesicles can be classified into three general groups: apoptotic bodies, exosomes, and microparticles. Extracellular vesicles, especially exosomes and microparticles, are attracting increasing attention from pulmonologists as tools for understanding pathogenesis and disease diagnosis. Here, we review studies, including our own, on exosomes and microparticles and their roles in both lung homeostasis and the pathogenesis of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive lung diseases, and acute respiratory distress syndrome. This review also addresses the roles of extracellular vesicles in COVID-19, the current global public health crisis.
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Affiliation(s)
- Mitsuhiro Yamada
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 9808574, Japan.
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