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Chen S, Zhang C, Luo J, Lin Z, Chang T, Dong L, Chen D, Tang ZH. Macrophage activation syndrome in Sepsis: from pathogenesis to clinical management. Inflamm Res 2024; 73:2179-2197. [PMID: 39404874 DOI: 10.1007/s00011-024-01957-7] [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: 03/20/2024] [Revised: 08/01/2024] [Accepted: 10/01/2024] [Indexed: 12/11/2024] Open
Abstract
BACKGROUND Sepsis represents a significant global health and hygiene challenge. Excessive activation of macrophages in sepsis can result in certain patients displaying characteristics akin to those observed in Macrophage Activation Syndrome (MAS). MAS represents a grave immune system disorder characterized by persistent and severe inflammation within the body. In the context of sepsis, MAS presents atypically, leading some researchers to refer to it as Macrophage Activation-Like Syndrome (MALS). However, there are currently no effective treatment measures for this situation. The purpose of this article is to explore potential treatment methods for sepsis-associated MALS. OBJECTIVE The objective of this review is to synthesize the specific pathophysiological mechanisms and treatment strategies of MAS to investigate potential therapeutic approaches for sepsis-associated MALS. METHOD We searched major databases (including PubMed, Web of Science, and Google Scholar etc.) for literature encompassing macrophage activation syndrome and sepsis up to Mar 2024 and combined with studies found in the reference lists of the included studies. CONCLUSION We have synthesized the underlying pathophysiological mechanism of MALS in sepsis, and then summarized the diagnostic criteria and the effects of various treatment modalities utilized in patients with MAS or MALS. In both scenarios, heterogeneous treatment responses resulting from identical treatment approaches were observed. The determination of whether the patient is genuinely experiencing MALS significantly impacts the ultimate outcomes of therapeutic efficacy. In order to tackle this concern, additional clinical trials and research endeavors are imperative.
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Affiliation(s)
- Shunyao Chen
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Cong Zhang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jialiu Luo
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zhiqiang Lin
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Teding Chang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Liming Dong
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Deng Chen
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Zhao-Hui Tang
- Department of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Cheung SWY, Chamley LW, Barrett CJ, Lau SYS. Extracellular vesicles and their effect on vascular haemodynamics: a systematic review. Hypertens Res 2024; 47:1588-1606. [PMID: 38600279 PMCID: PMC11150158 DOI: 10.1038/s41440-024-01659-x] [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: 07/12/2023] [Revised: 02/03/2024] [Accepted: 03/13/2024] [Indexed: 04/12/2024]
Abstract
Extracellular vesicles (EVs) are released from all cell types studied to date and act as intercellular communicators containing proteins, nucleic acids and lipid cargos. They have been shown to be involved in maintaining homoeostasis as well as playing a role in the development of pathology including hypertension and cardiovascular disease. It is estimated that there is 109-1010 circulating EVs/mL in the plasma of healthy individuals derived from various sources. While the effect of EVs on vascular haemodynamic parameters will be dependent on the details of the model studied, we systematically searched and summarized current literature to find patterns in how exogenously injected EVs affected vascular haemodynamics. Under homoeostatic conditions, evidence from wire and pressure myography data demonstrate that injecting isolated EVs derived from cell types found in blood and blood vessels resulted in the impairment of vasodilation in blood vessels ex vivo. Impaired vasodilation was also observed in rodents receiving intravenous injections of human plasma EVs from cardiovascular diseases including valvular heart disease, acute coronary syndrome, myocardial infarction and end stage renal disease. When EVs were derived from models of metabolic syndromes, such as diabetes, these EVs enhanced vasoconstriction responses in blood vessels ex vivo. There were fewer publications that assessed the effect of EVs in anaesthetised or conscious animals to confirm whether effects on the vasculature observed in ex vivo studies translated into alterations in vascular haemodynamics in vivo. In the available conscious animal studies, the in vivo data did not always align with the ex vivo data. This highlights the importance of in vivo work to determine the effects of EVs on the integrative vascular haemodynamics.
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Affiliation(s)
- Sharon W Y Cheung
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Lawrence W Chamley
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
- Hub for Extracellular Vesicle Investigations, The University of Auckland, Auckland, New Zealand
| | - Carolyn J Barrett
- Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Sien Yee S Lau
- Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
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Barbosa MS, de Lima F, Peachazepi Moraes CR, Borba-Junior IT, Huber SC, Santos I, Bombassaro B, Dertkigil SSJ, Ilich A, Key NS, Annichino-Bizzacchi JM, Orsi FA, Mansour E, Velloso LA, De Paula EV. Angiopoietin2 is associated with coagulation activation and tissue factor expression in extracellular vesicles in COVID-19. Front Med (Lausanne) 2024; 11:1367544. [PMID: 38803346 PMCID: PMC11128612 DOI: 10.3389/fmed.2024.1367544] [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: 01/08/2024] [Accepted: 04/12/2024] [Indexed: 05/29/2024] Open
Abstract
Coagulation activation in immunothrombosis involves various pathways distinct from classical hemostasis, offering potential therapeutic targets to control inflammation-induced hypercoagulability while potentially sparing hemostasis. The Angiopoietin/Tie2 pathway, previously linked to embryonic angiogenesis and sepsis-related endothelial barrier regulation, was recently associated with coagulation activation in sepsis and COVID-19. This study explores the connection between key mediators of the Angiopoietin/Tie2 pathway and coagulation activation. The study included COVID-19 patients with hypoxia and healthy controls. Blood samples were processed to obtain platelet-free plasma, and frozen until analysis. Extracellular vesicles (EVs) in plasma were characterized and quantified using flow cytometry, and their tissue factor (TF) procoagulant activity was measured using a kinetic chromogenic method. Several markers of hemostasis were assessed. Levels of ANGPT1, ANGPT2, and soluble Tie2 correlated with markers of coagulation and platelet activation. EVs from platelets and endothelial cells were increased in COVID-19 patients, and a significant increase in TF+ EVs derived from endothelial cells was observed. In addition, ANGPT2 levels were associated with TF expression and activity in EVs. In conclusion, we provide further evidence for the involvement of the Angiopoietin/Tie2 pathway in the coagulopathy of COVID-19 mediated in part by release of EVs as a potential source of TF activity.
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Affiliation(s)
- Mayck Silva Barbosa
- School of Medical Sciences, Universidade Estadual de Campinas, Campinas, Brazil
| | - Franciele de Lima
- School of Medical Sciences, Universidade Estadual de Campinas, Campinas, Brazil
| | | | | | - Stephany Cares Huber
- Hematology and Hemotherapy Center, Universidade Estadual de Campinas, Campinas, Brazil
| | - Irene Santos
- Hematology and Hemotherapy Center, Universidade Estadual de Campinas, Campinas, Brazil
| | - Bruna Bombassaro
- Obesity and Comorbidities Research Center, Universidade Estadual de Campinas, Campinas, Brazil
| | | | - Anton Ilich
- Blood Research Center, University of North Carolina, Chapel Hill, NC, United States
- Division of Hematology, Department of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Nigel S. Key
- Blood Research Center, University of North Carolina, Chapel Hill, NC, United States
- Division of Hematology, Department of Medicine, University of North Carolina, Chapel Hill, NC, United States
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Joyce M. Annichino-Bizzacchi
- School of Medical Sciences, Universidade Estadual de Campinas, Campinas, Brazil
- Hematology and Hemotherapy Center, Universidade Estadual de Campinas, Campinas, Brazil
| | - Fernanda Andrade Orsi
- Hematology and Hemotherapy Center, Universidade Estadual de Campinas, Campinas, Brazil
| | - Eli Mansour
- School of Medical Sciences, Universidade Estadual de Campinas, Campinas, Brazil
| | - Licio A. Velloso
- School of Medical Sciences, Universidade Estadual de Campinas, Campinas, Brazil
- Obesity and Comorbidities Research Center, Universidade Estadual de Campinas, Campinas, Brazil
| | - Erich Vinicius De Paula
- School of Medical Sciences, Universidade Estadual de Campinas, Campinas, Brazil
- Hematology and Hemotherapy Center, Universidade Estadual de Campinas, Campinas, Brazil
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Ortmann W, Such A, Kolaczkowska E. Impact of microparticles released during murine systemic inflammation on macrophage activity and reactive nitrogen species regulation. Immunol Res 2024; 72:299-319. [PMID: 38008825 PMCID: PMC11031483 DOI: 10.1007/s12026-023-09436-7] [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: 04/06/2023] [Accepted: 11/13/2023] [Indexed: 11/28/2023]
Abstract
Microparticles (MPs) packaged with numerous bioactive molecules are essential vehicles in cellular communication in various pathological conditions, including systemic inflammation, Whereas MPs are studied mostly upon isolation, their detection in vivo is limited. Impact of MPs might depend on target cell type and cargo they carry; thus herein, we aimed at verifying MPs' impact on macrophages. Unlike neutrophils, monocytes/macrophages are rather inactive during sepsis, and we hypothesized this might be at least partially controlled by MPs. For the above reasons, we focused on the detection of MPs with intravital microscopy (IVM) and report the presence of putative neutrophil-derived MPs in the vasculature of cremaster muscle of endotoxemic mice. Subsequently, we characterized MPs isolated not only from their blood but also from the peritoneal cavity and observed differences in their size, concentration, and cargo. Such MPs were then used to study their impact on RAW 264.7 macrophage cell line performance (cell viability/activity, cytokines, oxygen, and nitrogen reactive species). Addition of MPs to macrophages with or without co-stimulation with lipopolysaccharide did not affect respiratory burst, somewhat decreased mitochondrial activity but increased inducible nitric oxide synthase (iNOS) expression, and NO production especially in case of plasma-derived MPs. The latter MPs carried more iNOS-controlling ceruloplasmin than those discharged into the peritoneal cavity. We conclude that MPs can be detected in vivo with IVM and their cellular origin identified. They are heterogeneous in nature depending on the site of their release. Consequently, microparticles released during systemic inflammation to various body compartments differentially affect macrophages.
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Affiliation(s)
- Weronika Ortmann
- Laboratory of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9 Street, 30-387, Krakow, Poland
| | - Anna Such
- Laboratory of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9 Street, 30-387, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | - Elzbieta Kolaczkowska
- Laboratory of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9 Street, 30-387, Krakow, Poland.
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Gaceb A, Roupé L, Enström A, Almasoudi W, Carlsson R, Lindgren AG, Paul G. Pericyte Microvesicles as Plasma Biomarkers Reflecting Brain Microvascular Signaling in Patients With Acute Ischemic Stroke. Stroke 2024; 55:558-568. [PMID: 38323422 PMCID: PMC10896197 DOI: 10.1161/strokeaha.123.045720] [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: 08/15/2023] [Revised: 01/07/2024] [Accepted: 01/19/2024] [Indexed: 02/08/2024]
Abstract
BACKGROUND Blood-based biomarkers have the potential to reflect cerebrovascular signaling after microvascular injury; yet, the detection of cell-specific signaling has proven challenging. Microvesicles retain parental cell surface antigens allowing detection of cell-specific signaling encoded in their cargo. In ischemic stroke, the progression of pathology involves changes in microvascular signaling whereby brain pericytes, perivascular cells wrapping the microcapillaries, are one of the early responders to the ischemic insult. Intercepting the pericyte signaling response peripherally by isolating pericyte-derived microvesicles may provide not only diagnostic information on microvascular injury but also enable monitoring of important pathophysiological mechanisms. METHODS Plasma samples were collected from patients with acute ischemic stroke (n=39) at 3 time points after stroke onset: 0 to 6 hours, 12 to 24 hours, and 2 to 6 days, and compared with controls (n=39). Pericyte-derived microvesicles were isolated based on cluster of differentiation 140b expression and quantified by flow cytometry. The protein content was evaluated using a proximity extension assay, and vascular signaling pathways were examined using molecular signature hallmarks and gene ontology. RESULTS In this case-control study, patients with acute ischemic stroke showed significantly increased numbers of pericyte-derived microvesicles (median, stroke versus controls) at 12 to 24 hours (1554 versus 660 microvesicles/μL; P=0.0041) and 2 to 6 days after stroke (1346 versus 660 microvesicles/μL; P=0.0237). Their proteome revealed anti-inflammatory properties mediated via downregulation of Kirsten rat sarcoma virus and IL (interleukin)-6/JAK/STAT3 signaling at 0 to 6 hours, but proangiogenic as well as proinflammatory signals at 12 to 24 hours. Between 2 and 6 days, proteins were mainly associated with vascular remodeling as indicated by activation of Hedgehog signaling in addition to proangiogenic signals. CONCLUSIONS We demonstrate that the plasma of patients with acute ischemic stroke reflects (1) an early and time-dependent increase of pericyte-derived microvesicles and (2) changes in the protein cargo of microvesicles over time indicating cell signaling specifically related to inflammation and vascular remodeling.
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Affiliation(s)
- Abderahim Gaceb
- Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center (A.G., A.E., R.C., G.P.), Lund University, Sweden
| | - Linnea Roupé
- Department of Neurology, Scania University Hospital, Lund, Sweden (L.R., W.A., A.G.L., G.P.)
| | - Andreas Enström
- Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center (A.G., A.E., R.C., G.P.), Lund University, Sweden
| | - Wejdan Almasoudi
- Department of Neurology, Scania University Hospital, Lund, Sweden (L.R., W.A., A.G.L., G.P.)
| | - Robert Carlsson
- Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center (A.G., A.E., R.C., G.P.), Lund University, Sweden
| | - Arne G. Lindgren
- Department of Neurology, Scania University Hospital, Lund, Sweden (L.R., W.A., A.G.L., G.P.)
| | - Gesine Paul
- Translational Neurology Group, Department of Clinical Science, Wallenberg Neuroscience Center (A.G., A.E., R.C., G.P.), Lund University, Sweden
- Wallenberg Center for Molecular Medicine (G.P.), Lund University, Sweden
- Department of Neurology, Scania University Hospital, Lund, Sweden (L.R., W.A., A.G.L., G.P.)
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Kisielewska M, Rakoczy K, Skowron I, Górczyńska J, Kacer J, Bocheńska A, Choromańska A. Utilizing Extracellular Vesicles for Eliminating 'Unwanted Molecules': Harnessing Nature's Structures in Modern Therapeutic Strategies. Molecules 2024; 29:948. [PMID: 38474460 DOI: 10.3390/molecules29050948] [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: 01/14/2024] [Revised: 02/09/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Extracellular vesicles (EVs) are small phospholipid bilayer-bond structures released by diverse cell types into the extracellular environment, maintaining homeostasis of the cell by balancing cellular stress. This article provides a comprehensive overview of extracellular vesicles, their heterogeneity, and diversified roles in cellular processes, emphasizing their importance in the elimination of unwanted molecules. They play a role in regulating oxidative stress, particularly by discarding oxidized toxic molecules. Furthermore, endoplasmic reticulum stress induces the release of EVs, contributing to distinct results, including autophagy or ER stress transmission to following cells. ER stress-induced autophagy is a part of unfolded protein response (UPR) and protects cells from ER stress-related apoptosis. Mitochondrial-derived vesicles (MDVs) also play a role in maintaining homeostasis, as they carry damaged mitochondrial components, thereby preventing inflammation. Moreover, EVs partake in regulating aging-related processes, and therefore they can potentially play a crucial role in anti-aging therapies, including the treatment of age-related diseases such as Alzheimer's disease or cardiovascular conditions. Overall, the purpose of this article is to provide a better understanding of EVs as significant mediators in both physiological and pathological processes, and to shed light on their potential for therapeutic interventions targeting EV-mediated pathways in various pathological conditions, with an emphasis on age-related diseases.
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Affiliation(s)
| | - Katarzyna Rakoczy
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Izabela Skowron
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Julia Górczyńska
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Julia Kacer
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Agata Bocheńska
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland
| | - Anna Choromańska
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Effah CY, Ding X, Drokow EK, Li X, Tong R, Sun T. Bacteria-derived extracellular vesicles: endogenous roles, therapeutic potentials and their biomimetics for the treatment and prevention of sepsis. Front Immunol 2024; 15:1296061. [PMID: 38420121 PMCID: PMC10899385 DOI: 10.3389/fimmu.2024.1296061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 01/24/2024] [Indexed: 03/02/2024] Open
Abstract
Sepsis is one of the medical conditions with a high mortality rate and lacks specific treatment despite several years of extensive research. Bacterial extracellular vesicles (bEVs) are emerging as a focal target in the pathophysiology and treatment of sepsis. Extracellular vesicles (EVs) derived from pathogenic microorganisms carry pathogenic factors such as carbohydrates, proteins, lipids, nucleic acids, and virulence factors and are regarded as "long-range weapons" to trigger an inflammatory response. In particular, the small size of bEVs can cross the blood-brain and placental barriers that are difficult for pathogens to cross, deliver pathogenic agents to host cells, activate the host immune system, and possibly accelerate the bacterial infection process and subsequent sepsis. Over the years, research into host-derived EVs has increased, leading to breakthroughs in cancer and sepsis treatments. However, related approaches to the role and use of bacterial-derived EVs are still rare in the treatment of sepsis. Herein, this review looked at the dual nature of bEVs in sepsis by highlighting their inherent functions and emphasizing their therapeutic characteristics and potential. Various biomimetics of bEVs for the treatment and prevention of sepsis have also been reviewed. Finally, the latest progress and various obstacles in the clinical application of bEVs have been highlighted.
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Affiliation(s)
- Clement Yaw Effah
- Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Zhengzhou Key Laboratory of Sepsis, Henan Sepsis Diagnosis and Treatment Center, Henan Key Laboratory of Sepsis in Health Commission, Zhengzhou, China
| | - Xianfei Ding
- Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Zhengzhou Key Laboratory of Sepsis, Henan Sepsis Diagnosis and Treatment Center, Henan Key Laboratory of Sepsis in Health Commission, Zhengzhou, China
| | - Emmanuel Kwateng Drokow
- Hunan Provincial Key Laboratory of Clinical Epidemiology, Department of Epidemiology and Biostatistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Xiang Li
- Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Zhengzhou Key Laboratory of Sepsis, Henan Sepsis Diagnosis and Treatment Center, Henan Key Laboratory of Sepsis in Health Commission, Zhengzhou, China
| | - Ran Tong
- Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Zhengzhou Key Laboratory of Sepsis, Henan Sepsis Diagnosis and Treatment Center, Henan Key Laboratory of Sepsis in Health Commission, Zhengzhou, China
| | - Tongwen Sun
- Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Critical Care Medicine, Henan Key Laboratory of Critical Care Medicine, Zhengzhou, China
- Zhengzhou Key Laboratory of Sepsis, Henan Sepsis Diagnosis and Treatment Center, Henan Key Laboratory of Sepsis in Health Commission, Zhengzhou, China
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Zhu Y, Wang K, Jia X, Fu C, Yu H, Wang Y. Antioxidant peptides, the guardian of life from oxidative stress. Med Res Rev 2024; 44:275-364. [PMID: 37621230 DOI: 10.1002/med.21986] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 08/01/2023] [Accepted: 08/06/2023] [Indexed: 08/26/2023]
Abstract
Reactive oxygen species (ROS) are produced during oxidative metabolism in aerobic organisms. Under normal conditions, ROS production and elimination are in a relatively balanced state. However, under internal or external environmental stress, such as high glucose levels or UV radiation, ROS production can increase significantly, leading to oxidative stress. Excess ROS production not only damages biomolecules but is also closely associated with the pathogenesis of many diseases, such as skin photoaging, diabetes, and cancer. Antioxidant peptides (AOPs) are naturally occurring or artificially designed peptides that can reduce the levels of ROS and other pro-oxidants, thus showing great potential in the treatment of oxidative stress-related diseases. In this review, we discussed ROS production and its role in inducing oxidative stress-related diseases in humans. Additionally, we discussed the sources, mechanism of action, and evaluation methods of AOPs and provided directions for future studies on AOPs.
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Affiliation(s)
- Yiyun Zhu
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Kang Wang
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Xinyi Jia
- National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu, China
- Department of Food Science and Technology, Food Science and Technology Center, National University of Singapore, Singapore, Singapore
| | - Caili Fu
- National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu, China
| | - Haining Yu
- Department of Bioscience and Biotechnology, Dalian University of Technology, Dalian, Liaoning, China
| | - Yipeng Wang
- Department of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
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Yang B, Wang X, Liu Z, Lu Z, Fang G, Xue X, Luo T. Endothelial-Related Biomarkers in Evaluation of Vascular Function During Progression of Sepsis After Severe Trauma: New Potential Diagnostic Tools in Sepsis. J Inflamm Res 2023; 16:2773-2782. [PMID: 37435113 PMCID: PMC10332413 DOI: 10.2147/jir.s418697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/03/2023] [Indexed: 07/13/2023] Open
Abstract
Purpose This study aimed to investigate the changes in endothelial-related biomarkers and their relationship with the incidence and prognosis of patients with sepsis after severe trauma. Methods A total of 37 severe trauma patients admitted to our hospital from Jan. to Dec. 2020 were enrolled in our research. All enrolled patients were divided into the sepsis and the non-sepsis groups. Endothelial progenitor cells (EPCs), circulating endothelial cells (CECs), and endothelial microparticles (EMPs) were detected on admission time; 24-48 hours and 48-72 hours after admission respectively. Demographic data, Acute Physiology, Chronic Health Evaluation (APACHE) II, and Sequential Organ Failure Assessment (SOFA) score were calculated every 24 h of admission to assess the severity of organ dysfunction. Receiver operating characteristic (ROC) curves were drawn to compare the areas under the curve (AUC) of endothelial-related biomarkers for the diagnosis of sepsis. Results The incidence rate of sepsis was 45.95% in all patients. The SOFA score in the sepsis group was significantly higher than that in the non-sepsis group (2 points vs 0 points, P<0.01). The number of EPCs, CECs, and EMPs all rose quickly in the early phase after trauma. The number of EPCs was similar in both groups, but the number of CECs and EMPs in the Sepsis Group was much higher than in the non-Sepsis Group (all P<0.01). Logistic regression analysis showed that the occurrence of sepsis was closely related to the expression of 0-24h CECs and 0-24h EMPs. The AUC ROC for CECs in different time periods were 0.815, 0.877, and 0.882, respectively (all P<0.001). The AUC ROC for EMPs in 0-24h was 0.868 (P=0.005). Conclusion The expression of EMPs was higher in early severe trauma, and high levels of EMPs were significantly higher in patients with early sepsis and poor prognosis.
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Affiliation(s)
- Biao Yang
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Xiaoyong Wang
- Department of Gastrointestinal Surgery, People’s Hospital of Haimen City, Nantong, Jiangsu Province, 226100, People’s Republic of China
| | - Zhaorui Liu
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Zhengmao Lu
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Guoen Fang
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Xuchao Xue
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Tianhang Luo
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
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10
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Zhang HJ, Li JY, Wang C, Zhong GQ. Microvesicles with mitochondrial content are increased in patients with sepsis and associated with inflammatory responses. World J Clin Cases 2023; 11:342-356. [PMID: 36686348 PMCID: PMC9850980 DOI: 10.12998/wjcc.v11.i2.342] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/03/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Endothelial activation plays an important role in sepsis-mediated inflammation, but the triggering factors have not been fully elucidated. Microvesicles carrying mitochondrial content (mitoMVs) have been implicated in several diseases and shown to induce endothelial activation.
AIM To explore whether mitoMVs constitute a subset of MVs isolated from plasma of patients with sepsis and contribute to endothelial activation.
METHODS MVs were isolated from human plasma and characterized by confocal microscopy and flow cytometry. Proinflammatory cytokines, including interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-α, and soluble vascular cell adhesion molecule (sVCAM)-1 were detected by ELISA. Human umbilical vein endothelial cells (HUVECs) were stimulated with the circulating MVs to evaluate their effect on endothelial activation.
RESULTS MitoMVs were observed in plasma from patients with sepsis. Compared with those in healthy controls, expression of MVs, mitoMVs, proinflammatory cytokines and sVCAM-1 was increased. The number of mitoMVs was positively associated with TNF-α and sVCAM-1. In vitro, compared with MVs isolated from the plasma of healthy controls, MVs isolated from the plasma of patients with sepsis induced expression of OAS2, RSAD2, and CXCL10 in HUVECs. MitoMVs were taken up by HUVECs, and sonication of MVs significantly reduced the uptake of mitoMVs by HUVECs and expression of the above three type I IFN-dependent genes.
CONCLUSION MitoMVs are increased in the plasma of patients with sepsis, which induces elevated expression of type I IFN-dependent genes. This suggests that circulating mitoMVs activate the type I IFN signalling pathway in endothelial cells and lead to endothelial activation.
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Affiliation(s)
- Hai-Jun Zhang
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
- Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421000, Hunan Province, China
| | - Jin-Yi Li
- Department of Cardiology, The Affiliated Hospital of Guilin Medical University, Guilin 541000, Guangxi Zhuang Autonomous Region, China
| | - Chao Wang
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
| | - Guo-Qiang Zhong
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530000, Guangxi Zhuang Autonomous Region, China
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11
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Tian C, Wang K, Zhao M, Cong S, Di X, Li R. Extracellular vesicles participate in the pathogenesis of sepsis. Front Cell Infect Microbiol 2022; 12:1018692. [PMID: 36579343 PMCID: PMC9791067 DOI: 10.3389/fcimb.2022.1018692] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022] Open
Abstract
Sepsis is one of the leading causes of mortality worldwide and is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The early diagnosis and effective treatment of sepsis still face challenges due to its rapid progression, dynamic changes, and strong heterogeneity among different individuals. To develop novel strategies to control sepsis, a better understanding of the complex mechanisms of sepsis is vital. Extracellular vesicles (EVs) are membrane vesicles released from cells through different mechanisms. In the disease state, the number of EVs produced by activated or apoptotic cells and the cargoes they carry were altered. They regulated the function of local or distant host cells in autocrine or paracrine ways. Current studies have found that EVs are involved in the occurrence and development of sepsis through multiple pathways. In this review, we focus on changes in the cargoes of EVs in sepsis, the regulatory roles of EVs derived from host cells and bacteria, and how EVs are involved in multiple pathological processes and organ dysfunction in sepsis. Overall, EVs have great application prospects in sepsis, such as early diagnosis of sepsis, dynamic monitoring of disease, precise therapeutic targets, and prevention of sepsis as a vaccine platform.
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Affiliation(s)
- Chang Tian
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Ke Wang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Min Zhao
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Shan Cong
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xin Di
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Ranwei Li
- Department of Urinary Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China,*Correspondence: Ranwei Li,
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12
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Carter N, Mathiesen AH, Miller N, Brown M, Colunga Biancatelli RML, Catravas JD, Dobrian AD. Endothelial cell-derived extracellular vesicles impair the angiogenic response of coronary artery endothelial cells. Front Cardiovasc Med 2022; 9:923081. [PMID: 35928931 PMCID: PMC9343725 DOI: 10.3389/fcvm.2022.923081] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/28/2022] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular disease (CVD) is the most prominent cause of death of adults in the United States with coronary artery disease being the most common type of CVD. Following a myocardial event, the coronary endothelium plays an important role in the recovery of the ischemic myocardium. Specifically, endothelial cells (EC) must be able to elicit a robust angiogenic response necessary for tissue revascularization and repair. However, local or distant cues may prevent effective revascularization. Extracellular vesicles (EV) are produced by all cells and endothelium is a rich source of EVs that have access to the main circulation thereby potentially impacting local and distant tissue function. Systemic inflammation associated with conditions such as obesity as well as the acute inflammatory response elicited by a cardiac event can significantly increase the EV release by endothelium and alter their miRNA, protein or lipid cargo. Our laboratory has previously shown that EVs released by adipose tissue endothelial cells exposed to chronic inflammation have angiostatic effects on naïve adipose tissue EC in vitro. Whether the observed effect is specific to EVs from adipose tissue endothelium or is a more general feature of the endothelial EVs exposed to pro-inflammatory cues is currently unclear. The objective of this study was to investigate the angiostatic effects of EVs produced by EC from the coronary artery and adipose microvasculature exposed to pro-inflammatory cytokines (PIC) on naïve coronary artery EC. We have found that EVs from both EC sources have angiostatic effects on the coronary endothelium. EVs produced by cells in a pro-inflammatory environment reduced proliferation and barrier function of EC without impacting cellular senescence. Some of these functional effects could be attributed to the miRNA cargo of EVs. Several miRNAs such as miR-451, let-7, or miR-23a impact on multiple pathways responsible for proliferation, cellular permeability and angiogenesis. Collectively, our data suggests that EVs may compete with pro-angiogenic cues in the ischemic myocardium therefore slowing down the repair response. Acute treatments with inhibitors that prevent endogenous EV release immediately after an ischemic event may contribute to better efficacy of therapeutic approaches using functionalized exogenous EVs or other pro-angiogenic approaches.
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Affiliation(s)
- Nigeste Carter
- Department of Physiological Science, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Allison H. Mathiesen
- Department of Physiological Science, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Noel Miller
- Department of Physiological Science, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Michael Brown
- Department of Physiological Science, Eastern Virginia Medical School, Norfolk, VA, United States
| | | | - John D. Catravas
- Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States
- School of Medical Diagnostic and Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, VA, United States
| | - Anca D. Dobrian
- Department of Physiological Science, Eastern Virginia Medical School, Norfolk, VA, United States
- *Correspondence: Anca D. Dobrian,
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13
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Stampouloglou PK, Siasos G, Bletsa E, Oikonomou E, Vogiatzi G, Kalogeras K, Katsianos E, Vavuranakis MA, Souvaliotis N, Vavuranakis M. The Role of Cell Derived Microparticles in Cardiovascular Diseases: Current Concepts. Curr Pharm Des 2022; 28:1745-1757. [DOI: 10.2174/1381612828666220429081555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/15/2022] [Indexed: 12/07/2022]
Abstract
Abstract:
Cardiovascular disease remains the main cause of human morbidity and mortality in the developed countries. Microparticles (MPs) are small vesicles originating from the cell membrane as a result of various stimuli and particularly of biological processes that constitute the pathophysiology of atherosclerosis, such as endothelial damage. They form vesicles that can transfer various molecules and signals to remote target cells without direct cell to cell interaction. Circulating microparticles have been associated with cardiovascular diseases. Therefore, many studies have been designed to further investigate the role of microparticles as biomarkers for diagnosis, prognosis, and disease monitoring. To this concept the pro-thrombotic and atherogenic potential of platelets and endothelial derived MPs has gain research interest especially concerning accelerate atherosclerosis and acute coronary syndrome triggering and prognosis. MPs especially of endothelial origin have been investigated in different clinical scenarios of heart failure and in association of left ventricular loading conditions. Finally, most cardiovascular risk factors present unique patterns of circulating MPs population, highlighting their pathophysiologic link to cardiovascular disease progression. In this review article we present a synopsis of the biogenesis and characteristics of microparticles, as well as the most recent data concerning their implication in the cardiovascular settings.
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Affiliation(s)
- Panagiota K. Stampouloglou
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
| | - Gerasimos Siasos
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
- Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Evanthia Bletsa
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
| | - Georgia Vogiatzi
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
| | - Konstantinos Kalogeras
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
| | - Efstratios Katsianos
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
| | - Michael-Andrew Vavuranakis
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
| | - Nektarios Souvaliotis
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
| | - Manolis Vavuranakis
- 3rd Department of Cardiology, National and Kapodistrian University of Athens, Medical School, Sotiria Chest Disease Hospital, Athens. Greece
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14
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Cointe S, Vallier L, Esnault P, Dacos M, Bonifay A, Macagno N, Harti Souab K, Chareyre C, Judicone C, Frankel D, Robert S, Hraiech S, Alessi MC, Poncelet P, Albanese J, Dignat-George F, Lacroix R. Granulocyte microvesicles with a high plasmin generation capacity promote clot lysis and improve outcome in septic shock. Blood 2022; 139:2377-2391. [PMID: 35026004 PMCID: PMC11022829 DOI: 10.1182/blood.2021013328] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 12/16/2021] [Indexed: 11/20/2022] Open
Abstract
Microvesicles (MVs) have previously been shown to exert profibrinolytic capacity, which is increased in patients with septic shock (SS) with a favorable outcome. We, therefore, hypothesized that the plasmin generation capacity (PGC) could confer to MVs a protective effect supported by their capacity to lyse a thrombus, and we investigated the mechanisms involved. Using an MV-PGC kinetic assay, ELISA, and flow cytometry, we found that granulocyte MVs (Gran-MVs) from SS patients display a heterogeneous PGC profile driven by the uPA (urokinase)/uPAR system. In vitro, these MVs lyse a thrombus according to their MV-PGC levels in a uPA/uPAR-dependent manner, as shown in a fluorescent clot lysis test and a lysis front retraction assay. Fibrinolytic activators conveyed by MVs contribute to approximately 30% of the plasma plasminogenolytic capacity of SS patients. In a murine model of SS, the injection of high PGC Gran-MVs significantly improved mouse survival and reduced the number of thrombi in vital organs. This was associated with a modification of the mouse coagulation and fibrinolysis properties toward a more fibrinolytic profile. Interestingly, mouse survival was not improved when soluble uPA was injected. Finally, using a multiplex array on plasma from SS patients, we found that neutrophil elastase correlates with the effect of high-PGC-capacity plasma and modulates the Gran-MV plasmin generation capacity by cleaving uPA-PAI-1 complexes. In conclusion, we show that the high PGC level displayed by Gran-MVs reduces thrombus formation and improves survival, conferring to Gran-MVs a protective role in a murine model of sepsis.
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Affiliation(s)
- Sylvie Cointe
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
- Department of Hematology and Vascular Biology, CHU La Conception, APHM, Marseille, France
| | - Loris Vallier
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
| | - Pierre Esnault
- Intensive Care Unit, Sainte Anne Military Hospital, Toulon, France
| | - Mathilde Dacos
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
| | - Amandine Bonifay
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
| | - Nicolas Macagno
- Department of Pathology and Neuropathology, CHU Timone, APHM, Marseille, France
- Aix-Marseille University, INSERM, MMG, Marseille, France
| | | | - Corinne Chareyre
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
| | | | - Diane Frankel
- Department of Cell Biology, Aix-Marseille University, APHM, INSERM, MMG, CHU Timone, APHM, Marseille, France
| | - Stéphane Robert
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
| | - Sami Hraiech
- Intensive Care Unit, APHM, CHU Nord, CEReSS-Center for Studies and Research on Health Services and Quality of Life EA3279, Aix-Marseille University, Marseille, France
| | - Marie-Christine Alessi
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
- Department of Hematology, CHU La Timone, APHM, Marseille, France
| | | | | | - Françoise Dignat-George
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
- Department of Hematology and Vascular Biology, CHU La Conception, APHM, Marseille, France
| | - Romaric Lacroix
- Aix-Marseille University, C2VN, INSERM 1263, INRA 1260, Marseille, France
- Department of Hematology and Vascular Biology, CHU La Conception, APHM, Marseille, France
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15
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Bonifay A, Robert S, Champagne B, Petit P, Eugène A, Chareyre C, Duchez A, Vélier M, Fritz S, Vallier L, Lacroix R, Dignat‐George F. A new strategy to count and sort neutrophil-derived extracellular vesicles: Validation in infectious disorders. J Extracell Vesicles 2022; 11:e12204. [PMID: 35362257 PMCID: PMC8971553 DOI: 10.1002/jev2.12204] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/27/2022] [Accepted: 03/01/2022] [Indexed: 01/13/2023] Open
Abstract
Newly recognized polymorphonuclear neutrophil (PMNs) functions include the ability to release subcellular mediators such as neutrophil-derived extracellular vesicles (NDEVs) involved in immune and thrombo-inflammatory responses. Elevation of their plasmatic level has been reported in a variety of infectious and cardiovascular disorders, but the clinical use of this potential biomarker is hampered by methodological issues. Although flow cytometry (FCM) is currently used to detect NDEVs in the plasma of patients, an extensive characterization of NDEVs has never been done. Moreover, their detection remains challenging because of their small size and low antigen density. Therefore, the objective of the present study was first to establish a surface antigenic signature of NDEVs detectable by FCM and therefore to improve their detection in biological fluids by developing a strategy allowing to overcome their low fluorescent signal and reduce the background noise. By testing a large panel of 54 antibody specificities already reported to be positive on PMNs, we identified a profile of 15 membrane protein markers, including 4 (CD157, CD24, CD65 and CD66c) never described on NDEVs. Among them, CD15, CD66b and CD66c were identified as the most sensitive and specific markers to detect NDEVs by FCM. Using this antigenic signature, we developed a new strategy combining the three best antibodies in a cocktail and reducing the background noise by size exclusion chromatography (SEC). This strategy allowed a significant improvement in NDEVs enumeration in plasma from sepsis patients and made it feasible to efficiently sort NDEVs from COVID-19 patients. Altogether, this work opens the door to a more valuable measurement of NDEVs as a potential biomarker in clinical practice. A similar strategy could also be applied to improve detection by FCM of other rare subpopulations of EVs generated by tissues with limited access, such as vascular endothelium, cancer cells or placenta.
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Affiliation(s)
- Amandine Bonifay
- Aix‐Marseille University, C2VN, INSERM 1263, INRA 1260MarseilleFrance
- Department of Hematology and Vascular BiologyCHU La Conception, APHMMarseilleFrance
| | - Stéphane Robert
- Aix‐Marseille University, C2VN, INSERM 1263, INRA 1260MarseilleFrance
| | - Belinda Champagne
- Aix‐Marseille University, C2VN, INSERM 1263, INRA 1260MarseilleFrance
| | - Paul‐Rémi Petit
- Department of Hematology and Vascular BiologyCHU La Conception, APHMMarseilleFrance
| | - Aude Eugène
- Department of Hematology and Vascular BiologyCHU La Conception, APHMMarseilleFrance
| | - Corinne Chareyre
- Aix‐Marseille University, C2VN, INSERM 1263, INRA 1260MarseilleFrance
| | | | - Mélanie Vélier
- Aix‐Marseille University, C2VN, INSERM 1263, INRA 1260MarseilleFrance
- Department of Hematology and Vascular BiologyCHU La Conception, APHMMarseilleFrance
| | - Shirley Fritz
- Department of Hematology and Vascular BiologyCHU La Conception, APHMMarseilleFrance
| | - Loris Vallier
- Aix‐Marseille University, C2VN, INSERM 1263, INRA 1260MarseilleFrance
| | - Romaric Lacroix
- Aix‐Marseille University, C2VN, INSERM 1263, INRA 1260MarseilleFrance
- Department of Hematology and Vascular BiologyCHU La Conception, APHMMarseilleFrance
| | - Françoise Dignat‐George
- Aix‐Marseille University, C2VN, INSERM 1263, INRA 1260MarseilleFrance
- Department of Hematology and Vascular BiologyCHU La Conception, APHMMarseilleFrance
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16
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Zhou YK, Patel HH, Roth DM. Extracellular Vesicles: A New Paradigm for Cellular Communication in Perioperative Medicine, Critical Care, and Pain Management. Anesth Analg 2021; 133:1162-1179. [PMID: 34304233 PMCID: PMC8542619 DOI: 10.1213/ane.0000000000005655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Extracellular vesicles (EVs) play critical roles in many health and disease states, including ischemia, inflammation, and pain, which are major concerns in the perioperative period and in critically ill patients. EVs are functionally active, nanometer-sized, membrane-bound vesicles actively secreted by all cells. Cell signaling is essential to physiological and pathological processes, and EVs have recently emerged as key players in intercellular communication. Recent studies in EV biology have improved our mechanistic knowledge of the pathophysiological processes in perioperative and critical care patients. Studies also show promise in using EVs in novel diagnostic and therapeutic clinical applications. This review considers the current advances and gaps in knowledge of EVs in the areas of ischemia, inflammation, pain, and in organ systems that are most relevant to anesthesiology, perioperative medicine, critical care, and pain management. We expect the reader will better understand the relationship between EVs and perioperative and critical care pathophysiological states and their potential use as novel diagnostic and therapeutic modalities.
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Affiliation(s)
- Yingqiu K. Zhou
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
| | - Hemal H. Patel
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
| | - David M. Roth
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
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17
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Takahashi T, Schleimer RP. Epithelial-Cell-Derived Extracellular Vesicles in Pathophysiology of Epithelial Injury and Repair in Chronic Rhinosinusitis: Connecting Immunology in Research Lab to Biomarkers in Clinics. Int J Mol Sci 2021; 22:11709. [PMID: 34769139 PMCID: PMC8583779 DOI: 10.3390/ijms222111709] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 10/26/2021] [Accepted: 10/27/2021] [Indexed: 11/17/2022] Open
Abstract
Epithelial barrier disruption and failure of epithelial repair by aberrant epithelial-mesenchymal transition (EMT)-induced basal cells observed in nasal mucosa of chronic rhinosinusitis (CRS) are speculated to play important roles in disease pathophysiology. Microparticles (MPs) are a type of extracellular vesicle (EV) released by budding or shedding from the plasma membrane of activated or apoptotic cells. MPs are detected in nasal lavage fluids (NLFs) and are now receiving attention as potential biomarkers to evaluate the degree of activation of immune cells and injury of structural cells in nasal mucosa of subjects with sinus disease. There are three types of epithelial-cell-derived MPs, which are defined by the expression of different epithelial specific markers on their surface: EpCAM, E-cadherin, and integrin β6 (ITGB6). When these markers are on MPs that are also carrying canonical EMT/mesenchymal markers (Snail (SNAI1); Slug (SNAI2); alpha-smooth muscle actin (αSMA, ACTA2)) or pro- and anti-coagulant molecules (tissue factor (TF); tissue plasminogen activator (tPA); plasminogen activator inhibitor-1 (PAI-1)), they provide insight as to the roles of epithelial activation for EMT or regulation of coagulation in the underlying disease. In this review, we discuss the potential of epithelial MPs as research tools to evaluate status of nasal mucosae of CRS patients in the lab, as well as biomarkers for management and treatment of CRS in the clinic.
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Affiliation(s)
- Toru Takahashi
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;
| | - Robert P Schleimer
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;
- Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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18
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Sanwlani R, Gangoda L. Role of Extracellular Vesicles in Cell Death and Inflammation. Cells 2021; 10:2663. [PMID: 34685643 PMCID: PMC8534608 DOI: 10.3390/cells10102663] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 02/07/2023] Open
Abstract
Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in the close vicinity, as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions, such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.
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Affiliation(s)
- Rahul Sanwlani
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3083, Australia;
| | - Lahiru Gangoda
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3083, Australia;
- The Walter and Eliza Hall Institute of Medical Research (WEHI), 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
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19
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Karn V, Ahmed S, Tsai LW, Dubey R, Ojha S, Singh HN, Kumar M, Gupta PK, Sadhu S, Jha NK, Kumar A, Pandit S, Kumar S. Extracellular Vesicle-Based Therapy for COVID-19: Promises, Challenges and Future Prospects. Biomedicines 2021; 9:biomedicines9101373. [PMID: 34680490 PMCID: PMC8533559 DOI: 10.3390/biomedicines9101373] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/19/2021] [Accepted: 09/25/2021] [Indexed: 12/11/2022] Open
Abstract
The COVID-19 pandemic has become a serious concern and has negatively impacted public health and the economy. It primarily targets the lungs, causing acute respiratory distress syndrome (ARDS); however, it may also lead to multiple organ failure (MOF) and enhanced mortality rates. Hence, there is an urgent need to develop potential effective therapeutic strategies for COVID-19 patients. Extracellular vesicles (EVs) are released from various types of cells that participate in intercellular communication to maintain physiological and pathological processes. EVs derived from various cellular origins have revealed suppressive effects on the cytokine storm during systemic hyper-inflammatory states of severe COVID-19, leading to enhanced alveolar fluid clearance, promoted epithelial and endothelial recovery, and cell proliferation. Being the smallest subclass of EVs, exosomes offer striking characteristics such as cell targeting, being nano-carriers for drug delivery, high biocompatibility, safety, and low-immunogenicity, thus rendering them a potential cell-free therapeutic candidate against the pathogeneses of various diseases. Due to these properties, numerous studies and clinical trials have been performed to assess their safety and therapeutic efficacy against COVID-19. Hence, in this review, we have comprehensively described current updates on progress and challenges for EVs as a potential therapeutic agent for the management of COVID-19.
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Affiliation(s)
- Vamika Karn
- Department of Biotechnology, Amity University, Mumbai 410221, India;
| | - Shaista Ahmed
- Faculty of Medical and Paramedical Sciences, Aix-Marseille University, 13005 Marseille, France;
| | - Lung-Wen Tsai
- Department of Medicine Research, Taipei Medical University Hospital, Taipei 11031, Taiwan; (L.-W.T.); (R.D.)
- Department of Information Technology Office, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Rajni Dubey
- Department of Medicine Research, Taipei Medical University Hospital, Taipei 11031, Taiwan; (L.-W.T.); (R.D.)
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi P.O. Box 17666, United Arab Emirates;
| | - Himanshu Naryan Singh
- Department of System Biology, Columbia University Irving Medical Center, New York, NY 10032, USA;
| | - Mukesh Kumar
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India;
| | - Piyush Kumar Gupta
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Soumi Sadhu
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida 201310, India;
| | - Ashutosh Kumar
- Department of Anatomy, All India Institute of Medical Sciences, Patna 801507, India;
| | - Soumya Pandit
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
| | - Sanjay Kumar
- Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida 201310, India; (P.K.G.); (S.S.); (S.P.)
- Correspondence: or ; Tel.: +91-120-4570-000
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20
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Qi H, Wang Y, Fa S, Yuan C, Yang L. Extracellular Vesicles as Natural Delivery Carriers Regulate Oxidative Stress Under Pathological Conditions. Front Bioeng Biotechnol 2021; 9:752019. [PMID: 34557480 PMCID: PMC8452933 DOI: 10.3389/fbioe.2021.752019] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles are cellular secretory particles that can be used as natural drug delivery carriers. They have successfully delivered drugs including chemotherapeutics, proteins, and genes to treat various diseases. Oxidative stress is an abnormal physiological phenomenon, and it is associated with nearly all diseases. In this short review, we summarize the regulation of EVs on oxidative stress. There are direct effects and indirect effects on the regulation of oxidative stress through EVs. On the one hand, they can deliver antioxidant substances or oxides to recipient cells, directly relieving or aggravating oxidative stress. On the other hand, regulate factors of oxidative stress-related signaling pathways can be delivered to recipient cells by the mediation of EVs, realizing the indirect regulation of oxidative stress. To the best of our knowledge, however, only endogenous drugs have been delivered by EVs to regulate oxidative stress till now. And the heterogeneity of EVs may complicate the regulation of oxidative stress. Therefore, this short review aims to draw more attention to the EVs-based regulation of oxidative stress, and we hope excellent EVs-based delivery carriers that can deliver exogenous drugs to regulate oxidative stress can be exploited.
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Affiliation(s)
- Hongzhao Qi
- Department of Aging Research, Institute of Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China
| | - Yingruo Wang
- Shandong University of Science and Technology, Qingdao, China
| | - Shunxin Fa
- School of Stomatology, Qingdao University, Qingdao, China.,York School, Monterey, CA, United States
| | - Changqing Yuan
- School of Stomatology, Qingdao University, Qingdao, China
| | - Lijun Yang
- Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, China
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21
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Puzyrenko A, Jacobs ER, Sun Y, Felix JC, Sheinin Y, Ge L, Lai S, Dai Q, Gantner BN, Nanchal R, North PE, Simpson PM, Rui H, Benjamin IJ. Pneumocytes are distinguished by highly elevated expression of the ER stress biomarker GRP78, a co-receptor for SARS-CoV-2, in COVID-19 autopsies. Cell Stress Chaperones 2021; 26:859-868. [PMID: 34382151 PMCID: PMC8357488 DOI: 10.1007/s12192-021-01230-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022] Open
Abstract
Vaccinations are widely credited with reducing death rates from COVID-19, but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammation, non-cardiogenic edema, and hyaline membrane formation. Because proteostatic pathways play central roles in cellular protection, immune modulation, protein degradation, and tissue repair, we examined the pathological features for the unfolded protein response (UPR) using the surrogate biomarker glucose-regulated protein 78 (GRP78) and co-receptor for SARS-CoV-2. At autopsy, immunostaining of COVID-19 lungs showed highly elevated expression of GRP78 in both pneumocytes and macrophages compared with that of non-COVID control lungs. GRP78 expression was detected in both SARS-CoV-2-infected and un-infected pneumocytes as determined by multiplexed immunostaining for nucleocapsid protein. In macrophages, immunohistochemical staining for GRP78 from deceased COVID-19 patients was increased but overlapped with GRP78 expression taken from surgical resections of non-COVID-19 controls. In contrast, the robust in situ GRP78 immunostaining of pneumocytes from COVID-19 autopsies exhibited no overlap and was independent of age, race/ethnicity, and gender compared with that from non-COVID-19 controls. Our findings bring new insights for stress-response pathways involving the proteostatic network implicated for host resilience and suggest that targeting of GRP78 expression with existing therapeutics might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.
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Affiliation(s)
- Andrii Puzyrenko
- MCW Cancer Center, Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Elizabeth R Jacobs
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Clement J. Zablocki VA Medical Center, Milwaukee, WI, USA
| | - Yunguang Sun
- MCW Cancer Center, Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Juan C Felix
- MCW Cancer Center, Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Yuri Sheinin
- MCW Cancer Center, Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Linna Ge
- MCW Cancer Center, Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Shuping Lai
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Qiang Dai
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Benjamin N Gantner
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Rahul Nanchal
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Paula E North
- MCW Cancer Center, Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Pippa M Simpson
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
- Children's Research Institute, Milwaukee, WI, USA
| | - Hallgeir Rui
- MCW Cancer Center, Department of Pathology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
| | - Ivor J Benjamin
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
- Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
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22
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Burgelman M, Vandendriessche C, Vandenbroucke RE. Extracellular Vesicles: A Double-Edged Sword in Sepsis. Pharmaceuticals (Basel) 2021; 14:ph14080829. [PMID: 34451925 PMCID: PMC8399948 DOI: 10.3390/ph14080829] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 01/08/2023] Open
Abstract
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection. Several studies on mouse and patient sepsis samples have revealed that the level of extracellular vesicles (EVs) in the blood is altered compared to healthy controls, but the different functions of EVs during sepsis pathology are not yet completely understood. Sepsis EVs are described as modulators of inflammation, lymphocyte apoptosis, coagulation and organ dysfunction. Furthermore, EVs can influence clinical outcome and it is suggested that EVs can predict survival. Both detrimental and beneficial roles for EVs have been described in sepsis, depending on the EV cellular source and the disease phase during which the EVs are studied. In this review, we summarize the current knowledge of EV sources and functions during sepsis pathology based on in vitro and mouse models, as well as patient samples.
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Affiliation(s)
- Marlies Burgelman
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (M.B.); (C.V.)
- Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
| | - Charysse Vandendriessche
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (M.B.); (C.V.)
- Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
| | - Roosmarijn E. Vandenbroucke
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; (M.B.); (C.V.)
- Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
- Correspondence: ; Tel.: +32-9-3313730
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23
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Karpman D, Tontanahal A. Extracellular vesicles in renal inflammatory and infectious diseases. Free Radic Biol Med 2021; 171:42-54. [PMID: 33933600 DOI: 10.1016/j.freeradbiomed.2021.04.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/21/2021] [Accepted: 04/26/2021] [Indexed: 11/29/2022]
Abstract
Extracellular vesicles can mediate cell-to-cell communication, or relieve the parent cell of harmful substances, in order to maintain cellular integrity. The content of extracellular vesicles includes miRNAs, mRNAs, growth factors, complement factors, cytokines, chemokines and receptors. These may contribute to inflammatory and infectious diseases by the exposure or transfer of potent effectors that induce vascular inflammation by leukocyte recruitment and thrombosis. Furthermore, vesicles release cytokines and induce their release from cells. Extracellular vesicles possess immune modulatory and anti-microbial properties, and induce receptor signaling in the recipient cell, not least by the transfer of pro-inflammatory receptors. Additionally, the vesicles may carry virulence factors systemically. Extracellular vesicles in blood and urine can contribute to the development of kidney diseases or exhibit protective effects. In this review we will describe the role of EVs in inflammation, thrombosis, immune modulation, angiogenesis, oxidative stress, renal tubular regeneration and infection. Furthermore, we will delineate their contribution to renal ischemia/reperfusion, vasculitis, glomerulonephritis, lupus nephritis, thrombotic microangiopathies, IgA nephropathy, acute kidney injury, urinary tract infections and renal transplantation. Due to their content of miRNAs and growth factors, or when loaded with nephroprotective modulators, extracellular vesicles have the potential to be used as therapeutics for renal regeneration.
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Affiliation(s)
- Diana Karpman
- Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185, Lund, Sweden.
| | - Ashmita Tontanahal
- Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185, Lund, Sweden
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24
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Kronstadt SM, Pottash AE, Levy D, Wang S, Chao W, Jay SM. Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment. ADVANCED THERAPEUTICS 2021; 4:2000259. [PMID: 34423113 PMCID: PMC8378673 DOI: 10.1002/adtp.202000259] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Indexed: 12/14/2022]
Abstract
Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.
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Affiliation(s)
- Stephanie M Kronstadt
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Alex E Pottash
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Daniel Levy
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Sheng Wang
- Translational Research Program, Department of Anesthesiology and Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology and Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Steven M Jay
- Fischell Department of Bioengineering and Program in Molecular and, Cell Biology, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
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25
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Meng S, Kang K, Fei D, Yang S, Gu Q, Pan S, Zhao M. Preliminary study of microparticle coagulation properties in septic patients with disseminated intravascular coagulation. J Int Med Res 2021; 49:3000605211014094. [PMID: 34034547 PMCID: PMC8161883 DOI: 10.1177/03000605211014094] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Background Sepsis typically results in enhanced coagulation system activation and microthrombus formation. Microparticle (MP) production promotes coagulation and enhances pro-coagulation. This study investigated how circulating MP levels and tissue factor-bearing MP (TF+-MP) activity caused coagulation in patients with septic disseminated intravascular coagulation (DIC). Methods Thirty patients with septic DIC and 30 healthy controls were studied from December 2017 to March 2019. Patient blood samples were collected at enrolment (day 1) and on days 3 and 5; DIC scores and Sequential Organ Failure Assessment (SOFA) scores were recorded. TF+-MP activity was measured using TF-dependent factor Xa generation experiments. Circulating MP concentrations were determined by MP capture assay. Clotting factor activity, antithrombin level, soluble thrombomodulin, and serum tissue factor pathway inhibitor (TFPI) concentrations were measured. Results Patients with septic DIC had lower circulating MP levels than healthy control patients. Circulating MP levels in patients with septic DIC were positively correlated with DIC scores and negatively correlated with coagulation factors, but TF+-MP activity did not correlate with clotting factor levels and TFPI. Conclusions In patients with septic DIC, circulating MP levels are important in promoting coagulation activation and increasing clotting factor consumption. TF+-MP activity may not be the main form of active TF.
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Affiliation(s)
- Shishuai Meng
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Kai Kang
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Dongsheng Fei
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Songlin Yang
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - Quankuan Gu
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
| | - ShangHa Pan
- The Key Hepatosplenic Surgery Laboratory, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, P.R. China
| | - Mingyan Zhao
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
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26
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Matei E, Aschie M, Mitroi AF, Ghinea MM, Gheorghe E, Petcu L, Dobrin N, Chisoi A, Mihaela M. Biomarkers involved in evaluation of platelets function in South-Eastern Romanian patients with hematological malignancies subtypes. Medicine (Baltimore) 2021; 100:e25944. [PMID: 34011073 PMCID: PMC8137019 DOI: 10.1097/md.0000000000025944] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 04/02/2021] [Accepted: 04/23/2021] [Indexed: 01/05/2023] Open
Abstract
ABSTRACT At present, various researches presented how subtypes of hematological malignancies are related to stages of the immune response, because the activated immune system represents a promising form in cancer treatment. This study explores the relationship between the adaptive immune system (T cells), and the coagulation system (platelets, platelet membrane glycoproteins, platelets derivate microparticles) which seems to play an important role in host immune defense of patients with acute myeloblastic leukemia (AML) or B cell lymphoma (BCL), 2 of the most common hematological malignancies subtypes.Blood samples (n = 114) obtained from patients with AML or BCL were analyzed for platelet membrane glycoproteins (CD42b, CD61), glycoprotein found on the surface of the T helper cells (CD4+), protein complex-specific antigen for T cells (CD3+), platelet-derived microparticles (CD61 PMP) biomarkers by flow cytometry, and hematological parameters were quantified by usual methods.In patients with AML, the means of the percentage of the expressions of the molecules on platelet surfaces (CD61 and CD42b, P < .01; paired T test) were lower as compared to both control subgroups. The expression of cytoplasmic granules content (CD61 PMP) had a significantly higher value in patients with AML reported to controlling subgroups (P < .01; paired T test), which is suggesting an intravascular activation of platelets.The platelet activation status was presented in patients with low stage BCL because CD61 and CD42b expressions were significantly higher than control subgroups, but the expression of CD 61 PMP had a significantly decreased value reported to control subgroups (all P < .01; paired T test). T helper/inducer lineage CD4+ and T lymphoid lineage CD3+ expressions presented significant differences between patients with AML or low stage BCL reported to control subgroups (all P < .01; paired T test).Platelet-lymphocyte interactions are involved in malignant disorders, and CD61, CD42b present on platelet membranes, as functionally active surface receptors mediate the adhesion of active platelets to lymphocytes, endothelial cells, and cancer cells.
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MESH Headings
- Aged
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/metabolism
- Blood Platelets/immunology
- Blood Platelets/metabolism
- CD3 Complex/blood
- Cell Adhesion/immunology
- Cell-Derived Microparticles
- Female
- Flow Cytometry
- Humans
- Integrin beta3/blood
- Leukemia, Myeloid, Acute/blood
- Leukemia, Myeloid, Acute/immunology
- Lymphocyte Activation
- Lymphocyte Count
- Lymphoma, B-Cell/blood
- Lymphoma, B-Cell/immunology
- Male
- Middle Aged
- Platelet Activation/immunology
- Platelet Count
- Platelet Glycoprotein GPIb-IX Complex/analysis
- Romania
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
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Affiliation(s)
- Elena Matei
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, CEDMOG
| | - Mariana Aschie
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, CEDMOG
- Clinical Service of Pathology
| | - Anca Florentina Mitroi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, CEDMOG
- Clinical Service of Pathology
| | - Mihaela Maria Ghinea
- Internal Medicine-Hematology Department, “Sf. Apostol Andrei” Emergency County Hospital
| | - Emma Gheorghe
- Medicine Faculty, “Ovidius” University of Constanta, Constanta, Romania
| | - Lucian Petcu
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, CEDMOG
| | - Nicolae Dobrin
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, CEDMOG
| | - Anca Chisoi
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, CEDMOG
- Internal Medicine-Hematology Department, “Sf. Apostol Andrei” Emergency County Hospital
| | - Manea Mihaela
- Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, CEDMOG
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27
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Circulating Exosomes From Lipopolysaccharide-Induced Ards Mice Trigger Endoplasmic Reticulum Stress in Lung Tissue. Shock 2021; 54:110-118. [PMID: 32530844 DOI: 10.1097/shk.0000000000001397] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a critical clinical syndrome with high mortality rate, and few effective therapies have been found in the past 50 years, indicating that the pathogenesis of ARDS remains unclear. Exosomes, a novel cross-communication mechanism, are involved in critical diseases. However, the role of circulating exosomes in the development of ARDS remains poorly understood. METHODS In the present study, naive mice were treated with circulating exosomes from lipopolysaccharide (LPS)-induced ARDS mice or exosome-depleted serum. Histological lung damage, bronchoalveolar lavage fluid (BALF), and endoplasmic reticulum (ER) stress were measured. RESULTS Increased tumor necrosis factor (TNF)-α, interleukin (IL)-6, total cell counts, polymorphonuclear (PMN) leukocyte proportions and myeloperoxidase (MPO) activity in BALF, and increased wet/dry weight ratios and protein concentrations in BALF were found in mice after exosome injection but not in mice treated with exosome-depleted serum. Furthermore, western blot analysis showed that circulating exosomes from ARDS mice upregulated glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) expression and downregulated β-Catenin and VE-cadherin expression in lung tissues. CONCLUSIONS Collectively, these data demonstrate that circulating exosomes from LPS-induced ARDS mice trigger ER stress in lung tissue, facilitating the development of ARDS, at least partly by promoting endothelial dysfunction.
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28
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Chatterjee V, Yang X, Ma Y, Wu MH, Yuan SY. Extracellular vesicles: new players in regulating vascular barrier function. Am J Physiol Heart Circ Physiol 2020; 319:H1181-H1196. [PMID: 33035434 PMCID: PMC7792704 DOI: 10.1152/ajpheart.00579.2020] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/21/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022]
Abstract
Extracellular vesicles (EVs) have attracted rising interests in the cardiovascular field not only because they serve as serological markers for circulatory disorders but also because they participate in important physiological responses to stress and inflammation. In the circulation, these membranous vesicles are mainly derived from blood or vascular cells, and they carry cargos with distinct molecular signatures reflecting the origin and activation state of parent cells that produce them, thus providing a powerful tool for diagnosis and prognosis of pathological conditions. Functionally, circulating EVs mediate tissue-tissue communication by transporting bioactive cargos to local and distant sites, where they directly interact with target cells to alter their function. Recent evidence points to the critical contributions of EVs to the pathogenesis of vascular endothelial barrier dysfunction during inflammatory response to injury or infection. In this review, we provide a brief summary of the current knowledge on EV biology and advanced techniques in EV isolation and characterization. This is followed by a discussion focusing on the role and mechanisms of EVs in regulating blood-endothelium interactions and vascular permeability during inflammation. We conclude with a translational perspective on the diagnostic and therapeutic potential of EVs in vascular injury or infectious diseases, such as COVID-19.
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Affiliation(s)
- Victor Chatterjee
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Xiaoyuan Yang
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Yonggang Ma
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Mack H Wu
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Sarah Y Yuan
- Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida
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Integrin and PD-1 Ligand Expression on Circulating Extracellular Vesicles in Systemic Inflammatory Response Syndrome and Sepsis. Shock 2020; 52:13-22. [PMID: 30036273 DOI: 10.1097/shk.0000000000001228] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Extracellular vesicles (EVs) in the plasma mediate important intercellular communications in the pathogenesis of cancer and inflammatory diseases. EVs express integrins that regulate target specificities and programmed cell death ligand 1 and 2 (PD-L1 and 2) that suppress lymphocyte activation. However, the roles of these molecules on EVs in systemic inflammatory response syndrome (SIRS) and sepsis remain little understood. This study aimed to investigate how the EV expression of integrins and PD-1 ligands might differ in SIRS and sepsis, compared with healthy controls, and to correlate their expression with the clinical parameters reflecting pathogenesis. Twenty-seven SIRS patients without sepsis, 27 sepsis patients, and 18 healthy volunteers were included. EVs were isolated from plasma samples. The expression of three major integrins (β1, β2, β3 integrins) and PD-L1 and 2 were measured. The EV expression of β2 integrin and PD-L2 was significantly increased in sepsis patients compared with healthy controls. EV expression of PD-L1 was not elevated in sepsis and SIRS; however, circulating soluble PD-L1 levels were significantly higher in sepsis. Furthermore, EV expression of β2 integrin in sepsis patients correlated with hypotension and reduced kidney function. In addition, soluble PD-L1 levels correlated with sepsis severity, impaired kidney function, and impaired central nervous system function. These results suggest the potential involvements of the EV β2 integrin, as well as EV PD-L2 and soluble PD-L1, in the septic pathogenesis that occurs with the systemic immune activation leading to multiple organ dysfunctions.
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Oggero S, Austin-Williams S, Norling LV. The Contrasting Role of Extracellular Vesicles in Vascular Inflammation and Tissue Repair. Front Pharmacol 2019; 10:1479. [PMID: 31920664 PMCID: PMC6928593 DOI: 10.3389/fphar.2019.01479] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/13/2019] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles are a heterogeneous family of vesicles, generated from different subcellular compartments and released into the extracellular space. Composed of a lipid bilayer encompassing both soluble cytosolic material and nuclear components, these organelles have been recently described as novel regulators of intercellular communication between adjacent and remote cells. Due to their diversified composition and biological content, they portray specific signatures of cellular activation and pathological processes, their potential as diagnostic and prognostic biomarkers has raised significant interest in cardiovascular diseases. Circulating vesicles, especially those released from platelets, leukocytes, and endothelial cells are found to play a critical role in activating several fundamental cells within the vasculature, including endothelial cells and vascular smooth muscle cells. Their intrinsic activity and immunomodulatory properties lends them to not only promote vascular inflammation, but also enhance tissue regeneration, vascular repair, and indeed resolution. In this review we aim to recapitulate the recent findings concerning the roles played by EVs that originate from different circulating cells, with particular reference to their action on the endothelium. We focus herein, on the interaction of platelet and leukocyte EVs with the endothelium. In addition, their potential biological function in promoting tissue resolution and vascular repair will also be discussed.
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Affiliation(s)
- Silvia Oggero
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Shani Austin-Williams
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Lucy Victoria Norling
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom
- Centre for Inflammation and Therapeutic Innovation Queen Mary University of London, London, United Kingdom
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31
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Balducci E, Leroyer AS, Lacroix R, Robert S, Todorova D, Simoncini S, Lyonnet L, Chareyre C, Zaegel-Faucher O, Micallef J, Poizot-Martin I, Roll P, Dignat-George F. Extracellular vesicles from T cells overexpress miR-146b-5p in HIV-1 infection and repress endothelial activation. Sci Rep 2019; 9:10299. [PMID: 31311940 PMCID: PMC6635508 DOI: 10.1038/s41598-019-44743-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 05/07/2019] [Indexed: 01/06/2023] Open
Abstract
Human immunodeficiency virus type 1 (HIV-1) infection promotes a generalized activation of host responses that involves not only CD4 T cells, but also cells of the microenvironment, which are not directly infected, such as endothelial cells. The mechanisms triggering HIV-1-associated vascular alterations remain poorly understood. Extracellular vesicles (EVs), implicated in cell-to-cell communication, have been recently described as carriers of microRNAs (miRNAs). Here, we show that miR-146b-5p is upregulated in both CD4 T cells, CD4 T cell-derived EVs and circulating EVs obtained from antiretroviral therapy-naive HIV-1-infected patients. We further demonstrate that EVs from T cell line overexpressing miR-146b-5p mimics (miR-146b-EVs): 1) protect their miRNA cargo from RNase degradation, 2) transfer miR-146b-5p mimics into endothelial cells and 3) reduce endothelial inflammatory responses in vitro and in vivo in the lungs of mice through the downregulation of nuclear factor-κB-responsive molecules. These data advance our understanding on chronic inflammatory responses affecting endothelial homeostasis, in infectious and non-infectious diseases and pave the way for potential new anti-inflammatory strategies.
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Affiliation(s)
- Estelle Balducci
- Aix Marseille Univ, INSERM, C2VN, Marseille, France.,APHM, Hôpital La Conception, Laboratoire d'Hématologie et de biologie vasculaire, Marseille, France
| | | | - Romaric Lacroix
- Aix Marseille Univ, INSERM, C2VN, Marseille, France.,APHM, Hôpital La Conception, Laboratoire d'Hématologie et de biologie vasculaire, Marseille, France
| | | | | | | | - Luc Lyonnet
- APHM, Hôpital La Conception, Laboratoire d'Hématologie et de biologie vasculaire, Marseille, France
| | | | - Olivia Zaegel-Faucher
- APHM, Hôpital Sainte-Marguerite, Service d'Immuno-hématologie clinique, Marseille, France
| | - Joëlle Micallef
- APHM, Hôpital la Timone, Service de Pharmacologie, Marseille, France.,Aix Marseille Univ, CNRS, INT, Inst Neurosci Timone, Marseille, France
| | - Isabelle Poizot-Martin
- APHM, Hôpital Sainte-Marguerite, Service d'Immuno-hématologie clinique, Marseille, France.,Aix Marseille Univ, Inserm U912 (SESSTIM), Marseille, France
| | - Patrice Roll
- Aix Marseille Univ, INSERM, MMG, Marseille, France.,APHM, Hôpital la Timone, Service de Biologie Cellulaire, Marseille, France
| | - Françoise Dignat-George
- Aix Marseille Univ, INSERM, C2VN, Marseille, France. .,APHM, Hôpital La Conception, Laboratoire d'Hématologie et de biologie vasculaire, Marseille, France.
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Bodega G, Alique M, Puebla L, Carracedo J, Ramírez RM. Microvesicles: ROS scavengers and ROS producers. J Extracell Vesicles 2019; 8:1626654. [PMID: 31258880 PMCID: PMC6586107 DOI: 10.1080/20013078.2019.1626654] [Citation(s) in RCA: 148] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 05/27/2019] [Accepted: 05/29/2019] [Indexed: 12/14/2022] Open
Abstract
This review analyzes the relationship between microvesicles and reactive oxygen species (ROS). This relationship is bidirectional; on the one hand, the number and content of microvesicles produced by the cells are affected by oxidative stress conditions; on the other hand, microvesicles can directly and/or indirectly modify the ROS content in the extra- as well as the intracellular compartments. In this regard, microvesicles contain a pro-oxidant or antioxidant machinery that may produce or scavenge ROS: direct effect. This mechanism is especially suitable for eliminating ROS in the extracellular compartment. Endothelial microvesicles, in particular, contain a specific and well-developed antioxidant machinery. On the other hand, the molecules included in microvesicles can modify (activate or inhibit) ROS metabolism in their target cells: indirect effect. This can be achieved by the incorporation into the cells of ROS metabolic enzymes included in the microvesicles, or by the regulation of signaling pathways involved in ROS metabolism. Proteins, as well as miRNAs, are involved in this last effect.
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Affiliation(s)
- G Bodega
- Departamento de Biomedicina y Biotecnología, Universidad de Alcalá, Alcalá de Henares, Spain
| | - M Alique
- Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Spain
| | - L Puebla
- Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Spain
| | - J Carracedo
- Departamento de Genética, Fisiología y Microbiología, Facultad de Biología, Universidad Complutense, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain
| | - R M Ramírez
- Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Spain
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Cell-derived microvesicles in infective endocarditis: Role in diagnosis and potential for risk stratification at hospital admission. J Infect 2019; 79:101-107. [PMID: 31207323 DOI: 10.1016/j.jinf.2019.06.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/09/2019] [Accepted: 06/10/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVES To characterize the plasmatic profile of cell-derived microvesicles (MVs) at diagnosis and during the treatment of patients with infective endocarditis (IE). METHODS Blood samples from 57 patients with IE were obtained on 3 consecutive moments: upon admission (T0), at 2 weeks (T1), and at the end of treatment (T2), and were compared with 22 patients with other bacterial infections. MPs were measured by flow cytometry and labeled for specific cell markers of CD45 (leukocytes), CD66b (neutrophils), CD14 (monocytes), CD41a (platelets), CD51 (endothelial cells), CD3 (T lymphocyte) and CD235a (erythrocytes). RESULTS MVs from platelets (pltMVs), leukocytes (leukMVs), neutrophils (neutMVs), monocytes (monoMVs) and lymphocytes (lymphMVs) were significantly more elevated in the patients with IE, compared to the patients with other bacterial infections, despite comparable age, sex, blood counts and C-reactive protein levels. MVs values revealed a relatively stable pattern over time in IE, except for a significant increase in leukMVs and neutMVs in T1. LeukMVs (p = 0.011), neutMVs (p = 0.010), monoMVs (p = 0.016) and lymphMVs (p = 0.020), measured at admission, were significantly higher in IE patients that died during hospitalization in comparison with those that survived. In a multivariable analyses, the levels of neutMVs remained as an independent factor associated with mortality (odds ratio 2.203; 95% confidence interval 1.217 - 3.988; p = 0.009), adjustment for heart failure during the treatment. CONCLUSIONS Plasma levels of pltMVs, leukMVs, neutMVs, monoMVs and lymphMVs were significantly more elevated in patients with IE than in patients with other bacterial infections at hospital admission. Furthermore, neutMVs at admission have been identified as an independent predictor of mortality in patients with IE. Thus, cell derived MPs may become an important tool in the differential diagnosis and mortality risk assessment early in the course of IE suspected cases.
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Microvesicle Subsets in Sepsis Due to Community Acquired Pneumonia Compared to Faecal Peritonitis. Shock 2019; 49:393-401. [PMID: 28930915 DOI: 10.1097/shk.0000000000000989] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
RATIONALE Microvesicles (MV) act as a nonsoluble means of intercellular communication, with effector roles in disease pathogenesis and potentially as biomarkers. Previously, we reported that neutrophil MV expressing alpha-2-macroglobulin (A2MG) are protective in experimental sepsis and associate with survival in a small cohort of patients with sepsis due to community acquired pneumonia (CAP). OBJECTIVES To characterize MV profiles in sepsis due to CAP or fecal peritonitis (FP) and determine their relation to outcome. To investigate the effects of novel sepsis treatments (granulocyte-macrophage colony stimulating factor (GM-CSF) and interferon-υ (IFN-γ)) on MV production and functions in vitro. METHODS Flow cytometry analysis of MV identified the cell of origin and the proportion of A2MG expression in the plasma of patients with sepsis secondary to CAP (n = 60) or FP (n = 40) and compared with healthy volunteers (HV, n = 10). The association between MV subsets and outcome was examined. The ability of GM-CSF and IFN-γ on A2MG MV production from whole blood was examined together with the assessment of their effect on neutrophil and endothelial functions. RESULTS Circulating cell-derived and A2MG MV were higher in CAP compared with FP and HV. A2MG MV were higher in survivors of CAP, but not in FP. GM-CSF and IFN-γ enhanced A2MG MV production, with these MV eliciting pathogen clearance in vitro. CONCLUSIONS Plasma MV profiles vary according to the source of infection. A2MG MV are associated with survival in CAP but not FP. We propose specific MV subsets as novel biomarkers in sepsis and potential effector for some of the actions of experimental therapeutic interventions.
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Agouni A, Parray AS, Akhtar N, Mir FA, Bourke PJ, Joseph S, Morgan DM, Santos MD, Wadiwala MF, Kamran S, Sivaraman SK, Shuaib A. There Is Selective Increase in Pro-thrombotic Circulating Extracellular Vesicles in Acute Ischemic Stroke and Transient Ischemic Attack: A Study of Patients From the Middle East and Southeast Asia. Front Neurol 2019; 10:251. [PMID: 30941096 PMCID: PMC6434679 DOI: 10.3389/fneur.2019.00251] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 02/25/2019] [Indexed: 12/14/2022] Open
Abstract
Stroke attacks were found to be present at a younger age in patients from Southeast Asia (SE) and the Middle East (ME) resident in the state of Qatar. Extracellular vesicles (EVs), which are small membrane vesicles with pro-thrombotic properties, may contribute to the high risk of stroke in this population. Thus, total and cell-specific medium size EVs were counted by flow cytometry in platelet-free plasma from healthy volunteers and patients with transient ischemic attacks (TIA) and acute ischemic stroke (AIS) from SE and ME. Acutely, within 48 h of attacks, there was an increase in total endothelial EVs in TIA (6.73 ± 1.77; P = 0.0156; n = 21) and AIS (11.23 ± 1.95; P = 0.0007; n = 66) patients compared to controls (2.04 ± 0.78; n = 24). Similar increases were also evident in EVs originating from platelets, erythrocytes, granulocytes, and leukocytes. Compared to controls, there was also an increase in EVs derived from activated endothelial cells, platelets, granulocytes, leukocytes, and pro-coagulant EVs (Annexin V+) at 5 and 30-days following the acute events, while a decrease was observed in erythrocyte-derived EVs. This is the first study characterizing EVs in TIA and AIS patients from ME and SE showing an increase in EVs associated with endothelial and platelet cell activation, which may contribute to the elevated risk of stroke at a younger age in this population.
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Affiliation(s)
- Abdelali Agouni
- Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University, Doha, Qatar
| | - Aijaz S Parray
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Naveed Akhtar
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Fayaz A Mir
- Interim Translational Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Paula J Bourke
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Sujata Joseph
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Deborah M Morgan
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Mark D Santos
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Muhammad F Wadiwala
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Saadat Kamran
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Siveen K Sivaraman
- Interim Translational Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ashfaq Shuaib
- The Stroke Program, The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.,Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada
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Molecular Mechanisms Underpinning Microparticle-Mediated Cellular Injury in Cardiovascular Complications Associated with Diabetes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6475187. [PMID: 30915196 PMCID: PMC6399542 DOI: 10.1155/2019/6475187] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Accepted: 01/13/2019] [Indexed: 12/15/2022]
Abstract
Microparticles (MPs) are small vesicles shed from the cytoplasmic membrane of healthy, activated, or apoptotic cells. MPs are very heterogeneous in size (100–1,000 nm), and they harbor proteins and surface antigens specific to cells they originate from. Virtually, all cells can shed MPs, and therefore, they can be found in all body fluids, but also entrapped in tissues. Of interest and because of their easy detection using a variety of techniques, circulating MPs were recognized as biomarkers for cell activation. MPs were also found to mediate critical actions in intercellular communication and transmitting biological messages by acting as paracrine vehicles. High plasma numbers of MPs were reported in many cardiovascular and metabolic disturbances that are closely associated with insulin resistance and low-grade inflammation and have been linked to adverse actions on cardiovascular function. This review highlights the involvement of MPs in cardiovascular complications associated with diabetes and discusses the molecular mechanisms that underpin the pathophysiological role of MPs in the onset and progression of cellular injury in diabetes.
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Exosomes and microvesicles in normal physiology, pathophysiology, and renal diseases. Pediatr Nephrol 2019; 34:11-30. [PMID: 29181712 PMCID: PMC6244861 DOI: 10.1007/s00467-017-3816-z] [Citation(s) in RCA: 251] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 09/16/2017] [Accepted: 09/19/2017] [Indexed: 12/18/2022]
Abstract
Extracellular vesicles are cell-derived membrane particles ranging from 30 to 5,000 nm in size, including exosomes, microvesicles, and apoptotic bodies. They are released under physiological conditions, but also upon cellular activation, senescence, and apoptosis. They play an important role in intercellular communication. Their release may also maintain cellular integrity by ridding the cell of damaging substances. This review describes the biogenesis, uptake, and detection of extracellular vesicles in addition to the impact that they have on recipient cells, focusing on mechanisms important in the pathophysiology of kidney diseases, such as thrombosis, angiogenesis, tissue regeneration, immune modulation, and inflammation. In kidney diseases, extracellular vesicles may be utilized as biomarkers, as they are detected in both blood and urine. Furthermore, they may contribute to the pathophysiology of renal disease while also having beneficial effects associated with tissue repair. Because of their role in the promotion of thrombosis, inflammation, and immune-mediated disease, they could be the target of drug therapy, whereas their favorable effects could be utilized therapeutically in acute and chronic kidney injury.
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40
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Cheng X, Dang A, Lv N, Zhao T. Microparticles from Endothelial Cells and Immune Cells in Patients with Takayasu Arteritis. J Atheroscler Thromb 2018; 26:547-558. [PMID: 30555130 PMCID: PMC6545457 DOI: 10.5551/jat.45351] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
AIM This study was designed to analyze microparticles (MPs) from endothelial cells (EMPs) and immune cells from healthy individuals and paitents with Takayasu arteritis (TA), and any possible relationships between MPs and TA acitivity. METHODS MPs derived from the plasma of 51 subjects were analyzed, including 32 patients with TA and 19 healthy individuals. Flow cytometry was performed with Annexin (Anx)-V and antibodies against surface markers of endothelial cells (CD144), T cells (CD3), B cells (CD19), and monocytes (CD14). RESULTS The concentrations of total EMPs, AnxV＋ EMPs and AnxV- EMPs were significantly increased when comparing patients with TA and healthy controls (54×103 vs. 32×103 MPs /ml, P=0.0004; 22×103 vs. 12×103 MPs /ml, P=0.0006; and 31×103 vs. 19×103 MPs /ml, P=0.0005), and comparing active TA patients with remission ones (85×103 vs. 45×103 MPs /ml, P=0.016; 39×103 vs. 14×103 MPs /ml, P=0.0092; and 47×103 vs.29×103 MPs /ml, P=0.0371). In addition, the concentrations of total EMPs (odds ratio [OR]=1.024, 95% confidence interval [CI]: 1.001 to 1.048, P=0.037), AnxV＋(OR=1.089, 95%CI: 1.011 to 1.172, P=0.024), and AnxV- EMPs (OR=1.029, 95% CI: 1.002 to 1.056, P=0.034) were positively related to TA activity. With multiple linear regression analysis, platelet was associated with both total and AnxV- EMP concentrations independently, while erythrocyte sedimentation rate was independently correlated with AnxV＋EMPs. CONCLUSION Concentrations of endothelial microparticles are correlated with inflammation in Takayasu arteritis and may be useful markers to assess disease activity.
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Affiliation(s)
- Xuesen Cheng
- Department of Special Care Center, National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Aimin Dang
- Department of Special Care Center, National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Naqiang Lv
- Department of Special Care Center, National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Tong Zhao
- Institute of Microbiology, Chinese Academy of Sciences
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Słomka A, Urban SK, Lukacs-Kornek V, Żekanowska E, Kornek M. Large Extracellular Vesicles: Have We Found the Holy Grail of Inflammation? Front Immunol 2018; 9:2723. [PMID: 30619239 PMCID: PMC6300519 DOI: 10.3389/fimmu.2018.02723] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 11/05/2018] [Indexed: 12/17/2022] Open
Abstract
The terms microparticles (MPs) and microvesicles (MVs) refer to large extracellular vesicles (EVs) generated from a broad spectrum of cells upon its activation or death by apoptosis. The unique surface antigens of MPs/MVs allow for the identification of their cellular origin as well as its functional characterization. Two basic aspects of MP/MV functions in physiology and pathological conditions are widely considered. Firstly, it has become evident that large EVs have strong procoagulant properties. Secondly, experimental and clinical studies have shown that MPs/MVs play a crucial role in the pathophysiology of inflammation-associated disorders. A cardinal feature of these disorders is an enhanced generation of platelets-, endothelial-, and leukocyte-derived EVs. Nevertheless, anti-inflammatory effects of miscellaneous EV types have also been described, which provided important new insights into the large EV-inflammation axis. Advances in understanding the biology of MPs/MVs have led to the preparation of this review article aimed at discussing the association between large EVs and inflammation, depending on their cellular origin.
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Affiliation(s)
- Artur Słomka
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
| | - Sabine Katharina Urban
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Veronika Lukacs-Kornek
- Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Ewa Żekanowska
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
| | - Miroslaw Kornek
- Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany
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Letsiou E, Bauer N. Endothelial Extracellular Vesicles in Pulmonary Function and Disease. CURRENT TOPICS IN MEMBRANES 2018; 82:197-256. [PMID: 30360780 DOI: 10.1016/bs.ctm.2018.09.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The pulmonary vascular endothelium is involved in the pathogenesis of acute and chronic lung diseases. Endothelial cell (EC)-derived products such as extracellular vesicles (EVs) serve as EC messengers that mediate inflammatory as well as cytoprotective effects. EC-EVs are a broad term, which encompasses exosomes and microvesicles of endothelial origin. EVs are comprised of lipids, nucleic acids, and proteins that reflect not only the cellular origin but also the stimulus that triggered their biogenesis and secretion. This chapter presents an overview of the biology of EC-EVs and summarizes key findings regarding their characteristics, components, and functions. The role of EC-EVs is specifically delineated in pulmonary diseases characterized by endothelial dysfunction, including pulmonary hypertension, acute respiratory distress syndrome and associated conditions, chronic obstructive pulmonary disease, and obstructive sleep apnea.
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Affiliation(s)
- Eleftheria Letsiou
- Division of Pulmonary Inflammation, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Natalie Bauer
- Department of Pharmacology & Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL, United States.
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Schwertz H, Rondina MT. Platelets and their Microparticles go hand in hand. Thromb Res 2018; 168:164-165. [PMID: 30060877 DOI: 10.1016/j.thromres.2018.07.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 07/11/2018] [Indexed: 10/28/2022]
Affiliation(s)
- Hansjörg Schwertz
- Program in Molecular Medicine in Salt Lake City, Utah, USA; Rocky Mountain Center for Occupational and Environmental Health in Salt Lake City, Utah, USA.
| | - Matthew T Rondina
- Program in Molecular Medicine in Salt Lake City, Utah, USA; The Department of Internal Medicine, in Salt Lake City, Utah, USA; University of Utah, Salt Lake City, Utah, USA, and the Department of Internal Medicine at the George E. Wahlen Salt Lake City VAMC in Salt Lake City, Utah, USA
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Puskarich MA, Cornelius DC, Bandyopadhyay S, McCalmon M, Tramel R, Dale WD, Jones AE. Phosphatidylserine expressing platelet microparticle levels at hospital presentation are decreased in sepsis non-survivors and correlate with thrombocytopenia. Thromb Res 2018; 168:138-144. [PMID: 30064685 DOI: 10.1016/j.thromres.2018.06.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/08/2018] [Accepted: 06/21/2018] [Indexed: 01/20/2023]
Abstract
BACKGROUND Sepsis induced platelet activation releases platelet microparticles (PMPs). PMPs express phosphatidylserine (PS) and can serve as a scaffold for the prothrombinase complex, thereby promoting coagulation. Studies of PMPs in intensive care unit sepsis patients demonstrate mixed results, while the earliest changes and potential effects of clinical interventions remain understudied. We hypothesized PMPs would be associated with patient outcome and dysfunctional coagulation shortly after emergency department presentation with sepsis. METHODS Cohort study of patients from a single center enrolled in a previously published randomized control trial comparing two early resuscitation strategies. Adults presenting to the emergency department (ED) with suspected infection, ≥2 SIRS criteria, and either systolic blood pressure <90 mm Hg or lactate >4 mmol/L were eligible. Triple positive platelet microparticles (PMPs) expressing phosphatidylserine and integrin complexes alphaIIb (CD41) and beta3 (CD61) were quantitated using plasma from the time of enrollment. The primary outcome was in-hospital mortality. Secondary outcomes included platelet count, disseminated intravascular coagulation (DIC), and prothrombin time (PT). RESULTS 193 patients were enrolled and 184 had samples available. In-hospital mortality was 21%. 10 (5%) patients developed DIC. Median platelet count was 197 (IQR 135, 280) and PT was 13.2 (IQR 11.9, 16.8). Median triple positive PMP counts were 932 per μL (IQR 381, 1872). PMPs were significantly lower in non-survivors (575 vs 1128, p = 0.02) and non-significantly lower in DIC (387 vs 942, p = 0.17). PMPs demonstrated a positive linear association with platelet count (p < 0.001, R2 = 0.21). After adjusting for platelet count, PMPs were no longer significant predictors of mortality (p = 0.28). We observed no association between PMPs and PT. CONCLUSION Similar to patients enrolled later in the intensive care unit, PS-expressing PMPs are lower in emergency department sepsis non-survivors. These changes primarily reflect the degree of thrombocytopenia, and an independent prognostic role was not observed. Future studies should control for platelet count in assessment of PMP prognosis in sepsis.
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Affiliation(s)
- Michael A Puskarich
- Department of Emergency Medicine, Hennepin County Medical Center, 701 Park Ave, Minneapolis, MN 55415, United States of America.
| | - Denise C Cornelius
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Sibali Bandyopadhyay
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Maggie McCalmon
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Robert Tramel
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Wood D Dale
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Alan E Jones
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, United States of America
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Raeven P, Zipperle J, Drechsler S. Extracellular Vesicles as Markers and Mediators in Sepsis. Am J Cancer Res 2018; 8:3348-3365. [PMID: 29930734 PMCID: PMC6010985 DOI: 10.7150/thno.23453] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 03/14/2018] [Indexed: 01/28/2023] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains a highly lethal condition in which current tools for early diagnosis and therapeutic decision-making are far from ideal. Extracellular vesicles (EVs), 30 nm to several micrometers in size, are released from cells upon activation and apoptosis and express membrane epitopes specific for their parental cells. Since their discovery two decades ago, their role as biomarkers and mediators in various diseases has been intensively studied. However, their potential importance in the sepsis syndrome has gained attention only recently. Sepsis and EVs are both complex fields in which standardization has long been overdue. In this review, several topics are discussed. First, we review current studies on EVs in septic patients with emphasis on their variable quality and clinical utility. Second, we discuss the diagnostic and therapeutic potential of EVs as well as their role as facilitators of cell communication via micro RNA and the relevance of micro-organism-derived EVs. Third, we give an overview over the potential beneficial but also detrimental roles of EVs in sepsis. Finally, we focus on the role of EVs in selected intensive care scenarios such as coagulopathy, mechanical ventilation and blood transfusion. Overall, the prospect for EV use in septic patients is bright, ranging from rapid and precise (point-of-care) diagnostics, prevention of harmful iatrogenic interventions, to using EVs as guides of individualized therapy. Before the above is achieved, however, the EV research field requires reliable standardization of the current methods and development of new analytical procedures that can close the existing technological gaps.
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Abstract
PURPOSE Endothelial pathology is considered to play a key role in septic shock. Since endothelial-derived microvesicles (MV) are elevated in various diseases associated with endothelial pathology, they are considered surrogate markers of the endothelial state. By analyzing the signature of circulating MV with high-sensitivity flow cytometry (hsFC), we wanted to test the hypothesis whether endothelial-derived MV are increased in septic shock. METHODS MV in blood from healthy volunteers and patients with septic shock treated in a medical intensive care unit were quantified by hsFC, which has an improved detection limit of approximately 0.3 μm. RESULTS Patients with septic shock (n = 30) showed 3-fold higher levels of CD31+/CD41- MV (58.5 (26.4-101.2) [median (25th-75th percentile)] vs. 19.5 (12.8-25.4) MV/μL; P <0.001) compared with healthy volunteers (n = 18). Absolute counts of CD144+, CD62E+, and CD106+ MV, specific for endothelial-derived MV, were low in all groups. The number of CD31+/CD41- MV correlated significantly with leukocyte count (rs = 0.64; P <0.001). Platelet-derived CD41+ MV were significantly elevated in the group dying within 48 h after inclusion (639.1 (321.3-969.7) vs. 221.5 (119.5-456.9) MV/μL; P = 0.037). Patients dying within 48 h had also significantly higher levels of CD31+/CD41-/AnnexinV- MV (51.9 (24.9-259.8) vs. 18.9 (9.7-31) MV/μL; P = 0.028). CONCLUSIONS Despite an improved detection limit for MV by using hsFC, counts of endothelial-specific MV are unexpectedly low in patients with septic shock. Increased amounts of CD41+ and CD31+/CD41-/AnnexinV- MV indicate release by activated platelets and possibly leukocytes correlating with unfavorable outcome.
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Šibíková M, Živný J, Janota J. Cell Membrane-Derived Microvesicles in Systemic Inflammatory Response. Folia Biol (Praha) 2018; 64:113-124. [PMID: 30724157 DOI: 10.14712/fb2018064040113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Human body reacts to physical, chemical and biological insults with a complex inflammatory reaction. Crucial components and executors of this response are endothelial cells, platelets, white blood cells, plasmatic coagulation system, and complement. Endothelial injury and inflammation are associated with elevated blood levels of cell membrane-derived microvesicles. Increased concentrations of microvesicles were found in several inflammatory reactions and diseases including acute coronary syndromes, stroke, vasculitis, venous thromboembolism, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, anti-phospholipid antibody syndrome, inflammatory bowel disease, thrombotic thrombocytopenic purpura, viral myocarditis, sepsis, disseminated intravascular coagulation, polytrauma, and burns. Microvesicles can modulate a variety of cellular processes, thereby having an impact on pathogenesis of diseases associated with inflammation. Microvesicles are important mediators and potential biomarkers of systemic inflammation. Measurement of inflammatory cell-derived microvesicles may be utilized in diagnostic algorithms and used for detection and determination of severity in diseases associated with inflammatory responses, as well as for prediction of their outcome. This review focuses on the mechanisms of release of microvesicles in diseases associated with systemic inflammation and their potential role in the regulation of cellular and humoral interactions.
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Affiliation(s)
- M Šibíková
- Third Faculty of Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - J Živný
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - J Janota
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Department of Neonatology, Thomayer Hospital, Prague, Czech Republic
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Degirmenci SE, Zobairi F, Berger A, Meyer G, Burban M, Mostefai HA, Levy B, Toti F, Boisramé-Helms J, Delabranche X, Meziani F. Pharmacological modulation of procoagulant microparticles improves haemodynamic dysfunction during septic shock in rats. Thromb Haemost 2017; 111:154-64. [DOI: 10.1160/th13-04-0313] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 09/04/2013] [Indexed: 01/02/2023]
Abstract
SummaryCirculating microparticles play a pro-inflammatory and procoagulant detrimental role in the vascular dysfunction of septic shock. It was the objective of this study to investigate mechanisms by which a pharmacological modulation of microparticles could affect vascular dysfunction in a rat model of septic shock. Septic or sham rats were treated by activated protein C (aPC) and resuscitated during 4 hours. Their microparticles were harvested and inoculated to another set of healthy recipient rats. Haemodynamic parameters were monitored, circulating total procoagulant microparticles assessed by prothrombinase assay, and their cell origin characterised. Mesenteric resistance arteries, aorta and heart were harvested for western blotting analysis. We found that a) the amount and phenotype of circulating microparticles were altered in septic rats with an enhanced endothelial, leucocyte and platelet contribution; b) aPC treatment significantly reduced the generation of leucocyte microparticles and norepinephrine requirements to reach the mean arterial pressure target in septic rats; c) Microparticles from untreated septic rats, but not from aPC-treated ones, significantly reduced the healthy recipients’ mean arterial pressure; d) Microparticle thromboxane content and aPC activity were significantly increased in aPC-treated septic rats. In inoculated naïve recipients, microparticles from aPC-treated septic rats prompted reduced NF-κB and cyclooxygenase-2 arterial activation, blunted the generation of pro-inflammatory iNOS and secondarily increased platelet and endothelial microparticles. In conclusion, in this septic shock model, increased circulating levels of procoagulant microparticles led to negative haemodynamic outcomes. Pharmacological treatment by aPC modified the cell origin and levels of circulating microparticles, thereby limiting vascular inflammation and favouring haemodynamic improvement.
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Microvesicle Involvement in Shiga Toxin-Associated Infection. Toxins (Basel) 2017; 9:toxins9110376. [PMID: 29156596 PMCID: PMC5705991 DOI: 10.3390/toxins9110376] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 11/15/2017] [Accepted: 11/16/2017] [Indexed: 12/16/2022] Open
Abstract
Shiga toxin is the main virulence factor of enterohemorrhagic Escherichia coli, a non-invasive pathogen that releases virulence factors in the intestine, causing hemorrhagic colitis and, in severe cases, hemolytic uremic syndrome (HUS). HUS manifests with acute renal failure, hemolytic anemia and thrombocytopenia. Shiga toxin induces endothelial cell damage leading to platelet deposition in thrombi within the microvasculature and the development of thrombotic microangiopathy, mostly affecting the kidney. Red blood cells are destroyed in the occlusive capillary lesions. This review focuses on the importance of microvesicles shed from blood cells and their participation in the prothrombotic lesion, in hemolysis and in the transfer of toxin from the circulation into the kidney. Shiga toxin binds to blood cells and may undergo endocytosis and be released within microvesicles. Microvesicles normally contribute to intracellular communication and remove unwanted components from cells. Many microvesicles are prothrombotic as they are tissue factor- and phosphatidylserine-positive. Shiga toxin induces complement-mediated hemolysis and the release of complement-coated red blood cell-derived microvesicles. Toxin was demonstrated within blood cell-derived microvesicles that transported it to renal cells, where microvesicles were taken up and released their contents. Microvesicles are thereby involved in all cardinal aspects of Shiga toxin-associated HUS, thrombosis, hemolysis and renal failure.
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Delano MJ, Ward PA. The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev 2017; 274:330-353. [PMID: 27782333 DOI: 10.1111/imr.12499] [Citation(s) in RCA: 515] [Impact Index Per Article: 64.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after "recovery" from acute events. As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long-term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality.
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Affiliation(s)
- Matthew J Delano
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Peter A Ward
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
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