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Gunn NA, Oo Y, Lee CWL, Heaney E, Tan NYT, Chan YZ, Wang SSY. Disseminated Intravascular Coagulopathy and Persistent Inflammation, Immunosuppression, and Catabolism Syndrome: Pathophysiology, shared pathways, and clinical implications. Thromb Res 2025; 250:109321. [PMID: 40286453 DOI: 10.1016/j.thromres.2025.109321] [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: 02/20/2025] [Revised: 03/31/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND Disseminated Intravascular Coagulopathy (DIC) and Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) are critical care syndromes that frequently coexist in critically ill patients, but mechanisms underlying their shared pathways are not well understood. OBJECTIVE This review discusses the pathophysiology of DIC and PICS and explores the shared mechanisms behind DIC and PICS and their implications for clinical management. FINDINGS DIC and PICS share a common pathophysiological foundation of endothelial dysfunction, coagulation dysregulation, and inflammation, leading to a vicious cycle of microvascular injury and systemic inflammation, culminating in organ dysfunction. DIC has also been identified as an independent risk factor for PICS. Anticoagulation therapies such as antithrombin, recombinant human soluble thrombomodulin (rhTM), and heparin attenuates inflammation, a mechanism underlying both syndromes, thereby improving outcomes in PICS. CONCLUSION DIC and PICS share critical pathophysiological pathways that exacerbate outcomes in critically ill patients. Recognizing these interconnections is essential for developing targeted therapies. Standardizing PICS definitions and advancing research to clarify mechanisms, interplay, and causality between DIC and PICS are crucial next steps.
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Affiliation(s)
- Nicole Ann Gunn
- University of Queensland School of Medicine, Herston, QLD 4006, Australia
| | - Yukei Oo
- University of Queensland School of Medicine, Herston, QLD 4006, Australia
| | | | - Edward Heaney
- University of Queensland School of Medicine, Herston, QLD 4006, Australia
| | | | - Yan Zhi Chan
- Duke-NUS Medical School, Singapore 169857, Singapore
| | - Samuel Sherng Young Wang
- Duke-NUS Medical School, Singapore 169857, Singapore; Department of Internal Medicine, Singapore General Hospital, Singapore 169608, Singapore.
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2
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Datta S, Rahman MA, Koka S, Boini KM. High mobility group box 1 (HMGB1) mediates nicotine-induced podocyte injury. Front Pharmacol 2025; 15:1540639. [PMID: 39840112 PMCID: PMC11747285 DOI: 10.3389/fphar.2024.1540639] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 12/18/2024] [Indexed: 01/23/2025] Open
Abstract
Introduction Cigarette smoking is a well-established risk factor for renal dysfunction. Smoking associated with renal damage bears distinct physiological correlations in conditions such as diabetic nephropathy and obesity-induced glomerulopathy. However, the cellular and molecular basis of such an association remains poorly understood. High mobility group box 1(HMGB1) is a highly conserved non-histone chromatin associated protein that largely contributes to the pathogenesis of chronic inflammatory and autoimmune diseases such as sepsis, atherosclerosis, and chronic kidney diseases. Hence, the present study tested whether HMGB1 contributes to nicotine-induced podocyte injury. Methods and Results Biochemical analysis showed that nicotine treatment significantly increased the HMGB1 expression and release compared to vehicle treated podocytes. However, prior treatment with glycyrrhizin (Gly), a HMGB1 binder, abolished the nicotine-induced HMGB1 expression and release in podocytes. Furthermore, immunofluorescent analysis showed that nicotine treatment significantly decreased the expression of podocyte functional proteins- podocin and nephrin as compared to control cells. However, prior treatment with Gly attenuated the nicotine-induced nephrin and podocin reduction. In addition, nicotine treatment significantly increased desmin expression and cell permeability compared to vehicle treated podocytes. However, prior treatment with Gly attenuated the nicotine-induced desmin expression and cell permeability. Mechanistic elucidation revealed that nicotine treatment augmented the expression of toll like receptor 4 (TLR4) and pre-treatment with Gly abolished nicotine induced TLR4 upregulation. Pharmacological inhibition of TLR4 with Resatorvid, a TLR4 specific inhibitor, also attenuated nicotine induced podocyte damage. Conclusion HMGB1 is one of the important mediators of nicotine-induced podocyte injury through TLR4 activation.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States
| | - Mohammad Atiqur Rahman
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX, United States
| | - Krishna M. Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States
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3
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Tourn J, Crescence L, Bruzzese L, Panicot-Dubois L, Dubois C. Cellular and Molecular Mechanisms Leading to Air Travel-Induced Thrombosis. Circ Res 2025; 136:115-134. [PMID: 39745986 DOI: 10.1161/circresaha.124.325208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Venous thromboembolism, characterized by deep vein thrombosis and pulmonary embolism, is the third cardiovascular disease in the world. Deep vein thrombosis occurs when a blood clot forms in areas of impaired blood flow, and it is significantly affected by environmental factors. Local hypoxia, caused by venous stasis, plays a critical role in deep vein thrombosis under normal conditions, and this effect is intensified when the Po2 decreases, such as during air travel or high-altitude exposure. The lower oxygen levels and reduced pressure at high altitudes further contribute to deep vein thrombosis development. These conditions increase the pro-coagulant activity of neutrophils, platelets, and red blood cells, which interact on the surface of activated endothelial cells, promoting clot formation. Understanding the mechanisms involved in thrombus formation when Po2 is reduced, with or without pressure reduction, is crucial for preventing the development of venous thromboembolisms in such conditions and identifying innovative therapeutic targets. This literature review explores the mechanisms involved in thrombus formation related to high-altitude conditions and discusses the pro-coagulant consequences induced by environmental disturbances.
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Affiliation(s)
- Julie Tourn
- Aix Marseille University, INSERM 1263, INRAE 1260, Center for CardioVascular and Nutrition Research (C2VN), Marseille, France (J.T., L.C., L.B., L.P.-D., C.D.)
| | - Lydie Crescence
- Aix Marseille University, INSERM 1263, INRAE 1260, Center for CardioVascular and Nutrition Research (C2VN), Marseille, France (J.T., L.C., L.B., L.P.-D., C.D.)
- Plateforme Aix Marseille, Plateforme d'Imagerie Vasculaire et de Microscopie Intravitale, C2VN, Marseille, France (L.C., L.B., L.P.-D., C.D.)
| | - Laurie Bruzzese
- Aix Marseille University, INSERM 1263, INRAE 1260, Center for CardioVascular and Nutrition Research (C2VN), Marseille, France (J.T., L.C., L.B., L.P.-D., C.D.)
- Plateforme Aix Marseille, Plateforme d'Imagerie Vasculaire et de Microscopie Intravitale, C2VN, Marseille, France (L.C., L.B., L.P.-D., C.D.)
| | - Laurence Panicot-Dubois
- Aix Marseille University, INSERM 1263, INRAE 1260, Center for CardioVascular and Nutrition Research (C2VN), Marseille, France (J.T., L.C., L.B., L.P.-D., C.D.)
- Plateforme Aix Marseille, Plateforme d'Imagerie Vasculaire et de Microscopie Intravitale, C2VN, Marseille, France (L.C., L.B., L.P.-D., C.D.)
| | - Christophe Dubois
- Aix Marseille University, INSERM 1263, INRAE 1260, Center for CardioVascular and Nutrition Research (C2VN), Marseille, France (J.T., L.C., L.B., L.P.-D., C.D.)
- Plateforme Aix Marseille, Plateforme d'Imagerie Vasculaire et de Microscopie Intravitale, C2VN, Marseille, France (L.C., L.B., L.P.-D., C.D.)
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4
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Vogel S. HMGB1 in platelets: a viable therapeutic target? J Thromb Haemost 2024; 22:3392-3394. [PMID: 39613347 DOI: 10.1016/j.jtha.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 12/01/2024]
Affiliation(s)
- Sebastian Vogel
- Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
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5
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Datta S, Rahman MA, Koka S, Boini KM. High Mobility Group Box 1 (HMGB1): Molecular Signaling and Potential Therapeutic Strategies. Cells 2024; 13:1946. [PMID: 39682695 PMCID: PMC11639863 DOI: 10.3390/cells13231946] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/19/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure-function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions.
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Affiliation(s)
- Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Mohammad Atiqur Rahman
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Saisudha Koka
- Department of Pharmaceutical Sciences, Irma Lerma College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA;
| | - Krishna M. Boini
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
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Vladimirova D, Staneva S, Ugrinova I. Multifaceted role of HMGB1: From nuclear functions to cytoplasmic and extracellular signaling in inflammation and cancer-Review. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 143:271-300. [PMID: 39843137 DOI: 10.1016/bs.apcsb.2024.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
High-mobility group box 1 (HMGB1) is a highly conserved nuclear protein involved in key nuclear processes such as DNA repair, replication, and gene regulation. Beyond its established nuclear roles, HMGB1 has crucial functions in the cytoplasm and extracellular environment. When translocated to the cytoplasm, HMGB1 plays a role in autophagy, cell survival, and immune response modulation. In its extracellular form, HMGB1 acts as a damage-associated molecular pattern molecule, initiating inflammatory responses by interacting with receptors such as Receptor for advanced glycation endproducts and Toll-like receptors. Recent studies have shown its role in promoting tissue regeneration, wound healing, and angiogenesis, highlighting its dual role in both inflammation and tissue repair. Notably, the redox status of HMGB1 influences its function, with the reduced form promoting autophagy and the disulfide form driving inflammation. Dysregulation of HMGB1 contributes to the progression of various diseases, including cancer, where it influences tumor growth, metastasis, and resistance to therapy. This review provides an overview of the nuclear, cytoplasmic, and extracellular roles of HMGB1, discussing its involvement in nuclear homeostasis, rare genetic diseases, autophagy, inflammation, cancer progression, and tissue regeneration.
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Affiliation(s)
- Desislava Vladimirova
- "Roumen Tsanev" Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Sonya Staneva
- "Roumen Tsanev" Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Iva Ugrinova
- "Roumen Tsanev" Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
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Albloshi AMK. Postmortem interval estimation of time since death: impact of non-histone binding proteins, immunohistochemical, and histopathological changes in vivo. J Med Life 2024; 17:897-902. [PMID: 39628967 PMCID: PMC11611056 DOI: 10.25122/jml-2024-0260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 08/17/2024] [Indexed: 12/06/2024] Open
Abstract
The postmortem interval (PMI) is one of the primary objectives and challenging tasks proposed for determining the time of death. This study aimed to estimate the PMI using serum levels of high mobility group box 1 (HMGB1), a biomarker of pyroptotic cell death, along with desmin immunohistochemical and histological analyses of the gastrocnemius muscle in rats at various time intervals. Serum and gastrocnemius muscle samples were collected at zero, 24-, 48-, 72-, and 96 hours postmortem from 50 rats maintained at 22 ± 2°C. The results revealed that the HMGB1 level peaked at 48 hours and dropped in a time-dependent manner afterward. Immunohistochemical analysis revealed a progressive decrease in desmin expression, with severe immunoreactivity (38.19%) at 0 hours, dropping to a minimal level (1.09%) 96 hours after death. Histological analysis of the gastrocnemius muscle at 96 hours revealed significant vacuolation, loss of normal architecture, reduced nuclear visibility, and complete autolysis of all myocytes. In conclusion, HMGB1 levels, desmin immunoreactivity, and histopathological alterations seen in the gastrocnemius muscle could be helpful, valuable, and potential markers for accurately determining PMIs in humans in future studies.
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Logotheti S, Pavlopoulou A, Rudsari HK, Galow AM, Kafalı Y, Kyrodimos E, Giotakis AI, Marquardt S, Velalopoulou A, Verginadis II, Koumenis C, Stiewe T, Zoidakis J, Balasingham I, David R, Georgakilas AG. Intercellular pathways of cancer treatment-related cardiotoxicity and their therapeutic implications: the paradigm of radiotherapy. Pharmacol Ther 2024; 260:108670. [PMID: 38823489 DOI: 10.1016/j.pharmthera.2024.108670] [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: 11/11/2023] [Revised: 05/16/2024] [Accepted: 05/25/2024] [Indexed: 06/03/2024]
Abstract
Advances in cancer therapeutics have improved patient survival rates. However, cancer survivors may suffer from adverse events either at the time of therapy or later in life. Cardiovascular diseases (CVD) represent a clinically important, but mechanistically understudied complication, which interfere with the continuation of best-possible care, induce life-threatening risks, and/or lead to long-term morbidity. These concerns are exacerbated by the fact that targeted therapies and immunotherapies are frequently combined with radiotherapy, which induces durable inflammatory and immunogenic responses, thereby providing a fertile ground for the development of CVDs. Stressed and dying irradiated cells produce 'danger' signals including, but not limited to, major histocompatibility complexes, cell-adhesion molecules, proinflammatory cytokines, and damage-associated molecular patterns. These factors activate intercellular signaling pathways which have potentially detrimental effects on the heart tissue homeostasis. Herein, we present the clinical crosstalk between cancer and heart diseases, describe how it is potentiated by cancer therapies, and highlight the multifactorial nature of the underlying mechanisms. We particularly focus on radiotherapy, as a case known to often induce cardiovascular complications even decades after treatment. We provide evidence that the secretome of irradiated tumors entails factors that exert systemic, remote effects on the cardiac tissue, potentially predisposing it to CVDs. We suggest how diverse disciplines can utilize pertinent state-of-the-art methods in feasible experimental workflows, to shed light on the molecular mechanisms of radiotherapy-related cardiotoxicity at the organismal level and untangle the desirable immunogenic properties of cancer therapies from their detrimental effects on heart tissue. Results of such highly collaborative efforts hold promise to be translated to next-generation regimens that maximize tumor control, minimize cardiovascular complications, and support quality of life in cancer survivors.
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Affiliation(s)
- Stella Logotheti
- DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780, Athens, Greece; Biomedical Physics in Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Athanasia Pavlopoulou
- Izmir Biomedicine and Genome Center, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
| | | | - Anne-Marie Galow
- Institute for Genome Biology, Research Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - Yağmur Kafalı
- Izmir Biomedicine and Genome Center, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
| | - Efthymios Kyrodimos
- First Department of Otorhinolaryngology, Head and Neck Surgery, Hippocrateion General Hospital Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Aris I Giotakis
- First Department of Otorhinolaryngology, Head and Neck Surgery, Hippocrateion General Hospital Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Stephan Marquardt
- Institute of Translational Medicine for Health Care Systems, Medical School Berlin, Hochschule Für Gesundheit Und Medizin, 14197 Berlin, Germany
| | - Anastasia Velalopoulou
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ioannis I Verginadis
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Constantinos Koumenis
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Thorsten Stiewe
- Institute of Molecular Oncology, Philipps-University, 35043 Marburg, Germany; German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), 35043 Marburg, Germany; Genomics Core Facility, Philipps-University, 35043 Marburg, Germany; Institute for Lung Health (ILH), Justus Liebig University, 35392 Giessen, Germany
| | - Jerome Zoidakis
- Department of Biotechnology, Biomedical Research Foundation, Academy of Athens, Athens, Greece; Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Robert David
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany; Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Alexandros G Georgakilas
- DNA Damage Laboratory, Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens (NTUA), Zografou, 15780, Athens, Greece.
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Yong J, Toh CH. The convergent model of coagulation. J Thromb Haemost 2024; 22:2140-2146. [PMID: 38815754 DOI: 10.1016/j.jtha.2024.05.014] [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: 01/15/2024] [Revised: 04/18/2024] [Accepted: 05/10/2024] [Indexed: 06/01/2024]
Abstract
It is increasingly apparent that the pathologic interplay between coagulation and innate immunity, ie, immunothrombosis, forms the common basis of many challenges across the boundaries of specialized medicine and cannot be fully explained by the conventional concepts of cascade and cell-based coagulation. To improve our understanding of coagulation, we propose a model of coagulation that converges with inflammation and innate immune activation as a unified response toward vascular injury. Evolutionarily integral to the convergent response are damage-associated molecular patterns, which are released as a consequence of injury. Damage-associated molecular patterns facilitate diverse interactions within and between systems, not only to complement and reinforce cell-based clot formation but also to steer the response toward clot resolution and wound healing. By extending coagulation beyond its current boundaries, the convergent model aims to deliver novel diagnostics and therapeutics for contemporary and unexpected challenges across medicine, as exposed by COVID-19 and vaccine-induced immune thrombotic thrombocytopenia.
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Affiliation(s)
- Jun Yong
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
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Williams B, Zou L, Pittet JF, Chao W. Sepsis-Induced Coagulopathy: A Comprehensive Narrative Review of Pathophysiology, Clinical Presentation, Diagnosis, and Management Strategies. Anesth Analg 2024; 138:696-711. [PMID: 38324297 PMCID: PMC10916756 DOI: 10.1213/ane.0000000000006888] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2023] [Indexed: 02/08/2024]
Abstract
Physiological hemostasis is a balance between pro- and anticoagulant pathways, and in sepsis, this equilibrium is disturbed, resulting in systemic thrombin generation, impaired anticoagulant activity, and suppression of fibrinolysis, a condition termed sepsis-induced coagulopathy (SIC). SIC is a common complication, being present in 24% of patients with sepsis and 66% of patients with septic shock, and is often associated with poor clinical outcomes and high mortality. 1 , 2 Recent preclinical and clinical studies have generated new insights into the molecular pathogenesis of SIC. In this article, we analyze the complex pathophysiology of SIC with a focus on the role of procoagulant innate immune signaling in hemostatic activation--tissue factor production, thrombin generation, endotheliopathy, and impaired antithrombotic functions. We also review clinical presentations of SIC, the diagnostic scoring system and laboratory tests, the current standard of care, and clinical trials evaluating the efficacies of anticoagulant therapies.
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Affiliation(s)
- Brittney Williams
- From the Division of Cardiothoracic Anesthesia, Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
| | - Lin Zou
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
| | - Jean-Francois Pittet
- Division of Critical Care, Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland
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Gando S, Levi M, Toh CH. Trauma-induced innate immune activation and disseminated intravascular coagulation. J Thromb Haemost 2024; 22:337-351. [PMID: 37816463 DOI: 10.1016/j.jtha.2023.09.028] [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: 05/19/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/12/2023]
Abstract
Dysregulated innate immunity participates in the pathomechanisms of disseminated intravascular coagulation (DIC) in trauma-induced coagulopathy. Accidental and regulated cell deaths and neutrophil extracellular traps release damage-associated molecular patterns (DAMPs), such as histones, nuclear and mitochondrial DNA, and high-mobility group box 1, into circulation immediately after trauma. DAMP-induced inflammation activation releases tissue factor-bearing procoagulant extracellular vesicles through gasdermin D-mediated pore formation and plasma membrane rupture by regulated cell death. DAMPs also evoke systemic inflammation, platelet, coagulation activation, and impaired fibrinolysis associated with endothelial injury, leading to the dysfunction of anticoagulation systems, which are the main pathophysiological mechanisms of DIC. All these processes induce systemic thrombin generation in vivo, not restricted to the injury sites immediately after trauma. Thrombin generation at the site of injury stops bleeding and maintains homeostasis. However, DIC associated with endothelial injury generates massive thrombin, enhancing protease-activated, receptor-mediated bidirectional interplays between inflammation and coagulation, aggravating the diverse actions of thrombin and disturbing homeostasis. Insufficiently regulated thrombin causes disseminated microvascular thrombosis, resulting in tissue hypoxia due to reduced oxygen delivery, and mitochondrial dysfunction due to DAMPs causes tissue dysoxia. In addition, DAMP-induced calcium influx and overload, as well as neutrophil activation, play a role in endothelial cell injury. Tissue hypoxia and cytotoxicity result in multiple organ dysfunction in DIC after trauma. Controls against dysregulated innate immunity evoking systemic inflammation, thrombin generation, and cytotoxicity are key issues in improving the prognosis of DIC in trauma-induced coagulopathy.
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Affiliation(s)
- Satoshi Gando
- Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan; Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan.
| | - Marcel Levi
- Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands; Department of Medicine, University College London Hospitals NHS Foundation Trust, and Cardio-Metabolic Program - NIHR UCLH/UCL BRC London, London, United Kingdom
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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Yong J, Toh CH. Rethinking coagulation: from enzymatic cascade and cell-based reactions to a convergent model involving innate immune activation. Blood 2023; 142:2133-2145. [PMID: 37890148 DOI: 10.1182/blood.2023021166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/12/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open
Abstract
ABSTRACT Advancements in the conceptual thinking of hemostasis and thrombosis have been catalyzed by major developments within health research over several decades. The cascade model of coagulation was first described in the 1960s, when biochemistry gained prominence through innovative experimentation and technical developments. This was followed by the cell-based model, which integrated cellular coordination to the enzymology of clot formation and was conceptualized during the growth period in cell biology at the turn of the millennium. Each step forward has heralded a revolution in clinical therapeutics, both in procoagulant and anticoagulant treatments to improve patient care. In current times, the COVID-19 pandemic may also prove to be a catalyst: thrombotic challenges including the mixed responses to anticoagulant treatment and the vaccine-induced immune thrombotic thrombocytopenia have exposed limitations in our preexisting concepts while simultaneously demanding novel therapeutic approaches. It is increasingly clear that innate immune activation as part of the host response to injury is not separate but integrated into adaptive clot formation. Our review summarizes current understanding of the major molecules facilitating such a cross talk between immunity, inflammation and coagulation. We demonstrate how such effects can be layered upon the cascade and cell-based models to evolve conceptual understanding of the physiology of immunohemostasis and the pathology of immunothrombosis.
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Affiliation(s)
- Jun Yong
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
- The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
- The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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Wei T, Liu J, Li C, Tan Y, Wei R, Wang J, Wu H, Li Q, Liu H, Tang Y, Li X. Revealing the extracellular function of HMGB1 N-terminal region acetylation assisted by a protein semi-synthesis approach. Chem Sci 2023; 14:10297-10307. [PMID: 37772093 PMCID: PMC10530822 DOI: 10.1039/d3sc01109g] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 09/05/2023] [Indexed: 09/30/2023] Open
Abstract
HMGB1 (high-mobility group box 1) is a non-histone chromatin-associated protein that has been widely reported as a representative damage-associated molecular pattern (DAMP) and to play a pivotal role in the proinflammatory process once it is in an extracellular location. Accumulating evidence has shown that HMGB1 undergoes extensive post-translational modifications (PTMs) that actively regulate its conformation, localization, and intermolecular interactions. However, fully characterizing the functional implications of these PTMs has been challenging due to the difficulty in accessing homogeneous HMGB1 with site-specific PTMs of interest. In this study, we developed a streamlined protein semi-synthesis strategy via salicylaldehyde ester-mediated chemical ligations (Ser/Thr ligation and Cys/Pen ligation, STL/CPL). This methodology enabled us to generate a series of N-terminal region acetylated HMGB1 proteins. Further studies revealed that acetylation regulates HMGB1-heparin interaction and modulates HMGB1's stability against thrombin, representing a regulatory switch to control HMGB1's extracellular activity.
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Affiliation(s)
- Tongyao Wei
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Jiamei Liu
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Can Li
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Yi Tan
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Ruohan Wei
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Jinzheng Wang
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Hongxiang Wu
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Qingrong Li
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Heng Liu
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Yubo Tang
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
| | - Xuechen Li
- Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong Pokfulam Road Hong Kong SAR P. R. China
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14
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Shimono K, Ito T, Kamikokuryo C, Niiyama S, Yamada S, Onishi H, Yoshihara H, Maruyama I, Kakihana Y. Damage-associated molecular patterns and fibrinolysis perturbation are associated with lethal outcomes in traumatic injury. Thromb J 2023; 21:91. [PMID: 37674235 PMCID: PMC10481518 DOI: 10.1186/s12959-023-00536-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 08/28/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND Upon cellular injury, damage-associated molecular patterns (DAMPs) are released into the extracellular space and evoke proinflammatory and prothrombotic responses in animal models of sterile inflammation. However, in clinical settings, the dynamics of DAMP levels after trauma and links between DAMPs and trauma-associated coagulopathy remain largely undetermined. METHODS Thirty-one patients with severe trauma, who were transferred to Kagoshima City Hospital between June 2018 and December 2019, were consecutively enrolled in this study. Blood samples were taken at the time of delivery, and 6 and 12 h after the injury, and once daily thereafter. The time-dependent changes of coagulation/fibrinolysis markers, including thrombin-antithrombin complex, α2-plasmin inhibitor (α2-PI), plasmin-α2-PI complex, and plasminogen activator inhibitor-1 (PAI-1), and DAMPs, including high mobility group box 1 and histone H3, were analyzed. The relationship between coagulation/fibrinolysis markers, DAMPs, Injury Severity Score, in-hospital death, and amount of blood transfusion were analyzed. RESULTS The activation of coagulation/fibrinolysis pathways was evident at the time of delivery. In contrast, PAI-1 levels remained low at the time of delivery, and then were elevated at 6-12 h after traumatic injury. Histone H3 and high mobility group box 1 levels were elevated at admission, and gradually subsided over time. PAI-1 levels at 6 h were associated with serum histone H3 levels at admission. Increased histone H3 levels and plasmin-α2-PI complex levels were associated with in-hospital mortality. α2-PI levels at admission showed the strongest negative correlation with the amount of blood transfusion. CONCLUSION The elevation of histone H3 levels and fibrinolysis perturbation are associated with fatal outcomes in patients with traumatic injury. Patients with low α2-PI levels at admission tend to require blood transfusion.
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Affiliation(s)
- Kenshin Shimono
- Department of Emergency and Intensive Care Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Takashi Ito
- Department of Biomedical Laboratory Sciences, Faculty of Life Sciences, Kumamoto University, 4-24-1 Kuhonji, Kumamoto, 862-0976, Japan.
| | - Chinatsu Kamikokuryo
- Department of Emergency and Intensive Care Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shuhei Niiyama
- Department of Emergency and Intensive Care Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shingo Yamada
- Shino-Test Corporation, R&D Center, Sagamihara, Japan
| | - Hirokazu Onishi
- Emergency and Critical Care Center, Kagoshima City Hospital, Kagoshima, Japan
| | - Hideaki Yoshihara
- Emergency and Critical Care Center, Kagoshima City Hospital, Kagoshima, Japan
| | - Ikuro Maruyama
- Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yasuyuki Kakihana
- Department of Emergency and Intensive Care Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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15
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Unar A, Bertolino L, Patauner F, Gallo R, Durante-Mangoni E. Pathophysiology of Disseminated Intravascular Coagulation in Sepsis: A Clinically Focused Overview. Cells 2023; 12:2120. [PMID: 37681852 PMCID: PMC10486945 DOI: 10.3390/cells12172120] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/07/2023] [Accepted: 08/12/2023] [Indexed: 09/09/2023] Open
Abstract
Sepsis is a major global health problem that results from a dysregulated and uncontrolled host response to infection, causing organ failure. Despite effective anti-infective therapy and supportive treatments, the mortality rate of sepsis remains high. Approximately 30-80% of patients with sepsis may develop disseminated intravascular coagulation (DIC), which can double the mortality rate. There is currently no definitive treatment approach for sepsis, with etiologic treatment being the cornerstone of therapy for sepsis-associated DIC. Early detection, diagnosis, and treatment are critical factors that impact the prognosis of sepsis-related DIC. Over the past several decades, researchers have made continuous efforts to better understand the mechanisms of DIC in sepsis, as well as improve its quantitative diagnosis and treatment. This article aims to provide a comprehensive overview of the current understanding of sepsis-related DIC, focusing on common causes and diagnoses, with the goal of guiding healthcare providers in the care of patients with sepsis.
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Affiliation(s)
- Ahsanullah Unar
- Department of Precision Medicine, University of Campania ‘L. Vanvitelli’, 80138 Naples, Italy; (A.U.); (L.B.); (F.P.); (R.G.)
| | - Lorenzo Bertolino
- Department of Precision Medicine, University of Campania ‘L. Vanvitelli’, 80138 Naples, Italy; (A.U.); (L.B.); (F.P.); (R.G.)
| | - Fabian Patauner
- Department of Precision Medicine, University of Campania ‘L. Vanvitelli’, 80138 Naples, Italy; (A.U.); (L.B.); (F.P.); (R.G.)
| | - Raffaella Gallo
- Department of Precision Medicine, University of Campania ‘L. Vanvitelli’, 80138 Naples, Italy; (A.U.); (L.B.); (F.P.); (R.G.)
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania ‘L. Vanvitelli’, 80138 Naples, Italy; (A.U.); (L.B.); (F.P.); (R.G.)
- Unit of Infectious and Transplant Medicine, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
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16
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Arteaga A, Biguetti CC, Lakkasetter Chandrashekar B, Mora J, Qureshi A, Rodrigues DC. Biological Effects of New Titanium Surface Coatings Based on Ionic Liquids and HMGB1: A Cellular and Molecular Characterization in Lewis Rats. ACS Biomater Sci Eng 2023; 9:4709-4719. [PMID: 37418317 PMCID: PMC11292580 DOI: 10.1021/acsbiomaterials.3c00367] [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] [Indexed: 07/09/2023]
Abstract
High Mobility Group Box 1 (HMGB1) is a redox-sensitive molecule that plays dual roles in tissue healing and inflammation. We previously demonstrated that HMGB1 is stable when anchored by a well-characterized imidazolium-based ionic liquid (IonL), which serves as a delivery vehicle for exogenous HMGB1 to the site of injury and prevents denaturation from surface adherence. However, HMGB1 exists in different isoforms [fully reduced HMGB1 (FR), a recombinant version of FR resistant to oxidation (3S), disulfide HMGB1 (DS), and inactive sulfonyl HMGB1(SO)] that have distinct biological functions in health and disease. Thus, the goal of this study was to evaluate the effects of different recombinant HMGB1 isoforms on the host response using a rat subcutaneous implantation model. A total of 12 male Lewis rats (12-15 weeks) were implanted with titanium discs containing different treatments (n = 3/time point; Ti, Ti-IonL, Ti-IonL-DS, Ti-IonL-FR, and Ti-IonL-3S) and assessed at 2 and 14 days. Histological (H&E and Goldner trichrome staining), immunohistochemistry, and molecular analyses (qPCR) of surrounding implant tissues were employed for analysis of inflammatory cells, HMGB1 receptors, and healing markers. Ti-IonL-DS samples resulted in the thickest capsule formation, increased pro-inflammatory, and decreased anti-inflammatory cells, while Ti-IonL-3S samples demonstrated suitable tissue healing similar to uncoated Ti discs, as well as an upregulation of anti-inflammatory cells at 14 days compared to all other treatments. Thus, results from this study demonstrated that Ti-IonL-3S are safe alternatives for Ti biomaterials. Future studies are necessary to investigate the healing potential of Ti-IonL-3S in osseointegration scenarios.
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Affiliation(s)
- Alexandra Arteaga
- Department of Bioengineering, The University of Texas at Dallas, Richardson 75080-3021, Texas, United States
| | - Claudia Cristina Biguetti
- Department of Surgery and Biomechanics, School of Podiatric Medicine, The University of Texas Rio Grande Valley, Harlingen 78539, Texas, United States
| | | | - Jimena Mora
- Department of Bioengineering, The University of Texas at Dallas, Richardson 75080-3021, Texas, United States
| | - Adeena Qureshi
- Department of Bioengineering, The University of Texas at Dallas, Richardson 75080-3021, Texas, United States
| | - Danieli C Rodrigues
- Department of Bioengineering, The University of Texas at Dallas, Richardson 75080-3021, Texas, United States
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17
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Yong J, Abrams ST, Wang G, Toh CH. Cell-free histones and the cell-based model of coagulation. J Thromb Haemost 2023; 21:1724-1736. [PMID: 37116754 DOI: 10.1016/j.jtha.2023.04.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 04/06/2023] [Accepted: 04/20/2023] [Indexed: 04/30/2023]
Abstract
The cell-based model of coagulation remains the basis of our current understanding of clinical hemostasis and thrombosis. Its advancement on the coagulation cascade model has enabled new prohemostatic and anticoagulant treatments to be developed. In the past decade, there has been increasing evidence of the procoagulant properties of extracellular, cell-free histones (CFHs). Although high levels of circulating CFHs released following extensive cell death in acute critical illnesses, such as sepsis and trauma, have been associated with adverse coagulation outcomes, including disseminated intravascular coagulation, new information has also emerged on how its local effects contribute to physiological clot formation. CFHs initiate coagulation by tissue factor exposure, either by destruction of the endovascular barrier or induction of endoluminal tissue factor expression on endothelia and monocytes. CFHs can also bind prothrombin directly, generating thrombin via the alternative prothrombinase pathway. In amplifying and augmenting the procoagulant signal, CFHs activate and aggregate platelets, increase procoagulant material bioavailability through platelet degranulation and Weibel-Palade body exocytosis, activate intrinsic coagulation via platelet polyphosphate release, and induce phosphatidylserine exposure. CFHs also inhibit protein C activation and downregulate thrombomodulin expression to reduce anti-inflammatory and anticoagulant effects. In consolidating clot formation, CFHs augment the fibrin polymer to confer fibrinolytic resistance and integrate neutrophil extracellular traps into the clot structure. Such new information holds the promise of new therapeutic developments, including improved targeting of immunothrombotic pathologies in acute critical illnesses.
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Affiliation(s)
- Jun Yong
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK
| | - Simon T Abrams
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; Liverpool Clinical Laboratories, Liverpool, UK
| | - Guozheng Wang
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; Liverpool Clinical Laboratories, Liverpool, UK
| | - Cheng-Hock Toh
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK; The Roald Dahl Haemostasis and Thrombosis Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
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18
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Li J, Zhu CS, He L, Qiang X, Chen W, Wang H. A two-decade journey in identifying high mobility group box 1 (HMGB1) and procathepsin L (pCTS-L) as potential therapeutic targets for sepsis. Expert Opin Ther Targets 2023; 27:575-591. [PMID: 37477229 PMCID: PMC10530501 DOI: 10.1080/14728222.2023.2239495] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 07/18/2023] [Indexed: 07/22/2023]
Abstract
INTRODUCTION Microbial infections and resultant sepsis are leading causes of death in hospitals, representing approximately 20% of total deaths worldwide. Despite the difficulties in translating experimental insights into effective therapies for often heterogenous patient populations, an improved understanding of the pathogenic mechanisms underlying experimental sepsis is still urgently needed. Sepsis is partly attributable to dysregulated innate immune responses manifested by hyperinflammation and immunosuppression at different stages of microbial infections. AREAS COVERED Here we review our recent progress in searching for late-acting mediators of experimental sepsis and propose high mobility group box 1 (HMGB1) and procathepsin-L (pCTS-L) as potential therapeutic targets for improving outcomes of lethal sepsis and other infectious diseases. EXPERT OPINION It will be important to evaluate the efficacy of HMGB1- or pCTS-L-targeting agents for the clinical management of human sepsis and other infectious diseases in future studies.
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Affiliation(s)
- Jianhua Li
- The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA
| | - Cassie Shu Zhu
- The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY 11549, USA
| | - Li He
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Xiaoling Qiang
- The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY 11549, USA
| | - Weiqiang Chen
- The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY 11549, USA
| | - Haichao Wang
- The Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY 11549, USA
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19
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Sloos PH, Maas MAW, Meijers JCM, Nieuwland R, Roelofs JJTH, Juffermans NP, Kleinveld DJB. Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock. Br J Anaesth 2023; 130:687-697. [PMID: 36967283 DOI: 10.1016/j.bja.2023.01.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 01/09/2023] [Accepted: 01/30/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND Trauma-induced coagulopathy is associated with platelet dysfunction and contributes to early mortality after traumatic injury. Plasma concentrations of the damage molecule high-mobility group box-1 (HMGB-1) increase after trauma, which may contribute to platelet dysfunction. We hypothesised that inhibition of HMGB-1 with a monoclonal antibody (mAb) or with recombinant thrombomodulin (rTM) improves trauma-induced coagulopathy in a murine model of trauma and shock. METHODS Male 129S2/SvPasOrlRJ mice were anaesthetised, mechanically ventilated, and randomised into five groups: (i) ventilation control (VENT), (ii) trauma/shock (TS), (iii) TS+anti-HMGB-1 mAb (TS+AB), (iv) TS+rTM (TS+TM), and (v) TS+anti-HMGB-1 mAb+rTM (TS+COMBI). Primary outcome was rotational thromboelastometry EXTEM. Secondary outcomes included tail bleeding time, platelet count, plasma HMGB-1 concentration, and platelet activation. RESULTS Trauma and shock resulted in a hypocoagulable thromboelastometry profile, increased plasma HMGB-1, and increased platelet activation markers. TS+AB was associated with improved clot firmness after 5 min compared with TS (34 [33-37] vs 32 [29-34] mm; P=0.043). TS+COMBI was associated with decreased clot formation time (98 [92-125] vs 122 [111-148] s; P=0.018) and increased alpha angle (77 [72-78] vs 69 [64-71] degrees; P=0.003) compared with TS. TS+COMBI also reduced tail bleeding time compared with TS (P=0.007). The TS+TM and TS+COMBI groups had higher platelet counts compared with TS (P=0.044 and P=0.041, respectively). CONCLUSIONS Inhibition of HMGB-1 early after trauma in a mouse model improves clot formation and strength, preserves platelet count, and decreases bleeding time.
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Affiliation(s)
- Pieter H Sloos
- Amsterdam UMC Location University of Amsterdam, Department of Intensive Care Medicine, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam, the Netherlands
| | - M Adrie W Maas
- Amsterdam UMC Location University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam, the Netherlands
| | - Joost C M Meijers
- Amsterdam UMC Location University of Amsterdam, Department of Experimental Vascular Medicine, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, the Netherlands; Sanquin Research, Department of Molecular Hematology, Amsterdam, the Netherlands
| | - Rienk Nieuwland
- Amsterdam UMC Location University of Amsterdam, Laboratory of Experimental Clinical Chemistry, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Vesicle Observation Center, Amsterdam, the Netherlands
| | - Joris J T H Roelofs
- Amsterdam UMC Location University of Amsterdam, Department of Pathology, Amsterdam, the Netherlands
| | - Nicole P Juffermans
- Amsterdam UMC Location University of Amsterdam, Department of Intensive Care Medicine, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam, the Netherlands; Onze Lieve Vrouwe Gasthuis, Department of Intensive Care Medicine, Amsterdam, the Netherlands
| | - Derek J B Kleinveld
- Amsterdam UMC Location University of Amsterdam, Department of Intensive Care Medicine, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam, the Netherlands; Erasmus MC, Department of Anesthesiology, Rotterdam, the Netherlands.
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20
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Sepsis-Induced Coagulopathy: An Update on Pathophysiology, Biomarkers, and Current Guidelines. Life (Basel) 2023; 13:life13020350. [PMID: 36836706 PMCID: PMC9961497 DOI: 10.3390/life13020350] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/16/2023] [Accepted: 01/20/2023] [Indexed: 02/03/2023] Open
Abstract
Significant cross talk occurs between inflammation and coagulation. Thus, coagulopathy is common in sepsis, potentially aggravating the prognosis. Initially, septic patients tend to exhibit a prothrombotic state through extrinsic pathway activation, cytokine-induced coagulation amplification, anticoagulant pathways suppression, and fibrinolysis impairment. In late sepsis stages, with the establishment of disseminated intravascular coagulation (DIC), hypocoagulability ensues. Traditional laboratory findings of sepsis, including thrombocytopenia, increased prothrombin time (PT) and fibrin degradation products (FDPs), and decreased fibrinogen, only present late in the course of sepsis. A recently introduced definition of sepsis-induced coagulopathy (SIC) aims to identify patients at an earlier stage when changes to coagulation status are still reversible. Nonconventional assays, such as the measurement of anticoagulant proteins and nuclear material levels, and viscoelastic studies, have shown promising sensitivity and specificity in detecting patients at risk for DIC, allowing for timely therapeutic interventions. This review outlines current insights into the pathophysiological mechanisms and diagnostic options of SIC.
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21
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Coagulation Disorders in Sepsis and COVID-19-Two Sides of the Same Coin? A Review of Inflammation-Coagulation Crosstalk in Bacterial Sepsis and COVID-19. J Clin Med 2023; 12:jcm12020601. [PMID: 36675530 PMCID: PMC9866352 DOI: 10.3390/jcm12020601] [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: 11/22/2022] [Revised: 12/27/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Sepsis is a major cause of morbidity and mortality worldwide. Sepsis-associated coagulation disorders are involved in the pathogenesis of multiorgan failure and lead to a subsequently worsening prognosis. Alongside the global impact of the COVID-19 pandemic, a great number of research papers have focused on SARS-CoV-2 pathogenesis and treatment. Significant progress has been made in this regard and coagulation disturbances were once again found to underlie some of the most serious adverse outcomes of SARS-CoV-2 infection, such as acute lung injury and multiorgan dysfunction. In the attempt of untangling the mechanisms behind COVID-19-associated coagulopathy (CAC), a series of similarities with sepsis-induced coagulopathy (SIC) became apparent. Whether they are, in fact, the same disease has not been established yet. The clinical picture of CAC shows the unique feature of an initial phase of intravascular coagulation confined to the respiratory system. Only later on, patients can develop a clinically significant form of systemic coagulopathy, possibly with a consumptive pattern, but, unlike SIC, it is not a key feature. Deepening our understanding of CAC pathogenesis has to remain a major goal for the research community, in order to design and validate accurate definitions and classification criteria.
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22
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Zhao Z, Pan Z, Zhang S, Ma G, Zhang W, Song J, Wang Y, Kong L, Du G. Neutrophil extracellular traps: A novel target for the treatment of stroke. Pharmacol Ther 2023; 241:108328. [PMID: 36481433 DOI: 10.1016/j.pharmthera.2022.108328] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/30/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
Stroke is a threatening cerebrovascular disease caused by thrombus with high morbidity and mortality rates. Neutrophils are the first to be recruited in the brain after stroke, which aggravate brain injury through multiple mechanisms. Neutrophil extracellular traps (NETs), as a novel regulatory mechanism of neutrophils, can trap bacteria and secret antimicrobial molecules, thereby degrading pathogenic factors and killing bacteria. However, NETs also exacerbate certain non-infectious diseases by activating autoimmune or inflammatory responses. NETs have been found to play important roles in the pathological process of stroke in recent years. In this review, the mechanisms of NETs formation, the physiological roles of NETs, and the dynamic changes of NETs after stroke are summarized. NETs participate in stroke through various mechanisms. NETs promote the coagulation cascade and interact with platelets to induce thrombosis. tPA induces the degranulation of neutrophils to form NETs, leading to hemorrhagic transformation and thrombolytic resistance. NETs aggravate stroke by mediating inflammation, atherosclerosis and vascular injury. In addition, the regulation of NETs in stroke, the potential of NETs as biomarker and the treatment of stroke targeting NETs are discussed. The increasing evidences suggest that NETs may be a potential target for stroke treatment. Inhibition of NETs formation or promotion of NETs degradation plays protective effects in stroke. However, how to avoid the adverse effects of NETs-targeted therapy deserves further study. In summary, this review provides a reference for the pathogenesis, drug targets, biomarkers and drug development of NETs in stroke.
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Affiliation(s)
- Ziyuan Zhao
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Zirong Pan
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Sen Zhang
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Guodong Ma
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Wen Zhang
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Junke Song
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Yuehua Wang
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Linglei Kong
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
| | - Guanhua Du
- Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China.
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23
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Tonai K, Katayama S, Koyama K, Sata N, Tomioka Y, Imahase H, Nunomiya S. Association between hypomagnesemia and coagulopathy in sepsis: a retrospective observational study. BMC Anesthesiol 2022; 22:359. [PMID: 36424547 PMCID: PMC9685885 DOI: 10.1186/s12871-022-01903-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 11/11/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Hypomagnesemia reportedly has significant associations with poor clinical outcomes such as increased mortality and septic shock in patients with sepsis. Although the mechanism underlying these outcomes mostly remains unclear, some experimental data suggest that magnesium deficiency could potentiate coagulation activation in sepsis. However, in sepsis, the association between serum magnesium levels and coagulopathy, including disseminated intravascular coagulation (DIC), remains unknown. Thus, we aimed to investigate the relationship between serum magnesium levels and coagulation status and the association between hypomagnesemia and DIC in patients with sepsis. METHODS This retrospective observational study was conducted at the intensive care unit (ICU) of a university hospital from June 2011 to December 2017. Patients older than 19 years who met the Sepsis-3 definition were included. We categorized patients into three groups according to their serum magnesium levels: hypomagnesemia (< 1.6 mg/dL), normal serum magnesium level (1.6-2.4 mg/dL), and hypermagnesemia (> 2.4 mg/dL). We investigated the association between serum magnesium levels and overt DIC at the time of ICU admission according to the criteria of the International Society on Thrombosis and Haemostasis. RESULTS Among 753 patients included in this study, 181 had DIC, 105 had hypomagnesemia, 552 had normal serum magnesium levels, and 96 had hypermagnesemia. Patients with hypomagnesemia had a more activated coagulation status indicated by lower platelet counts, lower fibrinogen levels, higher prothrombin time-international normalized ratios, higher thrombin-antithrombin complex, and more frequent DIC than those with normal serum magnesium levels and hypermagnesemia (DIC: 41.9% vs. 20.6% vs. 24.0%, P < 0.001). The coagulation status in patients with hypomagnesemia was more augmented toward suppressed fibrinolysis than that in patients with normal serum magnesium levels and hypermagnesemia. Multivariate logistic regression revealed that hypomagnesemia was independently associated with DIC (odds ratio, 1.69; 95% confidence interval, 1.00-2.84; P = 0.048) after adjusting for several confounding variables. CONCLUSIONS Patients with hypomagnesemia had a significantly activated coagulation status and suppressed fibrinolysis. Hypomagnesemia was independently associated with DIC in patients with sepsis. Therefore, the treatment of hypomagnesemia may be a potential therapeutic strategy for the treatment of coagulopathy in sepsis.
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Affiliation(s)
- Ken Tonai
- grid.410804.90000000123090000Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
| | - Shinshu Katayama
- grid.410804.90000000123090000Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
| | - Kansuke Koyama
- grid.410804.90000000123090000Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
| | - Naho Sata
- grid.410804.90000000123090000Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
| | - Yoshihiro Tomioka
- grid.410804.90000000123090000Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
| | - Hisashi Imahase
- grid.410804.90000000123090000Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
| | - Shin Nunomiya
- grid.410804.90000000123090000Division of Intensive Care, Department of Anesthesiology and Intensive Care Medicine, Jichi Medical University School of Medicine, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498 Japan
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Bikomeye JC, Terwoord JD, Santos JH, Beyer AM. Emerging mitochondrial signaling mechanisms in cardio-oncology: beyond oxidative stress. Am J Physiol Heart Circ Physiol 2022; 323:H702-H720. [PMID: 35930448 PMCID: PMC9529263 DOI: 10.1152/ajpheart.00231.2022] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/29/2022] [Accepted: 07/29/2022] [Indexed: 12/27/2022]
Abstract
Many anticancer therapies (CTx) have cardiotoxic side effects that limit their therapeutic potential and cause long-term cardiovascular complications in cancer survivors. This has given rise to the field of cardio-oncology, which recognizes the need for basic, translational, and clinical research focused on understanding the complex signaling events that drive CTx-induced cardiovascular toxicity. Several CTx agents cause mitochondrial damage in the form of mitochondrial DNA deletions, mutations, and suppression of respiratory function and ATP production. In this review, we provide a brief overview of the cardiovascular complications of clinically used CTx agents and discuss current knowledge of local and systemic secondary signaling events that arise in response to mitochondrial stress/damage. Mitochondrial oxidative stress has long been recognized as a contributor to CTx-induced cardiotoxicity; thus, we focus on emerging roles for mitochondria in epigenetic regulation, innate immunity, and signaling via noncoding RNAs and mitochondrial hormones. Because data exploring mitochondrial secondary signaling in the context of cardio-oncology are limited, we also draw upon clinical and preclinical studies, which have examined these pathways in other relevant pathologies.
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Affiliation(s)
- Jean C Bikomeye
- Doctorate Program in Public and Community Health, Division of Epidemiology and Social Sciences, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Janée D Terwoord
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Biomedical Sciences Department, Rocky Vista University, Ivins, Utah
| | - Janine H Santos
- Mechanistic Toxicology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Andreas M Beyer
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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25
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Wang D, Ousaka D, Qiao H, Wang Z, Zhao K, Gao S, Liu K, Teshigawara K, Takada K, Nishibori M. Treatment of Marmoset Intracerebral Hemorrhage with Humanized Anti-HMGB1 mAb. Cells 2022; 11:cells11192970. [PMID: 36230933 PMCID: PMC9563572 DOI: 10.3390/cells11192970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/09/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is recognized as a severe clinical problem lacking effective treatment. High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity once released into the extracellular space from the nuclei. We previously demonstrated that intravenous injection of rat anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain injury in a rat ICH model. Therefore, we developed a humanized anti-HMGB1 mAb (OKY001) for clinical use. The present study examined whether and how the humanized anti-HMGB1 mAb ameliorates ICH injury in common marmosets. The results show that administration of humanized anti-HMGB1 mAb inhibited HMGB1 release from the brain into plasma, in association with a decrease of 4-hydroxynonenal (4-HNE) accumulation and a decrease in cerebral iron deposition. In addition, humanized anti-HMGB1 mAb treatment resulted in a reduction in brain injury volume at 12 d after ICH induction. Our in vitro experiment showed that recombinant HMGB1 inhibited hemoglobin uptake by macrophages through CD163 in the presence of haptoglobin, suggesting that the release of excess HMGB1 from the brain may induce a delay in hemoglobin scavenging, thereby allowing the toxic effects of hemoglobin, heme, and Fe2+ to persist. Finally, humanized anti-HMGB1 mAb reduced body weight loss and improved behavioral performance after ICH. Taken together, these results suggest that intravenous injection of humanized anti-HMGB1 mAb has potential as a novel therapeutic strategy for ICH.
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Affiliation(s)
- Dengli Wang
- Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
| | - Daiki Ousaka
- Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
| | - Handong Qiao
- Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
| | - Ziyi Wang
- Research Fellow of Japan Society for the Promotion of Science, Tokyo 1020083, Japan
- Department of Molecular Biology and Biochemistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
| | - Kun Zhao
- Department of Molecular Biology and Biochemistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
| | - Shangze Gao
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Keyue Liu
- Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
| | - Kiyoshi Teshigawara
- Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
| | - Kenzo Takada
- Sapporo Laboratory, EVEC, Inc., Sapporo 0606642, Japan
| | - Masahiro Nishibori
- Department of Translational Research and Drug Development, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
- Correspondence:
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26
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Terwoord JD, Beyer AM, Gutterman DD. Endothelial dysfunction as a complication of anti-cancer therapy. Pharmacol Ther 2022; 237:108116. [PMID: 35063569 PMCID: PMC9294076 DOI: 10.1016/j.pharmthera.2022.108116] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 12/16/2021] [Accepted: 01/12/2022] [Indexed: 12/14/2022]
Abstract
Recent strides in anti-cancer therapeutics have improved longevity and led to a growing population of cancer survivors, who are increasingly likely to die of other causes. Treatment-induced cardiotoxicity is a complication of several therapeutic agents with acute and long-term consequences for cancer patients. Vascular endothelial dysfunction is a precursor and hallmark of ischemic coronary disease and may play a role in anti-cancer therapy-induced cardiotoxicity. This review summarizes clinical evidence for endothelial dysfunction following anti-cancer therapy and extends the discussion to include the impact of therapeutic agents on conduit arteries and the microcirculation. We highlight the role of innate immune system activation and cross-talk between inflammation and oxidative stress as pathogenic mechanisms underlying anti-cancer therapy-induced vascular toxicity. Understanding the impact of anti-cancer agents on the vascular endothelium will inform therapeutic approaches to prevent or reverse treatment-induced cardiotoxicity and may serve as an important tool to predict, monitor, and prevent adverse cardiovascular outcomes in patients undergoing treatment.
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Affiliation(s)
- Janée D Terwoord
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States of America; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America.
| | - Andreas M Beyer
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States of America; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, United States of America
| | - David D Gutterman
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States of America; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, United States of America
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27
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Sloos PH, Vulliamy P, van 't Veer C, Gupta AS, Neal MD, Brohi K, Juffermans NP, Kleinveld DJB. Platelet dysfunction after trauma: From mechanisms to targeted treatment. Transfusion 2022; 62 Suppl 1:S281-S300. [PMID: 35748694 PMCID: PMC9546174 DOI: 10.1111/trf.16971] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Pieter H. Sloos
- Department of Intensive Care Medicine, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Paul Vulliamy
- Centre for Trauma Sciences, Blizard Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Cornelis van 't Veer
- Center for Experimental and Molecular Medicine, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Anirban Sen Gupta
- Department of Biomedical EngineeringCase Western Reserve UniversityClevelandOhioUSA
| | - Matthew D. Neal
- Pittsburgh Trauma and Transfusion Medicine Research Center and Division of Trauma and Acute Care SurgeryUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Karim Brohi
- Centre for Trauma Sciences, Blizard Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | - Nicole P. Juffermans
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Intensive Care MedicineOLVG HospitalAmsterdamThe Netherlands
| | - Derek J. B. Kleinveld
- Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
- Department of Intensive Care MedicineErasmus MCRotterdamThe Netherlands
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28
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Ebeyer-Masotta M, Eichhorn T, Weiss R, Lauková L, Weber V. Activated Platelets and Platelet-Derived Extracellular Vesicles Mediate COVID-19-Associated Immunothrombosis. Front Cell Dev Biol 2022; 10:914891. [PMID: 35874830 PMCID: PMC9299085 DOI: 10.3389/fcell.2022.914891] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/08/2022] [Indexed: 12/12/2022] Open
Abstract
Activated platelets and platelet-derived extracellular vesicles (EVs) have emerged as central players in thromboembolic complications associated with severe coronavirus disease 2019 (COVID-19). Platelets bridge hemostatic, inflammatory, and immune responses by their ability to sense pathogens via various pattern recognition receptors, and they respond to infection through a diverse repertoire of mechanisms. Dysregulated platelet activation, however, can lead to immunothrombosis, a simultaneous overactivation of blood coagulation and the innate immune response. Mediators released by activated platelets in response to infection, such as antimicrobial peptides, high mobility group box 1 protein, platelet factor 4 (PF4), and PF4+ extracellular vesicles promote neutrophil activation, resulting in the release of neutrophil extracellular traps and histones. Many of the factors released during platelet and neutrophil activation are positively charged and interact with endogenous heparan sulfate or exogenously administered heparin via electrostatic interactions or via specific binding sites. Here, we review the current state of knowledge regarding the involvement of platelets and platelet-derived EVs in the pathogenesis of immunothrombosis, and we discuss the potential of extracorporeal therapies using adsorbents functionalized with heparin to deplete platelet-derived and neutrophil-derived mediators of immunothrombosis.
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Affiliation(s)
- Marie Ebeyer-Masotta
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria
| | - Tanja Eichhorn
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria
| | - René Weiss
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria
| | - Lucia Lauková
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria
| | - Viktoria Weber
- Center for Biomedical Technology, Department for Biomedical Research, University for Continuing Education Krems, Krems, Austria
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29
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Block H, Rossaint J, Zarbock A. The Fatal Circle of NETs and NET-Associated DAMPs Contributing to Organ Dysfunction. Cells 2022; 11:1919. [PMID: 35741047 PMCID: PMC9222025 DOI: 10.3390/cells11121919] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/02/2022] [Accepted: 06/10/2022] [Indexed: 02/07/2023] Open
Abstract
The innate immune system is the first line of defense against invading pathogens or sterile injuries. Pattern recognition receptors (PRR) sense molecules released from inflamed or damaged cells, or foreign molecules resulting from invading pathogens. PRRs can in turn induce inflammatory responses, comprising the generation of cytokines or chemokines, which further induce immune cell recruitment. Neutrophils represent an essential factor in the early immune response and fulfill numerous tasks to fight infection or heal injuries. The release of neutrophil extracellular traps (NETs) is part of it and was originally attributed to the capture and elimination of pathogens. In the last decade studies revealed a detrimental role of NETs during several diseases, often correlated with an exaggerated immune response. Overwhelming inflammation in single organs can induce remote organ damage, thereby further perpetuating release of inflammatory molecules. Here, we review recent findings regarding damage-associated molecular patterns (DAMPs) which are able to induce NET formation, as well as NET components known to act as DAMPs, generating a putative fatal circle of inflammation contributing to organ damage and sequentially occurring remote organ injury.
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Affiliation(s)
| | | | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, 48149 Muenster, Germany; (H.B.); (J.R.)
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30
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Ding J, Song B, Xie X, Li X, Chen Z, Wang Z, Pan L, Lan D, Meng R. Inflammation in Cerebral Venous Thrombosis. Front Immunol 2022; 13:833490. [PMID: 35444662 PMCID: PMC9013750 DOI: 10.3389/fimmu.2022.833490] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 02/28/2022] [Indexed: 01/04/2023] Open
Abstract
Cerebral venous thrombosis (CVT) is a rare form of cerebrovascular disease that impairs people's wellbeing and quality of life. Inflammation is considered to play an important role in CVT initiation and progression. Several studies have reported the important role of leukocytes, proinflammatory cytokines, and adherence molecules in the CVT-related inflammatory process. Moreover, inflammatory factors exacerbate CVT-induced brain tissue injury leading to poor prognosis. Based on clinical observations, emerging evidence shows that peripheral blood inflammatory biomarkers-especially neutrophil-to-lymphocyte ratio (NLR) and lymphocyte count-are correlated with CVT [mean difference (MD) (95%CI), 0.74 (0.11, 1.38), p = 0.02 and -0.29 (-0.51, -0.06), p = 0.01, respectively]. Moreover, increased NLR and systemic immune-inflammation index (SII) portend poor patient outcomes. Evidence accumulated since the outbreak of coronavirus disease-19 (COVID-19) indicates that COVID-19 infection and COVID-19 vaccine can induce CVT through inflammatory reactions. Given the poor understanding of the association between inflammation and CVT, many conundrums remain unsolved. Further investigations are needed to elucidate the exact relationship between inflammation and CVT in the future.
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Affiliation(s)
- Jiayue Ding
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Baoying Song
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
| | - Xiran Xie
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
| | - Xaingyu Li
- Department of Neurology, Tianjin Huanhu Hospital, Tianjin, China
| | - Zhiying Chen
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
| | - Zhongao Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
| | - Liqun Pan
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
| | - Duo Lan
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Ran Meng
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
- Advanced Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
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31
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Kuroda H, Tatsumi H, Sonoda T, Masuda Y. A Suggested Link Between Antithrombin Dose and Rate of Recovery from Disseminated Intravascular Coagulation in Patients with Severe Organ Failure. Clin Appl Thromb Hemost 2022; 28:10760296221080942. [PMID: 35187966 PMCID: PMC8864266 DOI: 10.1177/10760296221080942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Introduction The efficacy of antithrombin (AT) supplementation against septic disseminated
intravascular coagulation (DIC) may depend on various pre-existing factors,
particularly the AT dose and multiple organ dysfunction severity. This study
aimed to identify the impactful factors for early DIC recovery. Methods Patients’ clinical records, including AT therapy and septic DIC data, were
retrospectively extracted from January 2015 to December 2020. The patients
were divided into those with early DIC recovery (n = 34) and those without
(n = 37). Multivariate logistic regression analysis determined significant
independent factors. Time-to-event analysis confirmed how these factors
affected the DIC recovery time. Results The AT dose per patient body weight (odds ratio [95% confidence interval]:
2.879 [1.031-8.042], P = 0.044) and pre-existing organ
dysfunction severity (0.333 [0.120-0.920], P = 0.034) were
significant independent factors affecting early DIC recovery. A higher AT
dose significantly shortened the DIC recovery time among patients with
severe organ dysfunction (P < 0.01), but not among
non-severe patients (P = 0.855). Conclusion The therapeutic efficacy of AT treatment for septic DIC might depend on the
severity of pre-existing organ failure and the AT dose per patient body
weight.
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Affiliation(s)
- Hiromitsu Kuroda
- Department of Intensive Care Medicine, 13035Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroomi Tatsumi
- Department of Intensive Care Medicine, 13035Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tomoko Sonoda
- Department of Public Health, 92187Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yoshiki Masuda
- Department of Intensive Care Medicine, 13035Sapporo Medical University School of Medicine, Sapporo, Japan
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Abd-Elhakim YM, Omran BHF, Ezzeldein SA, Ahmed AI, El-Sharkawy NI, Mohamed AAR. Time-dependent expression of high-mobility group box-1 and toll-like receptors proteins as potential determinants of skin wound age in rats: Forensic implication. Int J Legal Med 2022; 136:1781-1789. [PMID: 35132471 PMCID: PMC9576669 DOI: 10.1007/s00414-022-02788-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/21/2022] [Indexed: 12/03/2022]
Abstract
The skin wound age determination in living subjects is an imperative task for forensic experts. In this study, we investigated the time-dependent expression of high-mobility group box-1 (HMGB1) and toll-like receptors 2 and 4 (TLR2 and 4) in rat skin wounds using real-time PCR and seek their forensic potentials during the skin wound repair process. In addition, the levels of serum pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6)), as well as nitric oxide (NO) production, were measured. The wound tissue and serum samples were collected after 30 min, 2 h, 6 h, 12 h, 1 day, 3 days, 5 days, and 7 days after incision. As a control (zero time), skin specimens and blood samples were collected without incision. The results reveal that the HMGB1, TLR2, and TLR4 expression levels were increased in a time-dependent manner until the first day where the peak level was achieved for the three tested genes compared with the zero time. On the 7th day, the statistical significance was lost for TLR2 and TLR4 but persisted for HMGB1. The serum TNF-α, IL6, and NO levels peaked within 30 min and 1st and 3rd day after injury, respectively. On the 7th day after incision, no significant differences exist in the TNF-α serum level compared to the control group, but the statistical significance persisted for IL6 and NO. It was apparent that the analyzed genes in the wound tissues showed higher R2 values rather than the serum biochemical indicators. Of note, a strong positive correlation was evident between the HMGB1 and that of TLR2 and TLR4 relative expression as well as IL-6 serum level. Conclusively, based on the observed changes in the analyzed markers in wound tissues and serum and R2 values obtained from mathematical models established to determine the wound age, the relative expression of HMGB1, TLR2, and TLR4 could be a reliable indicator for wound age determination in living subjects. Further investigation of these markers and mathematical models in human tissues is necessary.
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Affiliation(s)
- Yasmina M Abd-Elhakim
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
| | - Bothina H F Omran
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt
| | - Shimaa A Ezzeldein
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Amany I Ahmed
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Nabela I El-Sharkawy
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Amany Abdel-Rahman Mohamed
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
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Ebeyer-Masotta M, Eichhorn T, Weiss R, Semak V, Lauková L, Fischer MB, Weber V. Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis, including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones. Int J Mol Sci 2022; 23:ijms23031823. [PMID: 35163743 PMCID: PMC8836755 DOI: 10.3390/ijms23031823] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/31/2022] [Accepted: 02/01/2022] [Indexed: 12/20/2022] Open
Abstract
Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents.
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Affiliation(s)
- Marie Ebeyer-Masotta
- Center for Biomedical Technology, Department for Biomedical Research, Danube University Krems, 3500 Krems, Austria; (M.E.-M.); (T.E.); (R.W.); (V.S.); (L.L.); (M.B.F.)
| | - Tanja Eichhorn
- Center for Biomedical Technology, Department for Biomedical Research, Danube University Krems, 3500 Krems, Austria; (M.E.-M.); (T.E.); (R.W.); (V.S.); (L.L.); (M.B.F.)
| | - René Weiss
- Center for Biomedical Technology, Department for Biomedical Research, Danube University Krems, 3500 Krems, Austria; (M.E.-M.); (T.E.); (R.W.); (V.S.); (L.L.); (M.B.F.)
| | - Vladislav Semak
- Center for Biomedical Technology, Department for Biomedical Research, Danube University Krems, 3500 Krems, Austria; (M.E.-M.); (T.E.); (R.W.); (V.S.); (L.L.); (M.B.F.)
| | - Lucia Lauková
- Center for Biomedical Technology, Department for Biomedical Research, Danube University Krems, 3500 Krems, Austria; (M.E.-M.); (T.E.); (R.W.); (V.S.); (L.L.); (M.B.F.)
| | - Michael B. Fischer
- Center for Biomedical Technology, Department for Biomedical Research, Danube University Krems, 3500 Krems, Austria; (M.E.-M.); (T.E.); (R.W.); (V.S.); (L.L.); (M.B.F.)
- Clinic for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Viktoria Weber
- Center for Biomedical Technology, Department for Biomedical Research, Danube University Krems, 3500 Krems, Austria; (M.E.-M.); (T.E.); (R.W.); (V.S.); (L.L.); (M.B.F.)
- Correspondence: ; Tel.: +43-2732-893-2601
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Tran HDN, Moonshi SS, Xu ZP, Ta HT. Influence of nanoparticles on the haemostatic balance: between thrombosis and haemorrhage. Biomater Sci 2021; 10:10-50. [PMID: 34775503 DOI: 10.1039/d1bm01351c] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Maintenance of a delicate haemostatic balance or a balance between clotting and bleeding is critical to human health. Irrespective of administration route, nanoparticles can reach the bloodstream and might interrupt the haemostatic balance by interfering with one or more components of the coagulation, anticoagulation, and fibrinolytic systems, which potentially lead to thrombosis or haemorrhage. However, inadequate understanding of their effects on the haemostatic balance, along with the fact that most studies mainly focus on the functionality of nanoparticles while forgetting or leaving behind their risk to the body's haemostatic balance, is a major concern. Hence, our review aims to provide a comprehensive depiction of nanoparticle-haemostatic balance interactions, which has not yet been covered. The synergistic roles of cells and plasma factors participating in haemostatic balance are presented. Possible interactions and interference of each type of nanoparticle with the haemostatic balance are comprehensively discussed, particularly focusing on the underlying mechanisms. Interactions of nanoparticles with innate immunity potentially linked to haemostasis are mentioned. Various physicochemical characteristics that influence the nanoparticle-haemostatic balance are detailed. Challenges and future directions are also proposed. This insight would be valuable for the establishment of nanoparticles that can either avoid unintended interference with the haemostatic balance or purposely downregulate/upregulate its key components in a controlled manner.
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Affiliation(s)
- Huong D N Tran
- Queensland Micro- and Nanotechnology, Griffith University, Nathan, Queensland 4111, Australia. .,Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland 4072, Australia
| | | | - Zhi Ping Xu
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland 4072, Australia
| | - Hang Thu Ta
- Queensland Micro- and Nanotechnology, Griffith University, Nathan, Queensland 4111, Australia. .,Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St Lucia, Queensland 4072, Australia.,School of Environment and Science, Griffith University, Nathan, Queensland 4111, Australia
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Giallauria F, Strisciuglio T, Cuomo G, Di Lorenzo A, D'Angelo A, Volpicelli M, Izzo R, Manzi MV, Barbato E, Morisco C. Exercise Training: The Holistic Approach in Cardiovascular Prevention. High Blood Press Cardiovasc Prev 2021; 28:561-577. [PMID: 34724167 PMCID: PMC8590648 DOI: 10.1007/s40292-021-00482-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 10/23/2021] [Indexed: 12/26/2022] Open
Abstract
Nowadays, there are robust clinical and pathophysiological evidence supporting the beneficial effects of physical activity on cardiovascular (CV) system. Thus, the physical activity is considered a key strategy for CV prevention. In fact, exercise training exerts favourable effects on all risk factors for CV diseases (i.e. essential hypertension, type 2 diabetes mellitus, hypercholesterolemia, obesity, metabolic syndrome, etc…). In addition, all training modalities such as the aerobic (continuous walking, jogging, cycling, etc.) or resistance exercise (weights), as well as the leisure-time physical activity (recreational walking, gardening, etc) prevent the development of the major CV risk factors, or delay the progression of target organ damage improving cardio-metabolic risk. Exercise training is also the core component of all cardiac rehabilitation programs that have demonstrated to improve the quality of life and to reduce morbidity in patients with CV diseases, mostly in patients with coronary artery diseases. Finally, it is still debated whether or not exercise training can influence the occurrence of atrial and ventricular arrhythmias. In this regard, there is some evidence that exercise training is protective predominantly for atrial arrhythmias, reducing the incidence of atrial fibrillation. In conclusion, the salutary effects evoked by physical acitvity are useful in primary and secondary CV prevention.
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Affiliation(s)
- Francesco Giallauria
- Department of Translational Medical Sciences, "Federico II" University of Naples, 80131, Naples, Italy
| | - Teresa Strisciuglio
- Department of Advanced Biomedical Sciences, "Federico II" University of Naples, 80131, Naples, Italy
| | - Gianluigi Cuomo
- Department of Translational Medical Sciences, "Federico II" University of Naples, 80131, Naples, Italy
| | - Anna Di Lorenzo
- Department of Translational Medical Sciences, "Federico II" University of Naples, 80131, Naples, Italy
| | - Andrea D'Angelo
- Department of Translational Medical Sciences, "Federico II" University of Naples, 80131, Naples, Italy
| | - Mario Volpicelli
- Department of Cardiology, "Santa Maria della Pietà" Hospital (ASL Napoli 3 Sud), 80035, Nola, NA, Italy
| | - Raffaele Izzo
- Department of Advanced Biomedical Sciences, "Federico II" University of Naples, 80131, Naples, Italy
| | - Maria Virginia Manzi
- Department of Advanced Biomedical Sciences, "Federico II" University of Naples, 80131, Naples, Italy
| | - Emanuele Barbato
- Department of Advanced Biomedical Sciences, "Federico II" University of Naples, 80131, Naples, Italy
| | - Carmine Morisco
- Department of Advanced Biomedical Sciences, "Federico II" University of Naples, 80131, Naples, Italy.
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Miao L, Zhang Z, Ren Z, Li Y. Reactions Related to CAR-T Cell Therapy. Front Immunol 2021; 12:663201. [PMID: 33995389 PMCID: PMC8113953 DOI: 10.3389/fimmu.2021.663201] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/13/2021] [Indexed: 12/11/2022] Open
Abstract
The application of chimeric antigen receptor (CAR) T-cell therapy as a tumor immunotherapy has received great interest in recent years. This therapeutic approach has been used to treat hematological malignancies solid tumors. However, it is associated with adverse reactions such as, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), off-target effects, anaphylaxis, infections associated with CAR-T-cell infusion (CTI), tumor lysis syndrome (TLS), B-cell dysplasia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) and coagulation disorders. These adverse reactions can be life-threatening, and thus they should be identified early and treated effectively. In this paper, we review the adverse reactions associated with CAR-T cells, the mechanisms driving such adverse reactions, and strategies to subvert them. This review will provide important reference data to guide clinical application of CAR-T cell therapy.
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Affiliation(s)
- Lele Miao
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhengchao Zhang
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Zhijian Ren
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Yumin Li
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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High-mobility Group Box 1 Protein in Pediatric Trauma Patients With Acute Traumatic Coagulopathy or Disseminated Intravascular Coagulation. J Pediatr Hematol Oncol 2020; 42:e712-e717. [PMID: 32218095 DOI: 10.1097/mph.0000000000001788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Trauma can induce the release of high-mobility group box 1 (HMGB1), which plays an important role in the activation of coagulation. In this study, we aimed to evaluate the role of HMGB1 in the early diagnosis of acute traumatic coagulopathy (ATC), disseminated intravascular coagulation, and clinical course. MATERIALS AND METHODS One hundred pediatric trauma patients and 50 healthy controls were enrolled. Demographic data, physical examination results, trauma scores, International Society on Thrombosis and Hemostasis score, laboratory values, transfusion requirements, and needs for mechanical ventilation were recorded. Blood samples for HMGB1 were assessed by an enzyme-linked immunosorbent assay. RESULTS Thirty-five patients had ATC and 3 patients had overt disseminated intravascular coagulation. In trauma patients, HMGB1 levels were statistically higher than those in the control group (P<0.001). There was a positive correlation between HMGB1 levels and D-dimer levels (r=0.589, P<0.001). ATC patients had higher plasma HMGB1 levels than those without ATC (P=0.008). High HMGB1 levels were associated with the duration of mechanical ventilation, need for intensive care unit observation, length of hospital stay, and mortality. CONCLUSION This study showed the early increase of HMGB1 in pediatric trauma cases and demonstrated the significant association of high HMGB1 levels with the development of ATC, disseminated intravascular coagulation, trauma severity, clinical outcome, and mortality.
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Rodrigues AT, Rodrigues JT, Rodrigues CT, Volpe CMDO, Rocha-Silva F, Nogueira-Machado JA, Alberti LR. Association between thrombomodulin and high mobility group box 1 in sepsis patients. World J Crit Care Med 2020; 9:63-73. [PMID: 33134112 PMCID: PMC7579433 DOI: 10.5492/wjccm.v9.i4.63] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/31/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND High mobility group box 1 (HMGB1) has been studied as a molecule associated with severe outcomes in sepsis and thrombomodulin (TM) seems to decrease HMGB1 activity. AIM To investigate the role of the thrombomodulin/high mobility group box 1 (T/H) ratio in patients with sepsis and their association with their clinic, testing the hypothesis that higher ratios are associated with better outcomes. METHODS Twenty patients diagnosed with sepsis or septic shock, according to the 2016 criteria sepsis and septic shock (Sepsis-3), were studied. Patients were followed until they left the intensive care unit or until they achieved 28 d of hospitalization (D28). The following clinical outcomes were observed: Sequential Organ Failure Assessment (SOFA) score; Need for mechanical pulmonary ventilation; Presence of septic shock; Occurrence of sepsis-induced coagulopathy; Need for renal replacement therapy (RRT); and Death. RESULTS The results showed that patients with SOFA scores greater than or equal to 12 points had higher serum levels of TM: 76.41 ± 29.21 pg/mL vs 37.41 ± 22.55 pg/mL among those whose SOFA scores were less than 12 points, P = 0.003. The T/H ratio was also higher in patients whose SOFA scores were greater than or equal to 12 points, P = 0.001. The T/H ratio was, on average, three times higher in patients in need of RRT (0.38 ± 0.14 vs 0.11 ± 0.09), P < 0.001. CONCLUSION Higher serum levels of TM and, therefore, higher T/H ratio in the first 24 h after the diagnosis of sepsis were associated with more severe disease and the need for renal replacement therapy, while those with better clinical outcomes and those who were discharged before D28 showed a tendency for lower T/H ratio values.
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Affiliation(s)
- Adriana Teixeira Rodrigues
- Department of Pediatrics, School of Medicine, Federal University of Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil
- Graduation Program in Medicine/Biomedicine - Santa Casa Hospital - Education and Research, Belo Horizonte 30150-240, Minas Gerais, Brazil
| | - Julia Teixeira Rodrigues
- Department of Pharmacy, Federal University of Minas Gerais, Belo Horizonte 31270-901, Minas Gerais, Brazil
| | | | - Caroline Maria de Oliveira Volpe
- Department of Immunology, Graduation Program in Medicine/Biomedicine - Santa Casa Hospital - Education and Research, Belo Horizonte 30150-240, Minas Gerais, Brazil
| | - Fabiana Rocha-Silva
- Clinical Laboratory, Graduation Program in Medicine/Biomedicine - Santa Casa Hospital - Education and Research, Belo Horizonte 30150-240, Minas Gerais, Brazil
| | - Jose Augusto Nogueira-Machado
- Department of Immunology, Graduation Program in Medicine/Biomedicine - Santa Casa Hospital - Education and Research, Belo Horizonte 30150-240, Minas Gerais, Brazil
| | - Luiz Ronaldo Alberti
- Graduation Program in Medicine/Biomedicine - Santa Casa Hospital - Education and Research, Belo Horizonte 30150-240, Minas Gerais, Brazil
- Department of Surgery, School of Medicine, Federal University of Minas Gerais, Belo Horizonte 30220-000, Minas Gerais, Brazil
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Lin XJ, Liu R, Li C, Yi X, Fu B, Walker MJ, Xu XM, Sun G, Lin CH. Melatonin ameliorates spatial memory and motor deficits via preserving the integrity of cortical and hippocampal dendritic spine morphology in mice with neurotrauma. Inflammopharmacology 2020; 28:1553-1566. [PMID: 32959092 DOI: 10.1007/s10787-020-00750-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 08/28/2020] [Indexed: 01/20/2023]
Abstract
We aimed to elucidate the role of cortical and hippocampal dendritic spines on neurological deficits associated with hippocampal microgliosis, hippocampal neurogenesis, and neuroinflammation in mice with cortical compact impact (CCI) injury. In the present study, we found that CCI reduced spatial memory mean latency (10 s. vs 50 s) and motor dysfunction (130 s. vs 150 s.) in mice, as determined by Morris water maze and rotarod test, respectively. Golgi staining of cortical pyramidal neurons revealed that, compared to the controls, the CCI group treated with vehicle solution had significantly lower values of dendritic order (or dendritic branch number) (4.0 vs 6.2), total spine length (400 μm vs 620 μm) and spine density (40 spines/μm vs 60 spines/μm), but had significantly higher values of dendritic beading (40 beadings/mm vs 20 beadings/mm). Additionally, Sholl analysis showed that, compared to controls, the CCI + NS group mice had significantly lower values of dendritic intersections (1.0 vs 2.0). Immunofluorescence assay also revealed that, compared to controls, the CCI + NS group mice had significantly higher values of the newly formed hippocampal cells (1250/mm2 vs 1000/mm2) but significantly lower values of dendritic order (2.0 branch # vs 4.2 branch #), total spine length (180 μm vs 320 μm) and intersection (1.0 vs 3.0). The CCI + NS group mice further showed significantly higher numbers of microglia in the dentate gyrus of the hippocampus and higher concentrations of pro-inflammatory cytokines in the cerebrospinal fluids. All the CCI-induced spatial memory (40 s) and motor (150 s) dysfunction, deranged dendritic and spine morphology of cortical pyramidal neurons or hippocampal newly formed cells, hippocampal microgliosis, and central neuroinflammation were all significantly reduced by melatonin administration during post-CCI. Simultaneously, melatonin therapy caused an enhancement in the compensatory hippocampal neurogenesis and neurotrophic growth factors (e.g., doublecortin-1) and compensatory central anti-inflammatory cytokines. Our results indicate that melatonin attenuates the spatial memory and motor deficits via the modification of cortical and hippocampal dendritic spine morphology, hippocampal microgliosis and neurogenesis, and neuroinflammation in mice with traumatic brain injury.
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Affiliation(s)
- Xiao-Jing Lin
- Department of Spinal Cord Injury and Repair, Trauma and Orthopedics Institute of Chinese PLA, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong, People's Republic of China
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, People's Republic of China
| | - Ruoxu Liu
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, People's Republic of China
| | - Chenyi Li
- Department of Spinal Cord Injury and Repair, Trauma and Orthopedics Institute of Chinese PLA, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong, People's Republic of China
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, People's Republic of China
| | - Xueqing Yi
- Department of Medical Imaging, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong, People's Republic of China
| | - Bo Fu
- Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, People's Republic of China
| | - M J Walker
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, USA
- Goodman and Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, USA
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, USA
| | - Xiao-Ming Xu
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA
- Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, USA
- Goodman and Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, USA
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, USA
| | - Gang Sun
- Department of Medical Imaging, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong, People's Republic of China.
| | - Cheng-Hsien Lin
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.
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Ikezoe T. Advances in the diagnosis and treatment of disseminated intravascular coagulation in haematological malignancies. Int J Hematol 2020; 113:34-44. [PMID: 32902759 DOI: 10.1007/s12185-020-02992-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/22/2020] [Accepted: 08/28/2020] [Indexed: 11/26/2022]
Abstract
Haematological malignancies, including acute leukaemia and non-Hodgkin lymphoma, are one of the underlying diseases that frequently cause disseminated intravascular coagulation (DIC), an acquired thrombotic disorder. Concomitant DIC is associated with the severity of the underlying disease and poor prognosis. The Japanese Society on Thrombosis and Hemostasis released the new DIC diagnostic criteria in 2017. This criteria include coagulation markers such as soluble fibrin and the thrombin-antithrombin complex to more accurately evaluate the hypercoagulable state in patients. Among several groups of anticoagulants available, recombinant human soluble thrombomodulin is most frequently used to treat DIC caused by haematological malignancies in Japan. DIC is remitted in parallel with the improvement of the underlying haematological diseases; thus, there is room for debate regarding whether the treatment of DIC would improve the prognosis of patients. Haematopoietic stem cell transplantation as well as the recently introduced chimeric antigen receptor (CAR)-T-cell therapy are innovative therapies to produce a cure in a subset of patients with haematological malignancies. However, coagulopathy frequently occurs after these therapies, which limits the success of the treatment. For example, DIC is noted in approximately 50% of patients after CAT-T-cell therapy in conjunction with cytokine release syndrome. Hematopoietic stem cell transplantation (HSCT) causes endotheliitis, which triggers coagulopathy and the development of potentially lethal complications, such as sinusoidal obstruction syndrome/veno-occlusive disease and transplant-associated thrombotic microangiopathy. This review article describes the pathogenesis, clinical manifestation, diagnosis, and treatment of DIC caused by haematological malignancies, CAR-T-cell therapy, and HSCT.
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Affiliation(s)
- Takayuki Ikezoe
- Department of Haematology, Fukushima Medical University, Fukushima, 960-1295, Japan.
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Vijayakumar EC, Bhatt LK, Prabhavalkar KS. High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics. Curr Drug Targets 2020; 20:1474-1485. [PMID: 31215389 DOI: 10.2174/1389450120666190618125100] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 05/29/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023]
Abstract
High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.
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Affiliation(s)
- Eyaldeva C Vijayakumar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Lokesh Kumar Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
| | - Kedar S Prabhavalkar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai, India
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Zhao Z, Hu Z, Zeng R, Yao Y. HMGB1 in kidney diseases. Life Sci 2020; 259:118203. [PMID: 32781069 DOI: 10.1016/j.lfs.2020.118203] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/31/2020] [Accepted: 08/01/2020] [Indexed: 12/20/2022]
Abstract
High mobility group box 1 (HMGB1) is a highly conserved nucleoprotein involving in numerous biological processes, and well known to trigger immune responses as the damage-associated molecular pattern (DAMP) in the extracellular environment. The role of HMGB1 is distinct due to its multiple functions in different subcellular location. In the nucleus, HMGB1 acts as a chaperone to regulate DNA events including DNA replication, repair and nucleosome stability. While in the cytoplasm, it is engaged in regulating autophagy and apoptosis. A great deal of research has explored its function in the pathogenesis of renal diseases. This review mainly focuses on the role of HMGB1 and summarizes the pathway and treatment targeting HMGB1 in the various renal diseases which may open the windows of opportunities for the development of desirable therapeutic ends in these pathological conditions.
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Affiliation(s)
- Zhi Zhao
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China
| | - Zhizhi Hu
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China
| | - Rui Zeng
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China.
| | - Ying Yao
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, China.
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Kim SW, Lee JK. Role of HMGB1 in the Interplay between NETosis and Thrombosis in Ischemic Stroke: A Review. Cells 2020; 9:cells9081794. [PMID: 32731558 PMCID: PMC7464684 DOI: 10.3390/cells9081794] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/24/2020] [Accepted: 07/25/2020] [Indexed: 12/17/2022] Open
Abstract
Neutrophil extracellular traps (NETs) comprise decondensed chromatin, histones and neutrophil granular proteins and are involved in the response to infectious as well as non-infectious diseases. The prothrombotic activity of NETs has been reported in various thrombus-related diseases; this activity can be attributed to the fact that the NETs serve as a scaffold for cells and numerous coagulation factors and stimulate fibrin deposition. A crosstalk between NETs and thrombosis has been indicated to play a role in numerous thrombosis-related conditions including stroke. In cerebral ischemia, neutrophils are the first group of cells to infiltrate the damaged brain tissue, where they produce NETs in the brain parenchyma and within blood vessels, thereby aggravating inflammation. Increasing evidences suggest the connection between NETosis and thrombosis as a possible cause of “tPA resistance”, a problem encountered during the treatment of stroke patients. Several damage-associated molecular pattern molecules have been proven to induce NETosis and thrombosis, with high mobility group box 1 (HMGB1) playing a critical role. This review discusses NETosis and thrombosis and their crosstalk in various thrombosis-related diseases, focusing on the role of HMGB1 as a mediator in stroke. We also addresses the function of peptidylarginine deiminase 4 with respect to the interplay with HMGB1 in NET-induced thrombosis.
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Affiliation(s)
- Seung-Woo Kim
- Department of Biomedical Sciences, Inha University School of Medicine, Inchon 22212, Korea;
- Medical Research Center, Inha University School of Medicine, Inchon 22212, Korea
| | - Ja-Kyeong Lee
- Medical Research Center, Inha University School of Medicine, Inchon 22212, Korea
- Department of Anatomy, Inha University School of Medicine, Inchon 22212, Korea
- Correspondence: ; Tel.: +82-32-860-9893; Fax: +82-32-884-2105
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Effects of Circulating HMGB-1 and Histones on Cardiomyocytes-Hemadsorption of These DAMPs as Therapeutic Strategy after Multiple Trauma. J Clin Med 2020; 9:jcm9051421. [PMID: 32403440 PMCID: PMC7291040 DOI: 10.3390/jcm9051421] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/29/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Background and purpose: The aim of the study was to determine the effects of post-traumatically released High Mobility Group Box-1 protein (HMGB1) and extracellular histones on cardiomyocytes (CM). We also evaluated a therapeutic option to capture circulating histones after trauma, using a hemadsorption filter to treat CM dysfunction. Experimental Approach: We evaluated cell viability, calcium handling and mitochondrial respiration of human cardiomyocytes in the presence of HMGB-1 and extracellular histones. In a translational approach, a hemadsorption filter was applied to either directly eliminate extracellular histones or to remove them from blood samples obtained from multiple injured patients. Key results: Incubation of human CM with HMGB-1 or histones is associated with changes in calcium handling, a reduction of cell viability and a substantial reduction of the mitochondrial respiratory capacity. Filtrating plasma from injured patients with a hemadsorption filter reduces histone concentration ex vivo and in vitro, depending on dosage. Conclusion and implications: Danger associated molecular patterns such as HMGB-1 and extracellular histones impair human CM in vitro. A hemadsorption filter could be a therapeutic option to reduce high concentrations of histones.
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Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia. Int J Hematol 2019; 111:378-387. [PMID: 31848990 DOI: 10.1007/s12185-019-02798-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 12/05/2019] [Accepted: 12/06/2019] [Indexed: 10/25/2022]
Abstract
Intranuclear proteins, including high mobility group box 1 (HMGB1) and histone H3, released from inflammatory cells activate platelets and the coagulation systems, leading to development of disseminated intravascular coagulation (DIC) in individuals with sepsis. These observations prompted us to hypothesize that HMGB1 and histone H3 liberated from leukemia cells undergoing apoptosis after chemotherapy might play a role in development of DIC. To test this hypothesis, we prospectively measured plasma levels of coagulation markers and intranuclear proteins in patients with newly diagnosed acute leukemia (n = 17) before and after chemotherapy. Ten of 17 patients were diagnosed with DIC at the time of diagnosis of leukemia. Serum levels of HMGB1 and histone H3 were significantly higher in patients with DIC than in non-DIC patients. Of note, seven patients developed DIC or experienced exacerbation of coagulopathy after administration of anti-leukemic agents. Intriguingly, an increase in levels of HMGB1 and histone H3 were detected in five of seven patients. These findings suggest that intranuclear proteins spontaneously released from leukemia cells may play a role in development of leukemia-related DIC. Additionally, remission induction chemotherapy causes apoptosis of leukemia cells, leading to forced release of intranuclear proteins, which may exacerbate coagulopathy.
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Eppensteiner J, Kwun J, Scheuermann U, Barbas A, Limkakeng AT, Kuchibhatla M, Elster EA, Kirk AD, Lee J. Damage- and pathogen-associated molecular patterns play differential roles in late mortality after critical illness. JCI Insight 2019; 4:127925. [PMID: 31434802 DOI: 10.1172/jci.insight.127925] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 07/26/2019] [Indexed: 12/17/2022] Open
Abstract
Multiple organ failure (MOF) is the leading cause of late mortality and morbidity in patients who are admitted to intensive care units (ICUs). However, there is an epidemiologic discrepancy in the mechanism of underlying immunologic derangement dependent on etiology between sepsis and trauma patients in MOF. We hypothesized that damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), while both involved in the development of MOF, contribute differently to the systemic innate immune derangement and coagulopathic changes. We found that DAMPs not only produce weaker innate immune activation than counterpart PAMPs, but also induce less TLR signal desensitization, contribute to less innate immune cell death, and propagate more robust systemic coagulopathic effects than PAMPs. This differential contribution to MOF provides further insight into the contributing factors to late mortality in critically ill trauma and sepsis patients. These findings will help to better prognosticate patients at risk of MOF and may provide future therapeutic molecular targets in this disease process.
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Affiliation(s)
- John Eppensteiner
- Department of Surgery and.,Division of Emergency Medicine, Duke University, Durham, North Carolina, USA.,Surgical Critical Care Initiative (SC2i), Bethesda, Maryland, USA
| | | | | | | | - Alexander T Limkakeng
- Department of Surgery and.,Division of Emergency Medicine, Duke University, Durham, North Carolina, USA.,Surgical Critical Care Initiative (SC2i), Bethesda, Maryland, USA
| | - Maggie Kuchibhatla
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, USA
| | - Eric A Elster
- Surgical Critical Care Initiative (SC2i), Bethesda, Maryland, USA.,Department of Surgery, Uniformed Services University of Health Sciences and Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Allan D Kirk
- Department of Surgery and.,Surgical Critical Care Initiative (SC2i), Bethesda, Maryland, USA
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Umit EG, Baysal M, Bas V, Goze H, Asoglu V, Kirkizlar O, Demir AM. Value of Extracellular High Mobility Group Box 1 (HMGB1) in the Clinical Context of Immune Thrombocytopenia. JOURNAL OF CLINICAL AND EXPERIMENTAL INVESTIGATIONS 2019. [DOI: 10.5799/jcei/5833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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48
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Therapeutic Role of Recombinant Human Soluble Thrombomodulin for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. ACTA ACUST UNITED AC 2019; 55:medicina55050172. [PMID: 31137593 PMCID: PMC6571552 DOI: 10.3390/medicina55050172] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/11/2019] [Accepted: 05/15/2019] [Indexed: 12/24/2022]
Abstract
Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an acute respiratory worsening of unidentifiable cause that sometimes develops during the clinical course of IPF. Although the incidence of AE-IPF is not high, prognosis is poor. The pathogenesis of AE-IPF is not well understood; however, evidence suggests that coagulation abnormalities and inflammation are involved. Thrombomodulin is a transmembranous glycoprotein found on the cell surface of vascular endothelial cells. Thrombomodulin combines with thrombin, regulates coagulation/fibrinolysis balance, and has a pivotal role in suppressing excess inflammation through its inhibition of high-mobility group box 1 protein and the complement system. Thus, thrombomodulin might be effective in the treatment of AE-IPF, and we and other groups found that recombinant human soluble thrombomodulin improved survival in patients with AE-IPF. This review summarizes the existing evidence and considers the therapeutic role of thrombomodulin in AE-IPF.
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Biguetti CC, Cavalla F, Silveira EV, Tabanez AP, Francisconi CF, Taga R, Campanelli AP, Trombone APF, Rodrigues DC, Garlet GP. HGMB1 and RAGE as Essential Components of Ti Osseointegration Process in Mice. Front Immunol 2019; 10:709. [PMID: 31024546 PMCID: PMC6461067 DOI: 10.3389/fimmu.2019.00709] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/15/2019] [Indexed: 12/31/2022] Open
Abstract
The release of the prototypic DAMP High Mobility Group Box 1 (HMGB1) into extracellular environment and its binding to the Receptor for Advanced Glycation End Products (RAGE) has been described to trigger sterile inflammation and regulate healing outcome. However, their role on host response to Ti-based biomaterials and in the subsequent osseointegration remains unexplored. In this study, HMGB1 and RAGE inhibition in the Ti-mediated osseointegration were investigated in C57Bl/6 mice. C57Bl/6 mice received a Ti-device implantation (Ti-screw in the edentulous alveolar crest and a Ti-disc in the subcutaneous tissue) and were evaluated by microscopic (microCT [bone] and histology [bone and subcutaneous]) and molecular methods (ELISA, PCR array) during 3, 7, 14, and 21 days. Mice were divided into 4 groups: Control (no treatment); GZA (IP injection of Glycyrrhizic Acid for HMGB1 inhibition, 4 mg/Kg/day); RAP (IP injection of RAGE Antagonistic Peptide, 4 mg/Kg/day), and vehicle controls (1.5% DMSO solution for GZA and 0.9% saline solution for RAP); treatments were given at all experimental time points, starting 1 day before surgeries. HMGB1 was detected in the Ti-implantation sites, adsorbed to the screws/discs. In Control and vehicle groups, osseointegration was characterized by a slight inflammatory response at early time points, followed by a gradual bone apposition and matrix maturation at late time points. The inhibition of HMGB1 or RAGE impaired the osseointegration, affecting the dynamics of mineralized and organic bone matrix, and resulting in a foreign body reaction, with persistence of macrophages, necrotic bone, and foreign body giant cells until later time points. While Control samples were characterized by a balance between M1 and M2-type response in bone and subcutaneous sites of implantation, and also MSC markers, the inhibition of HMGB1 or RAGE caused a higher expression M1 markers and pro-inflammatory cytokines, as well chemokines and receptors for macrophage migration until later time points. In conclusion, HMGB1 and RAGE have a marked role in the osseointegration, evidenced by their influence on host inflammatory immune response, which includes macrophages migration and M1/M2 response, MSC markers expression, which collectively modulate bone matrix deposition and osseointegration outcome.
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Affiliation(s)
- Claudia Cristina Biguetti
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Franco Cavalla
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil.,Department of Conservative Dentistry, School of Dentistry, University of Chile, Santiago, Chile
| | - Elcia Varize Silveira
- Department of Biological and Allied Health Sciences, Universidade Sagrado Coração, Bauru, Brazil
| | - André Petenuci Tabanez
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil
| | | | - Rumio Taga
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Ana Paula Campanelli
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil
| | | | - Danieli C Rodrigues
- Department of Bioengineering, University of Texas at Dallas, Dallas, TX, United States
| | - Gustavo Pompermaier Garlet
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, São Paulo, Brazil
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Walborn A, Rondina M, Mosier M, Fareed J, Hoppensteadt D. Endothelial Dysfunction Is Associated with Mortality and Severity of Coagulopathy in Patients with Sepsis and Disseminated Intravascular Coagulation. Clin Appl Thromb Hemost 2019; 25:1076029619852163. [PMID: 31140293 PMCID: PMC6714948 DOI: 10.1177/1076029619852163] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 04/25/2019] [Accepted: 04/26/2019] [Indexed: 01/08/2023] Open
Abstract
The role of the endothelium in sepsis-associated disseminated intravascular coagulation (DIC) is multifaceted and may contribute substantially to disease severity and outcome. The purpose of this study was to quantify measures of endothelial function, including markers of activation (endocan, Angiopoietin-2 [Ang-2], and von Willebrand Factor), endogenous anticoagulants (tissue factor pathway inhibitor and protein C), and damage-associated factors (High Mobility Group Box 1 [HMGB-1]) in the plasma of patients with sepsis and DIC, and to determine the relationship of these factors with severity of illness and outcome. Plasma samples were collected from 103 adult patients with sepsis within 48 hours of intensive care unit admission. Biomarker levels were measured using commercially available, standardized methods. Disseminated intravascular coagulation was diagnosed according to the International Society of Thrombosis and Hemostasis scoring algorithm. Twenty-eight-day mortality was used as the primary end point. In this study, endothelial damage and dysfunction were associated with the severity of coagulopathy and mortality in DIC patients. Loss of the endogenous anticoagulant protein C and elevation in the vascular regulator Ang-2 were associated with the development of overt DIC. In addition to Ang-2 and protein C, endocan, a biomarker of endothelial activation, and HMGB-1, a mediator of endothelial damage and activation, were significantly associated with mortality. This underscores the contribution of the endothelium to the pathogenesis of sepsis-associated DIC.
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Affiliation(s)
- Amanda Walborn
- Departments of Pathology and Pharmacology, Loyola University Medical Center, Maywood, IL, USA
| | - Matthew Rondina
- Department of Internal Medicine and the Molecular Medicine Program, University of Utah and the GRECC, George E. Wahlen VAMC, Salt Lake City, UT, USA
| | - Michael Mosier
- General Surgery, The Oregon Clinic, Surgical and Burn Specialists at Emanuel, Portland, OR, USA
| | - Jawed Fareed
- Departments of Pathology and Pharmacology, Loyola University Medical Center, Maywood, IL, USA
| | - Debra Hoppensteadt
- Departments of Pathology and Pharmacology, Loyola University Medical Center, Maywood, IL, USA
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