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Wang Y, Zhang Z, Qu X, Zhou G. Role of the endothelial cell glycocalyx in sepsis-induced acute kidney injury. Front Med (Lausanne) 2025; 12:1535673. [PMID: 40255592 PMCID: PMC12006053 DOI: 10.3389/fmed.2025.1535673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/25/2025] [Indexed: 04/22/2025] Open
Abstract
Sepsis-induced acute kidney injury (S-AKI) is a common complication of sepsis. It occurs at high incidence and is associated with a high level of mortality in the intensive care unit (ICU). The pathophysiologic mechanisms underlying S-AKI are complex, and include renal vascular endothelial cell dysfunction. The endothelial glycocalyx (EG) is a polysaccharide/protein complex located on the cell membrane at the luminal surface of vascular endothelial cells that has anti-inflammatory, anti-thrombotic, and endothelial protective effects. Recent studies have shown that glycocalyx damage plays a causal role in S-AKI progression. In this review, we first describe the structure, location, and basic function of the EG. Second, we analyze the underlying mechanisms of EG degradation in sepsis and S-AKI. Finally, we provide a summary of the potential therapeutic strategies that target the EG.
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Affiliation(s)
- Yixun Wang
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
- Department of Critical Care Medicine, Yichang Central People's Hospital, Yichang, China
- Yichang Sepsis Clinical Research Center, Yichang, Hubei, China
| | - Zhaohui Zhang
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
- Department of Critical Care Medicine, Yichang Central People's Hospital, Yichang, China
- Yichang Sepsis Clinical Research Center, Yichang, Hubei, China
| | - Xingguang Qu
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
- Department of Critical Care Medicine, Yichang Central People's Hospital, Yichang, China
- Yichang Sepsis Clinical Research Center, Yichang, Hubei, China
| | - Gaosheng Zhou
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, China
- Department of Critical Care Medicine, Yichang Central People's Hospital, Yichang, China
- Yichang Sepsis Clinical Research Center, Yichang, Hubei, China
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Zhan JH, Wei J, Liu YJ, Wang PX, Zhu XY. Sepsis-associated endothelial glycocalyx damage: a review of animal models, clinical evidence, and molecular mechanisms. Int J Biol Macromol 2025; 295:139548. [PMID: 39788232 DOI: 10.1016/j.ijbiomac.2025.139548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 12/21/2024] [Accepted: 01/05/2025] [Indexed: 01/12/2025]
Abstract
In the mammalian cardiovascular system, endothelial glycocalyx is a gel-like layer that covers the luminal surface of endothelial cells (ECs) and plays crucial roles in vascular homeostasis, permeability and leukocyte adhesion. Degradation of this structure occurs early in sepsis and becomes accordingly dysfunctional. In severe cases, it is not self-regulated by the organism. However, the relationship between the glycocalyx and the occurrence and development of sepsis remains poorly understood. One possibility is that thinned glycocalyx promotes leukocyte recognition and adhesion, thereby facilitating the elimination of pathogens from infected areas. This may represent a protective mechanism developed by the organism during through evolutionary processes. However, if the damage persists and disrupts the dynamic balance of the microcirculation, interstitial edema or organ failure can occur. Thus, we asked the questions, what is the precise composition and structure of the glycocalyx? How is it degraded? What animal models are available to study the relationship between the glycocalyx and sepsis? What glycocalyx biomarkers are found in the blood of patients with sepsis? To determine whether sepsis can be treated by interfering with the glycocalyx, this study provides a systematic summary and discussion of the latest progress in addressing these questions.
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Affiliation(s)
- Jun-Hui Zhan
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China; Department of Physiology, Naval Medical University, Shanghai 200433, China
| | - Juan Wei
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China
| | - Yu-Jian Liu
- School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China
| | - Peng-Xiang Wang
- Department of Physiology, Naval Medical University, Shanghai 200433, China.
| | - Xiao-Yan Zhu
- Department of Physiology, Naval Medical University, Shanghai 200433, China.
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3
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Yang Y, Schmidt EP. Alveolar glycocalyces during health and critical illness. PROTEOGLYCAN RESEARCH 2025; 3:e70022. [PMID: 40242042 PMCID: PMC11999102 DOI: 10.1002/pgr2.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 02/24/2025] [Indexed: 04/18/2025]
Abstract
The alveolus, the functional unit of the lung, is comprised of closely approximated alveolar epithelial and endothelial cells, across which gas exchange occurs. This alveolar septum also includes two substantial, intraluminal extracellular matrices: the alveolar epithelial and endothelial glycocalyces. This perspective investigates the distinct structures and homeostatic functions of these two glycocalyces, as well as their distinct fates and consequences during critical illnesses such as sepsis and the acute respiratory distress syndrome. We seek to identify key knowledge gaps, with the goal to inspire future mechanistic investigations that may substantially impact human health and disease.
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Affiliation(s)
- Yimu Yang
- Department of Medicine, Massachusetts General Hospital, Boston MA
| | - Eric P. Schmidt
- Department of Medicine, Massachusetts General Hospital, Boston MA
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4
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Lin Y, Li Y, Cui X, Zhu N, Li X. Hyaluronic Acid is Associated with Severity and Prognosis in Patients with Community-Acquired Pneumonia. J Inflamm Res 2024; 17:11829-11843. [PMID: 39802154 PMCID: PMC11725244 DOI: 10.2147/jir.s499326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 12/14/2024] [Indexed: 01/16/2025] Open
Abstract
Purpose Hyaluronic acid (HA) is a novel inflammatory biomarker with a prognostic value for several infectious diseases. This study investigated the association of HA with severity and prognosis in hospitalized patients with community-acquired pneumonia (CAP). Patients and Methods We analyzed the differences of HA levels in different groups. Logistic regression analysis was performed to identify independent risk factors for severe CAP (SCAP). The predictive value of HA for SCAP was assessed using receiver operating characteristic (ROC) curves. Kaplan-Meier survival analysis was used to compare 30-day mortality between the high and low HA groups. Results Compared to healthy controls (49.2 ± 15.3 ng/mL), patients with CAP exhibited significantly elevated levels of HA (P < 0.001). In CAP patients, increased HA levels were more pronounced in those with SCAP (SCAP vs non-SCAP:135.6 ± 51 ng/mL vs 100.7 ± 47.8 ng/mL, P < 0.001). Compared to survivors (109.9 ± 48.7 ng/mL), HA levels in non-survivors were significantly higher (180.9 ± 67.8 ng/mL) (P < 0.001). HA was an independent predictor of SCAP [odds ratio (OR): 1.013, 95% confidence interval (CI): 1.003-1.022, P = 0.011] with high diagnostic accuracy [areas under the curve (AUC): 0.709, 95% CI: 0.622-0.797, P = 0.001]. Additionally, HA was independently associated with death risk in patients with CAP (OR: 1.022, 95% CI: 1.005-1.039, P = 0.010). Kaplan-Meier survival curves indicated that CAP patients in the high HA group exhibit a higher 30-day mortality rate compared to those in the low HA group (8.6% vs 1.5%, P = 0.008). Post hoc analysis indicated that our study possessed 98.857% statistical power. Conclusion In conclusion, High HA levels are associated with severity and mortality in patients with CAP, and HA could serve as a novel serum biomarker to predict the risk of CAP progression.
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Affiliation(s)
- Yingying Lin
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, People’s Republic of China
| | - Yanyan Li
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Xinyu Cui
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Na Zhu
- Department of Center of Integrated Traditional Chinese and Western Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Xin Li
- Department of Center of Integrated Traditional Chinese and Western Medicine, Peking University Ditan Teaching Hospital, Beijing, People’s Republic of China
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Aksu U, Yavuz-Aksu B, Goswami N. Microcirculation: Current Perspective in Diagnostics, Imaging, and Clinical Applications. J Clin Med 2024; 13:6762. [PMID: 39597906 PMCID: PMC11595220 DOI: 10.3390/jcm13226762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 10/30/2024] [Accepted: 11/08/2024] [Indexed: 11/29/2024] Open
Abstract
This review discusses the pivotal role of microcirculation in maintaining tissue oxygenation and waste removal and highlights its significance in various pathological conditions. It delves into the cellular mechanisms underlying hemodynamic coherence, elucidating the roles of the endothelium, glycocalyx, and erythrocytes in sustaining microcirculatory integrity. Furthermore, the review gives comprehensive information about microcirculatory changes observed in cardiac surgery, sepsis, shock, and COVID-19 disease. Through comprehensive exploration, the review underscores the intricate relationship between microcirculation, disease states, and clinical outcomes, emphasizing the importance of understanding and monitoring microvascular dynamics in critical care settings.
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Affiliation(s)
- Ugur Aksu
- Biology Department, Science Faculty, Istanbul University, Istanbul 34459, Turkey
| | - Berna Yavuz-Aksu
- Duzen Laboratory Group, Biochemistry Section, Istanbul 34394, Turkey;
| | - Nandu Goswami
- Gravitational Physiology and Medicine Research Unit, Division of Physiology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, 3810 Graz, Austria
- Center for Space and Aviation Health, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 505055, United Arab Emirates
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Sallee CJ, Maddux AB, Hippensteel JA, Markovic D, Oshima K, Schwingshackl A, Mourani PM, Schmidt EP, Sapru A. CIRCULATING HEPARAN SULFATE PROFILES IN PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME. Shock 2024; 62:496-504. [PMID: 39331799 PMCID: PMC12080468 DOI: 10.1097/shk.0000000000002421] [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: 09/29/2024]
Abstract
ABSTRACT Introduction: Sepsis-induced degradation of endothelial glycocalyx heparan sulfate (HS) contributes to the pulmonary microvascular endothelial injury characteristic of acute respiratory distress syndrome (ARDS) pathogenesis. Our objectives were to (1) examine relationships between plasma indices of HS degradation and protein biomarkers of endothelial injury and (2) identify patient subgroups characterized by distinct profiles of HS degradation in children with ARDS. Methods: We analyzed prospectively collected plasma (2018-2020) from a cohort of invasively mechanically ventilated children (aged >1 month to <18 years) with ARDS. Mass spectrometry characterized and quantified patterns of HS disaccharide sulfation. Protein biomarkers reflective of endothelial injury (e.g., angiopoietin-2, vascular cell adhesion molecule-1, soluble thrombomodulin) were measured with a multiplex immunoassay. Pearson correlation coefficients were used to construct a biomarker correlation network. Centrality metrics detected influential biomarkers (i.e., network hubs). K-means clustering identified unique patient subgroups based on HS disaccharide profiles. Results: We evaluated 36 patients with pediatric ARDS. HS disaccharide sulfation patterns, 6S, NS, and NS2S, positively correlated with all biomarkers of endothelial injury (all P < 0.05) and were classified as network hubs. We identified three patient subgroups, with cluster 3 (n = 5) demonstrating elevated levels of 6S and N-sulfated HS disaccharides. In cluster 3, 60% of children were female and nonpulmonary sepsis accounted for 60% of cases. Relative to cluster 1 (n = 12), cluster 3 was associated with higher oxygen saturation index (P = 0.029) and fewer 28-day ventilator-free days (P = 0.016). Conclusions: Circulating highly sulfated HS fragments may represent emerging mechanistic biomarkers of endothelial injury and disease severity in pediatric ARDS.
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Affiliation(s)
- Colin J. Sallee
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles and Mattel Children’s Hospital, Los Angeles, California
| | - Aline B. Maddux
- Department of Pediatrics, Section of Pediatric Critical Care, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado
| | - Joseph A. Hippensteel
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Daniela Markovic
- Department of Medicine, Biostatistics Core, University of California Los Angeles, Los Angeles, California
| | - Kaori Oshima
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts
| | - Andreas Schwingshackl
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles and Mattel Children’s Hospital, Los Angeles, California
| | - Peter M. Mourani
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Arkansas
| | - Eric P. Schmidt
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts
| | - Anil Sapru
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles and Mattel Children’s Hospital, Los Angeles, California
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Drost CC, Rovas A, Osiaevi I, Schughart K, Lukasz A, Linke WA, Pavenstädt H, Kümpers P. Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis. Angiogenesis 2024; 27:411-422. [PMID: 38598083 PMCID: PMC11303473 DOI: 10.1007/s10456-024-09916-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 03/28/2024] [Indexed: 04/11/2024]
Abstract
Damage of the endothelial glycocalyx (eGC) plays a central role in the development of vascular hyperpermeability and organ damage during systemic inflammation. However, the specific signalling pathways for eGC damage remain poorly defined. Aim of this study was to combine sublingual video-microscopy, plasma proteomics and live cell imaging to uncover further pathways of eGC damage in patients with coronavirus disease 2019 (COVID-19) or bacterial sepsis. This secondary analysis of the prospective multicenter MICROCODE study included 22 patients with COVID-19 and 43 patients with bacterial sepsis admitted to intermediate or intensive care units and 10 healthy controls. Interleukin-6 (IL-6) was strongly associated with damaged eGC and correlated both with eGC dimensions (rs=0.36, p = 0.0015) and circulating eGC biomarkers. In vitro, IL-6 reduced eGC height and coverage, which was inhibited by blocking IL-6 signalling with the anti-IL-6 receptor antibody tocilizumab or the Janus kinase inhibitor tofacitinib. Exposure of endothelial cells to 5% serum from COVID-19 or sepsis patients resulted in a significant decrease in eGC height, which was attenuated by co-incubation with tocilizumab. In an external COVID-19 cohort of 219 patients from Massachusetts General Hospital, a previously identified proteomic eGC signature correlated with IL-6 (rs=-0.58, p < 0.0001) and predicted the combined endpoint of 28-day mortality and/or intubation (ROC-AUC: 0.86 [95% CI: 0.81-0.91], p < 0.001). The data suggest that IL-6 may significantly drive eGC damage in COVID-19 and bacterial sepsis. Our findings provide valuable insights into pathomechanisms of vascular dysfunction during systemic inflammation and highlight the need for further in vivo studies.
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Affiliation(s)
- Carolin Christina Drost
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Alexandros Rovas
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Irina Osiaevi
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
- Department of Medicine A, Hematology, Oncology and Pulmonary Medicine, University Hospital Muenster, 48149, Muenster, Germany
| | - Klaus Schughart
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA
- Institute of Virology Münster, University of Münster, Münster, Germany
| | - Alexander Lukasz
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Wolfgang A Linke
- Institute of Physiology II, University Hospital Münster, Robert-Koch-Straße 27b, 48149, Münster, Germany
| | - Hermann Pavenstädt
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Philipp Kümpers
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
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Li N, Hao R, Ren P, Wang J, Dong J, Ye T, Zhao D, Qiao X, Meng Z, Gan H, Liu S, Sun Y, Dou G, Gu R. Glycosaminoglycans: Participants in Microvascular Coagulation of Sepsis. Thromb Haemost 2024; 124:599-612. [PMID: 38242171 PMCID: PMC11199054 DOI: 10.1055/a-2250-3166] [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: 06/14/2023] [Accepted: 12/23/2023] [Indexed: 01/21/2024]
Abstract
Sepsis represents a syndromic response to infection and frequently acts as a common pathway leading to fatality in the context of various infectious diseases globally. The pathology of severe sepsis is marked by an excess of inflammation and activated coagulation. A substantial contributor to mortality in sepsis patients is widespread microvascular thrombosis-induced organ dysfunction. Multiple lines of evidence support the notion that sepsis induces endothelial damage, leading to the release of glycosaminoglycans, potentially causing microvascular dysfunction. This review aims to initially elucidate the relationship among endothelial damage, excessive inflammation, and thrombosis in sepsis. Following this, we present a summary of the involvement of glycosaminoglycans in coagulation, elucidating interactions among glycosaminoglycans, platelets, and inflammatory cells. In this section, we also introduce a reasoned generalization of potential signal pathways wherein glycosaminoglycans play a role in clotting. Finally, we discuss current methods for detecting microvascular conditions in sepsis patients from the perspective of glycosaminoglycans. In conclusion, it is imperative to pay closer attention to the role of glycosaminoglycans in the mechanism of microvascular thrombosis in sepsis. Dynamically assessing glycosaminoglycan levels in patients may aid in predicting microvascular conditions, enabling the monitoring of disease progression, adjustment of clinical treatment schemes, and mitigation of both acute and long-term adverse outcomes associated with sepsis.
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Affiliation(s)
- Nanxi Li
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Ruolin Hao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Peng Ren
- Beijing Institute of Basic Medical Sciences, Beijing, People Republic of China
| | - Jingya Wang
- Beijing Institute of Basic Medical Sciences, Beijing, People Republic of China
| | - Jiahui Dong
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Tong Ye
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Danyang Zhao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Xuan Qiao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Zhiyun Meng
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Hui Gan
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Shuchen Liu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Yunbo Sun
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Guifang Dou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
| | - Ruolan Gu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, People Republic of China
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9
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Soubihe Neto N, de Almeida MCV, Couto HDO, Miranda CH. Biomarkers of endothelial glycocalyx damage are associated with microvascular dysfunction in resuscitated septic shock patients. Microvasc Res 2024; 154:104683. [PMID: 38522507 DOI: 10.1016/j.mvr.2024.104683] [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: 11/24/2023] [Revised: 03/20/2024] [Accepted: 03/20/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Microvascular dysfunction plays a central role in organ dysfunction during septic shock. Endothelial glycocalyx (eGC) damage could contribute to impaired microcirculation. The aim was to assess whether several eGC-damaged biomarkers are associated with microvascular dysfunction in resuscitated septic shock patients. METHODS This cross-sectional study included resuscitated septic shock patients (N = 31), and a group of healthy individuals (N = 20). The eGC damage biomarkers measured were syndecan-1 (SDC-1), soluble CD44 (CD44s), hyaluronic acid (HYAL) in blood sample; sulfated glycosaminoglycans (GAGs) in urine sample; and thrombomodulin (TBML) in blood sample as biomarker of endothelial cell damage. Microcirculation was assessed through sublingual videocapillaroscopy using the GlycoCheck™, which estimated the perfused vascular density (PVD); the perfused boundary region (PBR), an inverse parameter of the eGC thickness; and the microvascular health score (MVHS). We defined a low MVHS (<50th percentile in septic patients) as a surrogate for more impaired microvascular function. RESULTS The SDC-1, CD44s, TBML and GAGs levels were correlated with impaired microvascular parameters (PVD of vessels with diameter < 10 μm, MVHS and flow-adjusted PBR); p < 0.05 for all comparisons, except for GAGs and flow-adjusted PBR. The SDC-1 [78 ng/mL (interquartile range (IQR) 45-336) vs. 48 ng/mL (IQR 9-85); p = 0.052], CD44s [796ρg/mL (IQR 512-1995) vs. 526ρg/mL (IQR 287-750); p = 0.036], TBML [734ρg/mL (IQR 237-2396) vs. 95ρg/mL (IQR 63-475); p = 0.012] and GAGs levels [0.42 ρg/mg (IQR 0.04-1.40) vs. 0.07 ρg/mg (IQR 0.02-0.20); p = 0.024]; were higher in septic patients with more impaired sublingual microvascular function (low MVHS vs. high MVHS). CONCLUSION SDC-1, CD44s, TBML and GAGs levels were associated with impaired microvascular function in resuscitated septic shock patients.
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Affiliation(s)
- Nazir Soubihe Neto
- Division of Emergency Medicine, Department of Internal Medicine, Ribeirão Preto School of Medicine, São Paulo University (USP), Ribeirão Preto, SP, Brazil
| | - Marcela Curci Vieira de Almeida
- Division of Emergency Medicine, Department of Internal Medicine, Ribeirão Preto School of Medicine, São Paulo University (USP), Ribeirão Preto, SP, Brazil
| | - Helton de Oliveira Couto
- Division of Emergency Medicine, Department of Internal Medicine, Ribeirão Preto School of Medicine, São Paulo University (USP), Ribeirão Preto, SP, Brazil
| | - Carlos Henrique Miranda
- Division of Emergency Medicine, Department of Internal Medicine, Ribeirão Preto School of Medicine, São Paulo University (USP), Ribeirão Preto, SP, Brazil.
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10
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Tyagi P, Tyagi S, Stewart L, Glickman S. SWOT and Root Cause Analyses of Antimicrobial Resistance to Oral Antimicrobial Treatment of Cystitis. Antibiotics (Basel) 2024; 13:328. [PMID: 38667004 PMCID: PMC11047466 DOI: 10.3390/antibiotics13040328] [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: 02/23/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/29/2024] Open
Abstract
Nearly 150 million cases of urinary tract infections (UTIs) are reported each year, of which uncomplicated cystitis triggers > 25% of outpatient prescriptions of oral antimicrobial treatment (OAT). OAT aids immune cells infiltrating the urothelium in eliminating uropathogens capable of invading the urothelium and surviving hyperosmotic urine. This self-evident adaptability of uropathogens and the short interval between the introduction of Penicillin and the first report of antimicrobial resistance (AMR) implicate AMR as an evolutionary conserved heritable trait of mutant strains selected by the Darwinian principle to survive environmental threats through exponential proliferation. Therefore, AMR can only be countered by antimicrobial stewardship (AMS) following the principle of the five Ds-drug, dose, duration, drug route, and de-escalation. While convenient to administer, the onset of the minimum inhibitory concentration (MIC) for OAT in urine leaves a window of opportunity for uropathogens to survive the first contact with an antimicrobial and arm their descendant colonies with AMR for surviving subsequent higher urine antimicrobial levels. Meanwhile, the initial dose of intravesical antimicrobial treatment (IAT) may be well above the MIC. Therefore, the widespread clinical use of OAT for cystitis warrants an analysis of the strengths, weaknesses, opportunity, and threats (SWOTs) and a root cause analysis of the AMR associated with OAT and IAT.
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Affiliation(s)
- Pradeep Tyagi
- Department of Urology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Shachi Tyagi
- Division of Geriatric Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;
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11
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Sallee CJ, Hippensteel JA, Miller KR, Oshima K, Pham AT, Richter RP, Belperio J, Sierra YL, Schwingshackl A, Mourani PM, Schmidt EP, Sapru A, Maddux AB. Endothelial Glycocalyx Degradation Patterns in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome: A Single Center Retrospective Observational Study. J Intensive Care Med 2024; 39:277-287. [PMID: 37670670 PMCID: PMC10845819 DOI: 10.1177/08850666231200162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/21/2023] [Accepted: 08/24/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND Sepsis-associated destruction of the pulmonary microvascular endothelial glycocalyx (EGCX) creates a vulnerable endothelial surface, contributing to the development of acute respiratory distress syndrome (ARDS). Constituents of the EGCX shed into circulation, glycosaminoglycans and proteoglycans, may serve as biomarkers of endothelial dysfunction. We sought to define the patterns of plasma EGCX degradation products in children with sepsis-associated pediatric ARDS (PARDS), and test their association with clinical outcomes. METHODS We retrospectively analyzed a prospective cohort (2018-2020) of children (≥1 month to <18 years of age) receiving invasive mechanical ventilation for acute respiratory failure for ≥72 h. Children with and without sepsis-associated PARDS were selected from the parent cohort and compared. Blood was collected at time of enrollment. Plasma glycosaminoglycan disaccharide class (heparan sulfate, chondroitin sulfate, and hyaluronan) and sulfation subtypes (heparan sulfate and chondroitin sulfate) were quantified using liquid chromatography tandem mass spectrometry. Plasma proteoglycans (syndecan-1) were measured through an immunoassay. RESULTS Among the 39 mechanically ventilated children (29 with and 10 without sepsis-associated PARDS), sepsis-associated PARDS patients demonstrated higher levels of heparan sulfate (median 639 ng/mL [interquartile range, IQR 421-902] vs 311 [IQR 228-461]) and syndecan-1 (median 146 ng/mL [IQR 32-315] vs 8 [IQR 8-50]), both p = 0.01. Heparan sulfate subtype analysis demonstrated greater proportions of N-sulfated disaccharide levels among children with sepsis-associated PARDS (p = 0.01). Increasing N-sulfated disaccharide levels by quartile were associated with severe PARDS (n = 9/29) with the highest quartile including >60% of the severe PARDS patients (test for trend, p = 0.04). Higher total heparan sulfate and N-sulfated disaccharide levels were independently associated with fewer 28-day ventilator-free days in children with sepsis-associated PARDS (all p < 0.05). CONCLUSIONS Children with sepsis-associated PARDS exhibited higher plasma levels of heparan sulfate disaccharides and syndecan-1, suggesting that EGCX degradation biomarkers may provide insights into endothelial dysfunction and PARDS pathobiology.
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Affiliation(s)
- Colin J. Sallee
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles and Mattel Children's Hospital, Los Angeles, CA, USA
| | - Joseph A. Hippensteel
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kristen R. Miller
- Department of Pediatrics, Section of Pediatric Critical Care, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
| | - Kaori Oshima
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA
| | - Andrew T. Pham
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Robert P. Richter
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - John Belperio
- Department of Medicine, Division of Pulmonary Critical Care and Sleep Medicine, David Geffen School of Medicine at University of California Los Angeles and Ronald Reagan Medical Center, Los Angeles, CA, USA
| | - Yamila L. Sierra
- Department of Pediatrics, Section of Pediatric Critical Care, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
| | - Andreas Schwingshackl
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles and Mattel Children's Hospital, Los Angeles, CA, USA
| | - Peter M. Mourani
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, USA
| | - Eric P. Schmidt
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA
| | - Anil Sapru
- Department of Pediatrics, Division of Pediatric Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles and Mattel Children's Hospital, Los Angeles, CA, USA
| | - Aline B. Maddux
- Department of Pediatrics, Section of Pediatric Critical Care, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
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12
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Nan Z, Soh S, Shim JK, Kim HB, Yang YS, Kwak YL, Song JW. Effect of 5% albumin on endothelial glycocalyx degradation during off-pump coronary artery bypass. Can J Anaesth 2024; 71:244-253. [PMID: 37989943 DOI: 10.1007/s12630-023-02652-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 07/23/2023] [Accepted: 08/08/2023] [Indexed: 11/23/2023] Open
Abstract
PURPOSE The integrity of the endothelial glycocalyx (EG), a critical player in vascular homeostasis, reportedly influences the outcomes of critically ill patients. We investigated the effect of 5% albumin, which preserved EG integrity in preclinical studies, vs balanced crystalloid solution on EG degradation in patients undergoing off-pump coronary surgery. METHODS Patients were randomized to receive either 5% albumin (N = 51) or balanced crystalloid solution (Plasma-Lyte [Baxter Incorporated, Seoul, Republic of Korea]; N = 53) for intravenous volume replacement during surgery (double-blinded). The primary outcome was plasma syndecan-1 concentration, a marker of EG degradation, measured after anesthetic induction (baseline), completion of grafting, and sternal closure. Secondary outcomes were atrial natriuretic peptide (ANP), tumour necrosis factor (TNF)-α, soluble thrombomodulin, and perioperative fluid balance. RESULTS The mean (standard deviation) fluid requirements were 833 (270) mL and 1,323 (492) mL in the albumin and Plasma-Lyte group, respectively (mean difference, -489 mL; 95% confidence interval [CI], -643 to -335; P < 0.001). Plasma syndecan-1 concentration increased after completion of grafting (median difference, 116 ng·mL-1; 95% CI, 67 to 184; P < 0.001) and sternal closure (median difference, 57 ng·mL-1; 95% CI, 36 to 80; P < 0.001) compared with those at baseline, without any intergroup differences. Atrial natriuretic peptide, TNF-α, and soluble thrombomodulin concentrations were similar between the two groups. The amount of chest tube drainage was greater in the albumin group than that in the Plasma-Lyte group (median difference, 190 mL; 95% CI, 18 to 276; P = 0.03). CONCLUSION Off-pump coronary surgery was associated with significant EG degradation. Yet, intraoperative fluid therapy with 5% albumin could not ameliorate EG degradation when compared with balanced crystalloid solution. TRIAL REGISTRATION ClinicalTrials.gov (NCT03699462); first posted 9 October 2018.
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Affiliation(s)
- Zhengyu Nan
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sarah Soh
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Kwang Shim
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hye Bin Kim
- Department of Anesthesiology and Pain Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Yun Seok Yang
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Lan Kwak
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jong Wook Song
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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13
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Oshima K, Siddiqui N, Orfila JE, Carter D, Laing J, Han X, Zakharevich I, Iozzo RV, Ghasabyan A, Moore H, Zhang F, Linhardt RJ, Moore EE, Quillinan N, Schmidt EP, Herson PS, Hippensteel JA. A role for decorin in improving motor deficits after traumatic brain injury. Matrix Biol 2024; 125:88-99. [PMID: 38135163 PMCID: PMC10922985 DOI: 10.1016/j.matbio.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023]
Abstract
Traumatic brain injury (TBI) is the leading cause of death and disability due to injury worldwide. Extracellular matrix (ECM) remodeling is known to significantly contribute to TBI pathophysiology. Glycosaminoglycans, which are long-chain, variably sulfated polysaccharides abundant within the ECM, have previously been shown to be substantially altered after TBI. In this study, we sought to delineate the dynamics of glycosaminoglycan alterations after TBI and discover the precise biologic processes responsible for observed glycosaminoglycan changes after injury. We performed state-of-the art mass spectrometry on brain tissues isolated from mice after TBI or craniotomy-alone. We observed dynamic changes in glycosaminoglycans at Day 1 and 7 post-TBI, with heparan sulfate, chondroitin sulfate, and hyaluronan remaining significantly increased after a week vis-à-vis craniotomy-alone tissues. We did not observe appreciable changes in circulating glycosaminoglycans in mice after experimental TBI compared to craniotomy-alone nor in patients with TBI and severe polytrauma compared to control patients with mild injuries, suggesting increases in injury site glycosaminoglycans are driven by local synthesis. We subsequently performed an unbiased whole genome transcriptomics analysis on mouse brain tissues 7 days post-TBI and discovered a significant induction of hyaluronan synthase 2, glypican-3, and decorin. The functional role of decorin after injury was further examined through multimodal behavioral testing comparing wild-type and Dcn-/- mice. We discovered that genetic ablation of Dcn led to an overall negative effect of TBI on function, exacerbating motor impairments after TBI. Collectively, our results provide a spatiotemporal characterization of post-TBI glycosaminoglycan alterations in the brain ECM and support an important adaptive role for decorin upregulation after TBI.
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Affiliation(s)
- Kaori Oshima
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Noah Siddiqui
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - James E Orfila
- Department of Neurosurgery, The Ohio State University, College of Medicine, Columbus, Ohio, USA
| | - Danelle Carter
- Department of Neurology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Justin Laing
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Xiaorui Han
- Departments of Chemistry and Chemical Biology, Chemical and Biological Engineering, and Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York, USA; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
| | - Igor Zakharevich
- Department of Biochemistry, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Renato V Iozzo
- Department of Pathology and Genomic Medicine and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Arsen Ghasabyan
- Department of Surgery, Ernest E. Moore Shock Trauma Center at Denver Health, University of Colorado, Denver, Colorado, USA
| | - Hunter Moore
- Department of Surgery, Ernest E. Moore Shock Trauma Center at Denver Health, University of Colorado, Denver, Colorado, USA
| | - Fuming Zhang
- Departments of Chemistry and Chemical Biology, Chemical and Biological Engineering, and Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York, USA
| | - Robert J Linhardt
- Departments of Chemistry and Chemical Biology, Chemical and Biological Engineering, and Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, New York, USA
| | - Ernest E Moore
- Department of Surgery, Ernest E. Moore Shock Trauma Center at Denver Health, University of Colorado, Denver, Colorado, USA
| | - Nidia Quillinan
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Eric P Schmidt
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paco S Herson
- Department of Neurosurgery, The Ohio State University, College of Medicine, Columbus, Ohio, USA
| | - Joseph A Hippensteel
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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14
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Xu QF, Zhang H, Zhao Y, Liu D, Wei J, Jiang L, Liu YJ, Zhu XY. Increased R-spondin 3 contributes to aerobic exercise-induced protection against renal vascular endothelial hyperpermeability and acute kidney injury. Acta Physiol (Oxf) 2023; 239:e14036. [PMID: 37607126 DOI: 10.1111/apha.14036] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 07/11/2023] [Accepted: 08/08/2023] [Indexed: 08/24/2023]
Abstract
AIM Exercise training exerts protective effects against sepsis-associated multiple organ dysfunction. This study aimed to investigate whether aerobic exercise protected against sepsis-associated acute kidney injury (AKI) via modulating R-spondin 3 (RSPO3) expression. METHODS To investigate the effects of aerobic exercise on lipopolysaccharide (LPS)-induced AKI, LPS (20 mg/kg) was intraperitoneally injected after six weeks of treadmill training. To investigate the role of RSPO3 in LPS-induced AKI, wild-type (WT) or inducible endothelial cell-specific RSPO3 knockout (RSPO3EC-/- ) mice were intraperitoneally injected with 12 mg/kg LPS. RSPO3 was intraperitoneally injected 30 min before LPS treatment. RESULTS Aerobic exercise-trained mice were more resistant to LPS-induced body weight loss and hypothermia and had a significant higher survival rate than sedentary mice exposed to LPS. Exercise training restored the LPS-induced decreases in serum and renal RSPO3 levels. Exercise or RSPO3 attenuated, whereas inducible endothelial cell-specific RSPO3 knockout exacerbated LPS-induced renal glycocalyx loss, endothelial hyperpermeability, inflammation, and AKI. Bioinformatics analysis results revealed significant increases in the expression of matrix metalloproteinases (MMPs) in kidney tissues of mice exposed to sepsis or endotoxaemia, which was validated in renal tissue from LPS-exposed mice and LPS-treated human microvascular endothelial cells (HMVECs). Both RSPO3 and MMPs inhibitor restored LPS-induced downregulation of tight junction protein, adherens junction protein, and glycocalyx components, thus ameliorating LPS-induced endothelial leakage. Exercise or RSPO3 reversed LPS-induced upregulation of MMPs in renal tissues. CONCLUSION Increased renal expression of RSPO3 contributes to aerobic exercise-induced protection against LPS-induced renal endothelial hyperpermeability and AKI by suppressing MMPs-mediated disruption of glycocalyx and tight and adherens junctions.
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Affiliation(s)
- Qing-Feng Xu
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China
- Department of Physiology, Navy Medical University, Shanghai, China
| | - Hui Zhang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ying Zhao
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Di Liu
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Juan Wei
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Lai Jiang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yu-Jian Liu
- Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China
| | - Xiao-Yan Zhu
- Department of Physiology, Navy Medical University, Shanghai, China
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15
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Rovas A, Neumann JK, Drost CC, Vollenberg R, Thölking G, Fobker M, Witzenrath M, Kümpers P. Analysis of Urinary Glycosaminoglycans to Predict Outcome in COVID-19 and Community-Acquired Pneumonia-A Proof-of-Concept Study. J Clin Med 2023; 12:5269. [PMID: 37629312 PMCID: PMC10455319 DOI: 10.3390/jcm12165269] [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: 06/26/2023] [Revised: 08/02/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Although coronavirus disease 2019 (COVID-19) is considered a systemic disease associated with vascular inflammation and eventual destruction of the protective endothelial glycocalyx (eGC), biomarkers of eGC damage are not yet available in the clinic. The most prominent components of eGC are sulphated glycosaminoglycans (sGAGs) attached to core proteoglycans. We hypothesised that the amount of sGAG fragments shed in urine (as a surrogate for systemic eGC damage) would correlate with disease severity and outcome. Total urinary sGAG concentration was measured using an in-house optimised 1,9-dimethylmethylene blue (DMMB) assay, which is highly accurate and insensitive to interferences. The median urinary sGAG concentration was significantly higher in 67 hospitalised patients with COVID-19 compared to 72 hospitalised patients with community-acquired pneumonia (CAP). In both groups, urinary sGAG concentrations predicted a combined endpoint (including intubation and death) with an area under the receiver operator characteristic curve of 0.72 (95% CI 0.55-0.88, p = 0.01) and 0.70 (95% CI 0.57-0.83, p = 0.007), respectively. In conclusion, the inexpensive and easy-to-perform DMMB assay provides a surrogate parameter for eGC damage that may be useful for risk stratification of patients with COVID-19 and CAP.
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Affiliation(s)
- Alexandros Rovas
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Muenster, 48149 Muenster, Germany; (J.K.N.); (C.C.D.); (P.K.)
| | - Julia Katharina Neumann
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Muenster, 48149 Muenster, Germany; (J.K.N.); (C.C.D.); (P.K.)
| | - Carolin Christina Drost
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Muenster, 48149 Muenster, Germany; (J.K.N.); (C.C.D.); (P.K.)
| | - Richard Vollenberg
- Department of Medicine B, Division of Gastroenterology, Hepatology, Endocrinology and Infectiology, University Hospital Münster, 48149 Muenster, Germany;
| | - Gerold Thölking
- Department of Internal Medicine and Nephrology, Marienhospital Steinfurt, 48565 Steinfurt, Germany;
| | - Manfred Fobker
- Center for Laboratory Medicine, University Hospital Münster, 48149 Muenster, Germany;
| | - Martin Witzenrath
- Division of Pulmonary Inflammation, Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
- German Center for Lung Research (DZL), 10117 Berlin, Germany
| | - Philipp Kümpers
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Muenster, 48149 Muenster, Germany; (J.K.N.); (C.C.D.); (P.K.)
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16
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Li JC, Wang LJ, Feng F, Chen TT, Shi WG, Liu LP. Role of heparanase in sepsis‑related acute kidney injury (Review). Exp Ther Med 2023; 26:379. [PMID: 37456170 PMCID: PMC10347300 DOI: 10.3892/etm.2023.12078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 06/08/2023] [Indexed: 07/18/2023] Open
Abstract
Sepsis-related acute kidney injury (S-AKI) is a common and significant complication of sepsis in critically ill patients, which can often only be treated with antibiotics and medications that reduce S-AKI symptoms. The precise mechanism underlying the onset of S-AKI is still unclear, thus hindering the development of new strategies for its treatment. Therefore, it is necessary to explore the pathogenesis of S-AKI to identify biomarkers and therapeutic targets for its early diagnosis and treatment. Heparanase (HPA), the only known enzyme that cleaves the side chain of heparan sulfate, has been widely studied in relation to tumor metabolism, procoagulant activity, angiogenesis, inflammation and sepsis. It has been reported that HPA plays an important role in the progression of S-AKI. The aim of the present review was to provide an overview of the function of HPA in S-AKI and to summarize its underlying molecular mechanisms, including mediating inflammatory response, immune response, autophagy and exosome biogenesis. It is anticipated that emerging discoveries about HPA in S-AKI will support HPA as a potential biomarker and therapeutic target to combat S-AKI.
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Affiliation(s)
- Jian-Chun Li
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Lin-Jun Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Fei Feng
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Ting-Ting Chen
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Wen-Gui Shi
- Cuiying Biomedical Research Center, The Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Li-Ping Liu
- Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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17
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Yu H, Song YY, Li XH. Early diabetic kidney disease: Focus on the glycocalyx. World J Diabetes 2023; 14:460-480. [PMID: 37273258 PMCID: PMC10236994 DOI: 10.4239/wjd.v14.i5.460] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/10/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
The incidence of diabetic kidney disease (DKD) is sharply increasing worldwide. Microalbuminuria is the primary clinical marker used to identify DKD, and its initiating step in diabetes is glomerular endothelial cell dysfunction, particularly glycocalyx impairment. The glycocalyx found on the surface of glomerular endothelial cells, is a dynamic hydrated layer structure composed of pro-teoglycans, glycoproteins, and some adsorbed soluble components. It reinforces the negative charge barrier, transduces the shear stress, and mediates the interaction of blood corpuscles and podocytes with endothelial cells. In the high-glucose environment of diabetes, excessive reactive oxygen species and proinflammatory cytokines can damage the endothelial glycocalyx (EG) both directly and indirectly, which induces the production of microalbuminuria. Further research is required to elucidate the role of the podocyte glycocalyx, which may, together with endothelial cells, form a line of defense against albumin filtration. Interestingly, recent research has confirmed that the negative charge barrier function of the glycocalyx found in the glomerular basement membrane and its repulsion effect on albumin is limited. Therefore, to improve the early diagnosis and treatment of DKD, the potential mechanisms of EG degradation must be analyzed and more responsive and controllable targets must be explored. The content of this review will provide insights for future research.
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Affiliation(s)
- Hui Yu
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Yi-Yun Song
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Xian-Hua Li
- Department of Nephrology, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
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18
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Rizzo AN, Schmidt EP. The role of the alveolar epithelial glycocalyx in acute respiratory distress syndrome. Am J Physiol Cell Physiol 2023; 324:C799-C806. [PMID: 36847444 PMCID: PMC10042597 DOI: 10.1152/ajpcell.00555.2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/14/2023] [Accepted: 02/14/2023] [Indexed: 03/01/2023]
Abstract
The alveolar epithelial glycocalyx is a dense anionic layer of glycosaminoglycans (GAGs) and proteoglycans that lines the apical surface of the alveolar epithelium. In contrast to the pulmonary endothelial glycocalyx, which has well-established roles in vascular homeostasis and septic organ dysfunction, the alveolar epithelial glycocalyx is less understood. Recent preclinical studies demonstrated that the epithelial glycocalyx is degraded in multiple murine models of acute respiratory distress syndrome (ARDS), particularly those that result from inhaled insults (so-called "direct" lung injury), leading to shedding of GAGs into the alveolar airspaces. Epithelial glycocalyx degradation also occurs in humans with respiratory failure, as quantified by analysis of airspace fluid obtained from ventilator heat moisture exchange (HME) filters. In patients with ARDS, GAG shedding correlates with the severity of hypoxemia and is predictive of the duration of respiratory failure. These effects may be mediated by surfactant dysfunction, as targeted degradation of the epithelial glycocalyx in mice was sufficient to cause increased alveolar surface tension, diffuse microatelectasis, and impaired lung compliance. In this review, we describe the structure of the alveolar epithelial glycocalyx and the mechanisms underlying its degradation during ARDS. We additionally review the current state of knowledge regarding the attributable effect of epithelial glycocalyx degradation in lung injury pathogenesis. Finally, we address glycocalyx degradation as a potential mediator of ARDS heterogeneity, and the subsequent value of point-of-care quantification of GAG shedding to potentially identify patients who are most likely to respond to pharmacological agents aimed at attenuating glycocalyx degradation.
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Affiliation(s)
- Alicia N Rizzo
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Eric P Schmidt
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
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19
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Nagayama I, Takayanagi K, Hasegawa H, Maeshima A. Tubule-Derived Follistatin Is Increased in the Urine of Rats with Renal Ischemia and Reflects the Severity of Acute Tubular Damage. Cells 2023; 12:801. [PMID: 36899937 PMCID: PMC10000847 DOI: 10.3390/cells12050801] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Activin A, a member of the TGF-beta superfamily, is a negative regulator of tubular regeneration after renal ischemia. Activin action is controlled by an endogenous antagonist, follistatin. However, the role of follistatin in the kidney is not fully understood. In the present study, we examined the expression and localization of follistatin in normal and ischemic rat kidneys and measured urinary follistatin in rats with renal ischemia to assess whether urinary follistatin could serve as a biomarker for acute kidney injury. Using vascular clamps, renal ischemia was induced for 45 min in 8-week-old male Wistar rats. In normal kidneys, follistatin was localized in distal tubules of the cortex. In contrast, in ischemic kidneys, follistatin was localized in distal tubules of both the cortex and outer medulla. Follistatin mRNA was mainly present in the descending limb of Henle of the outer medulla in normal kidneys but was upregulated in the descending limb of Henle of both the outer and inner medulla after renal ischemia. Urinary follistatin, which was undetectable in normal rats, was significantly increased in ischemic rats and peaked 24 h after reperfusion. There was no correlation between urinary follistatin and serum follistatin. Urinary follistatin levels were increased according to ischemic duration and were significantly correlated with the follistatin-positive area as well as the acute tubular damage area. These results suggest that follistatin normally produced by renal tubules increases and becomes detectable in urine after renal ischemia. Urinary follistatin might be useful to assess the severity of acute tubular damage.
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Affiliation(s)
| | | | | | - Akito Maeshima
- Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe 350-8550, Japan
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20
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Yao R, Chen T, Xue F. The association of IL-10-1082G/A gene polymorphism with the risk of acute lung injury/respiratory distress syndrome (ALI/RDS): A meta-analysis. Heart Lung 2023; 58:158-165. [PMID: 36521397 DOI: 10.1016/j.hrtlng.2022.11.019] [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: 04/29/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Several records have reported that single nucleotide polymorphism (SNP) at the interleukin 10 (IL-10)-1082G/A locus affects the risk of acute lung injury/respiratory distress syndrome (ALI/RDS), but the exact association between them has not been elucidated. OBJECTIVE This systematic review aims to elucidate the relationship between SNP at the IL-10-1082G/A locus and susceptibility to ALI/RDS by the method of meta-analysis, to identify the early warning indicators of ALI/RDS. METHODS Studies on IL-10-1082G/A SNP associated with ALI/RDS were obtained by thorough retrieval of four English databases from each database construction to April 1, 2022. We processed the data using Stata 15.0 software. RESULTS Eight eligible records were entered into this meta-analysis. The pooled analysis demonstrated that SNP at the IL-10-1082G/A locus contributed to the risk of ALI/RDS in the allelic (G vs. A: OR= 0.74, 95%CI: 0.55∼0.98) and recessive gene models (Genotype GG vs. GA+AA: OR= 0.57, 95%CI: 0.35∼0.93). The subgroup analysis based on case type showed that SNP at IL-10-1082G/A locus contributed to the risk of neonatal respiratory distress syndrome (NRDS) under all the gene models (Allele G vs. A: OR= 0.45, 95%CI: 0.29∼0.72; Genotype GG+GA vs. AA: OR= 0.36, 95%CI: 0.22∼0.58; Genotype GG vs. GA+AA: OR= 0.30, 95%CI: 0.09∼0.97; Genotype GA vs. AA: OR= 0.44, 95%CI: 0.27∼0.73), except the homozygous model. However, it was not found that SNP at the IL-10-1082G/A locus contributed to ALI or acute respiratory distress syndrome (ARDS). Moreover, the risk of ALI/RDS in Asia was associated with the IL-10-1082G/A locus in the allelic, recessive, and heterozygous models, while we did not observe this association across the Caucasian populations. CONCLUSION SNP at the IL-10-1082G/A locus contributed to the risk of ALI/RDS, allele G and genotype GG increasing the ALI/RDS risk, especially in Asia. Besides, allele G, genotype GG+GA, GG, and GA at the IL-10-1082G/A locus can increase susceptibility to NRDS.
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Affiliation(s)
- Renye Yao
- Department of Clinical Laboratory,Children's Hospital, Maternal and child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Ting Chen
- Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Feng Xue
- Department of Critical Care Medicine, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, China.
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21
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Rizzo AN, Aggarwal NR, Thompson BT, Schmidt EP. Advancing Precision Medicine for the Diagnosis and Treatment of Acute Respiratory Distress Syndrome. J Clin Med 2023; 12:1563. [PMID: 36836098 PMCID: PMC9966442 DOI: 10.3390/jcm12041563] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a common and life-threatening cause of respiratory failure. Despite decades of research, there are no effective pharmacologic therapies to treat this disease process and mortality remains high. The shortcomings of prior translational research efforts have been increasingly attributed to the heterogeneity of this complex syndrome, which has led to an increased focus on elucidating the mechanisms underlying the interpersonal heterogeneity of ARDS. This shift in focus aims to move the field towards personalized medicine by defining subgroups of ARDS patients with distinct biology, termed endotypes, to quickly identify patients that are most likely to benefit from mechanism targeted treatments. In this review, we first provide a historical perspective and review the key clinical trials that have advanced ARDS treatment. We then review the key challenges that exist with regards to the identification of treatable traits and the implementation of personalized medicine approaches in ARDS. Lastly, we discuss potential strategies and recommendations for future research that we believe will aid in both understanding the molecular pathogenesis of ARDS and the development of personalized treatment approaches.
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Affiliation(s)
- Alicia N. Rizzo
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144, USA
| | - Neil R. Aggarwal
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - B. Taylor Thompson
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144, USA
| | - Eric P. Schmidt
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144, USA
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22
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Douglas NM, Piera KA, Rumaseb A, Ley B, Anstey NM, Price RN. Primaquine-induced Severe Hemolysis in the Absence of Concomitant Malaria: Effects on G6PD Activity and Renal Function. Am J Trop Med Hyg 2023; 108:76-80. [PMID: 36509054 PMCID: PMC9833077 DOI: 10.4269/ajtmh.21-0834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 08/29/2022] [Indexed: 12/15/2022] Open
Abstract
Primaquine prevents relapses of Plasmodium vivax malaria but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The clinical and laboratory features of this outcome are usually confounded by the clinical and hemolytic effects of concomitant malaria. We describe a case of severe hemolysis occurring after a total dose of 2.04 mg/kg of primaquine used for prophylaxis in a young, G6PD-deficient (Kaiping variant), Australian man without malaria. During acute hemolysis, he had markedly elevated urinary beta-2-microglobulin, suggestive of renal tubular injury (a well-recognized complication of primaquine-induced hemolysis). He also had albuminuria and significantly increased excretion of glycocalyx metabolites, suggestive of glomerular glycocalyx degradation and injury. We show that regularly dosed paracetamol given for its putative renoprotective effect is safe in the context of severe oxidative hemolysis. Acute drug-induced hemolysis transiently increases G6PD activity. Cases such as this improve our understanding of primaquine-induced hemolysis and ultimately will help facilitate widespread safe and effective use of this critically important drug.
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Affiliation(s)
- Nicholas M. Douglas
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia
- Department of Infectious Diseases, Christchurch Hospital, Canterbury District Health Board, Christchurch, New Zealand
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Kim A. Piera
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia
| | - Angela Rumaseb
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia
| | - Benedikt Ley
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia
| | - Nicholas M. Anstey
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia
- Division of Infectious Diseases, Royal Darwin Hospital, Darwin, Australia
| | - Ric N. Price
- Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia
- Division of Infectious Diseases, Royal Darwin Hospital, Darwin, Australia
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
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23
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Suzuki K, Miura T, Okada H. The endothelial glycocalyx-All the same? No, it is not. Acute Med Surg 2023; 10:e896. [PMID: 37808968 PMCID: PMC10551284 DOI: 10.1002/ams2.896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 08/20/2023] [Accepted: 09/19/2023] [Indexed: 10/10/2023] Open
Abstract
The endothelial glycocalyx covers the lumen of blood vessels throughout the body and plays an important role in endothelial homeostasis. Advances in electron microscopy techniques have provided clues to better understand the structure and composition of identical vascular endothelial glycocalyx. The morphology and thickness of the endothelial glycocalyx differ from organ to organ. The content of the endothelial glycocalyx covering the vascular lumen differs even in the brain, heart, and lungs, which have the same continuous capillaries. Various types of inflammation are known to attenuate the endothelial glycocalyx; however, we found that the morphology of the glycocalyx damaged by acute inflammation differed from that damaged by chronic inflammation. Acute inflammation breaks the endothelial glycocalyx unevenly, whereas chronic inflammation leads to the overall shortening of the endothelial glycocalyx. The same drug has different effects on the endothelial glycocalyx, depending on the location of the target blood vessels. This difference in response may reflect not only the size and shape of the endothelial glycocalyx but also the different constituents. In the cardiac tissue, the expression of glypican-1, a core protein of the endothelial glycocalyx, was enhanced. By contrast, in the pulmonary tissue, the expression of heparan sulfate 6-O-sulfotransferase 1 and endothelial cell-specific molecule-1 significantly increased in the treatment group compared with that in the no-treatment group. In this review, we present the latest findings on the evolution of the vascular endothelial glycocalyx and consider the microstructural differences.
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Affiliation(s)
- Kodai Suzuki
- Department of Emergency and Disaster MedicineGifu University Graduate School of MedicineGifuJapan
- Department of Infection ControlGifu University Graduate School of MedicineGifuJapan
| | - Tomotaka Miura
- Department of Emergency and Disaster MedicineGifu University Graduate School of MedicineGifuJapan
| | - Hideshi Okada
- Department of Emergency and Disaster MedicineGifu University Graduate School of MedicineGifuJapan
- Center for One Medicine Innovative Translational ResearchGifu University Institute for Advanced StudyGifuJapan
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24
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Setting the stage for universal pharmacological targeting of the glycocalyx. CURRENT TOPICS IN MEMBRANES 2023; 91:61-88. [PMID: 37080681 DOI: 10.1016/bs.ctm.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
All cells in the human body are covered by a complex meshwork of sugars as well as proteins and lipids to which these sugars are attached, collectively termed the glycocalyx. Over the past few decades, the glycocalyx has been implicated in a range of vital cellular processes in health and disease. Therefore, it has attracted considerable interest as a therapeutic target. Considering its omnipresence and its relevance for various areas of cell biology, the glycocalyx should be a versatile platform for therapeutic intervention, however, the full potential of the glycocalyx as therapeutic target is yet to unfold. This might be attributable to the fact that glycocalyx alterations are currently discussed mainly in the context of specific diseases. In this perspective review, we shift the attention away from a disease-centered view of the glycocalyx, focusing on changes in glycocalyx state. Furthermore, we survey important glycocalyx-targeted drugs currently available and finally discuss future steps. We hope that this approach will inspire a unified, holistic view of the glycocalyx in disease, helping to stimulate novel glycocalyx-targeted therapy strategies.
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25
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Suzuki K, Okada H, Sumi K, Tomita H, Kobayashi R, Ishihara T, Mizuno Y, Yamaji F, Kamidani R, Miura T, Yasuda R, Kitagawa Y, Fukuta T, Suzuki K, Miyake T, Kanda N, Doi T, Yoshida T, Yoshida S, Tetsuka N, Ogura S, Suzuki A. Syndecan-1 as a severity biomarker for patients with trauma. Front Med (Lausanne) 2022; 9:985955. [PMID: 36237551 PMCID: PMC9550865 DOI: 10.3389/fmed.2022.985955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/29/2022] [Indexed: 11/15/2022] Open
Abstract
Tissue injury and hemorrhage induced by trauma lead to degradation of the endothelial glycocalyx, causing syndecan-1 (SDC-1) to be shed into the blood. In this study, we investigated whether serum SDC-1 is useful for evaluating trauma severity in patients. A single-center, retrospective, observational study was conducted at Gifu University Hospital. Patients transported to the emergency room for trauma and subsequently admitted to the intensive care unit from January 2019 to December 2021 were enrolled. A linear regression model was constructed to evaluate the association of serum SDC-1 with injury severity score (ISS) and probability of survival (Ps). A total of 76 trauma patients (54 men and 22 women) were analyzed. ISS was significantly associated with serum SDC-1 level in trauma patients. Among the six body regions defined in the AIS used to calculate the ISS score, “chest” and “abdominal or pelvic contents” were significantly associated with serum SDC-1 level, and “extremities or pelvic girdle” also tended to show an association with serum SDC-1 level. Moreover, increasing serum SDC-1 level was significantly correlated with decreasing Ps. Serum SDC-1 may be a useful biomarker for monitoring the severity of trauma in patients. Further large-scale studies are warranted to verify these results.
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Affiliation(s)
- Keiko Suzuki
- Department of Infection Control, Gifu University Graduate School of Medicine, Gifu, Japan
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
- Hideshi Okada
| | - Kazuyuki Sumi
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ryo Kobayashi
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
- Laboratory of Advanced Medical Pharmacy, Gifu Pharmaceutical University, Gifu, Japan
| | - Takuma Ishihara
- Innovative and Clinical Research Promotion Center, Gifu University Hospital, Gifu, Japan
| | - Yosuke Mizuno
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Fuminori Yamaji
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ryo Kamidani
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tomotaka Miura
- Department of Infection Control, Gifu University Graduate School of Medicine, Gifu, Japan
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ryu Yasuda
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yuichiro Kitagawa
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tetsuya Fukuta
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kodai Suzuki
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takahito Miyake
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Norihide Kanda
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tomoaki Doi
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takahiro Yoshida
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Shozo Yoshida
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
- Department of Abuse Prevention Emergency Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Nobuyuki Tetsuka
- Department of Infection Control, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Shinji Ogura
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Akio Suzuki
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
- Laboratory of Advanced Medical Pharmacy, Gifu Pharmaceutical University, Gifu, Japan
- *Correspondence: Akio Suzuki
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26
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Suzuki A, Tomita H, Okada H. Form follows function: The endothelial glycocalyx. Transl Res 2022; 247:158-167. [PMID: 35421613 DOI: 10.1016/j.trsl.2022.03.014] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 10/18/2022]
Abstract
Three types of capillaries, namely continuous, fenestrated, and sinusoidal, form the microvascular system; each type has a specialized structure and function to respond to the demands of the organs they supply. The endothelial glycocalyx, a gel-like layer of glycoproteins that covers the luminal surface of the capillary endothelium, is also thought to maintain organ and vascular homeostasis by exhibiting different morphologies based on the functions of the organs and capillaries in which it is found. Recent advances in analytical technology have enabled more detailed observations of the endothelial glycocalyx, revealing that it indeed differs in structure across various organs. Furthermore, differences in the lectin staining patterns suggest the presence of different endothelial glycocalyx components across various organs. Interestingly, injury to the endothelial glycocalyx due to various pathologic and physiological stimuli causes the release of these components into the blood. Thus, circulating glycocalyx components may be useful biomarkers of organ dysfunction and disease severity. Moreover, a recent study suggested that chronic injury to the glycocalyx reduces the production of these glycocalyx components and changes their structure, leading it to become more vulnerable to external stimuli. In this review, we have summarized the various endothelial glycocalyx structures and their functions.
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Affiliation(s)
- Akio Suzuki
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
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27
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Gatto F, Dabestani S, Bratulic S, Limeta A, Maccari F, Galeotti F, Volpi N, Stierner U, Nielsen J, Lundstam S. Plasma and Urine Free Glycosaminoglycans as Monitoring Biomarkers in Nonmetastatic Renal Cell Carcinoma-A Prospective Cohort Study. EUR UROL SUPPL 2022; 42:30-39. [PMID: 35911082 PMCID: PMC9334826 DOI: 10.1016/j.euros.2022.06.003] [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] [Accepted: 06/09/2022] [Indexed: 11/17/2022] Open
Abstract
Background No liquid biomarkers are approved in renal cell carcinoma (RCC), making early detection of recurrence in surgically treated nonmetastatic (M0) patients dependent on radiological imaging. Urine- and plasma free glycosaminoglycan profiles-or free GAGomes-are promising biomarkers reflective of RCC metabolism. Objective To explore whether free GAGomes could detect M0 RCC recurrence noninvasively. Design setting and participants Between June 2016 and February 2021, we enrolled a prospective consecutive series of patients elected for (1) partial or radical nephrectomy for clinical M0 RCC (cohort 1) or (2) first-line therapy following RCC metachronous metastatic recurrence (cohort 2) at Sahlgrenska University Hospital, Gothenburg, Sweden. The study population included M0 RCC patients with recurrent disease (RD) versus no evidence of disease (NED) in at least one follow-up visit. Plasma and urine free GAGomes-consisting of 40 chondroitin sulfate (CS), heparan sulfate, and hyaluronic acid (HA) features-were measured in a blinded central laboratory preoperatively and at each postoperative follow-up visit until recurrence or end of follow-up in cohort 1, or before treatment start in cohort 2. Outcome measurements and statistical analysis We used Bayesian logistic regression to correlate GAGome features with RD versus NED and with various histopathological variables. We developed three recurrence scores (plasma, urine, and combined) proportional to the predicted probability of RD. We internally validated the area under the curve (AUC) using bootstrap resampling. We performed a decision curve analysis to select a cutoff and report the corresponding net benefit, sensitivity, and specificity of each score. We used univariable analyses to correlate each preoperative score with recurrence-free survival (RFS). Results and limitations Of 127 enrolled patients in total, 62 M0 RCC patients were in the study population (median age: 63 year, 35% female, and 82% clear cell). The median follow-up time was 3 months, totaling 72 postoperative visits -17 RD and 55 NED cases. RD was compatible with alterations in 14 (52%) of the detectable GAGome features, mostly free CS. Eleven (79%) of these correlated with at least one histopathological variable. We developed a plasma, a urine, and a combined free CS RCC recurrence score to diagnose RD versus NED with AUCs 0.91, 0.93, and 0.94, respectively. At a cutoff equivalent to ≥30% predicted probability of RD, the sensitivity and specificity were, respectively, 69% and 84% in plasma, 81% and 80% in urine, and 80% and 82% when combined, and the net benefit was equivalent to finding an extra ten, 13, and 12 cases of RD per hundred patients without any unnecessary imaging for plasma, urine, and combined, respectively. The combined score was prognostic of RFS in univariable analysis (hazard ratio = 1.90, p = 0.02). Limitations include a lack of external validation. Conclusions Free CS scores detected postsurgical recurrence noninvasively in M0 RCC with substantial net benefit. External validity is required before wider clinical implementation. Patient summary In this study, we examined a new noninvasive blood and urine test to detect whether renal cell carcinoma recurred after surgery.
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Affiliation(s)
- Francesco Gatto
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Saeed Dabestani
- Department of Translational Medicine, Division of Urological Cancers, Lund University, Kristianstad Central Hospital, Region Skane, Lund, Sweden
- Department of Urology, Kristianstad Central Hospital, Region Skane, Kristianstad, Sweden
| | - Sinisa Bratulic
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Angelo Limeta
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Francesca Maccari
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Fabio Galeotti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Nicola Volpi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Ulrika Stierner
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
- BioInnovation Institute, Copenhagen N, Denmark
| | - Sven Lundstam
- Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Urology, Sahlgrenska University Hospital, Gothenburg, Sweden
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28
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Lawrence-Mills SJ, Hughes D, Hezzell MJ, Butler M, Neal C, Foster RR, Welsh GI, Finch N. The microvascular endothelial glycocalyx: An additional piece of the puzzle in veterinary medicine. Vet J 2022; 285:105843. [PMID: 35654338 PMCID: PMC9587354 DOI: 10.1016/j.tvjl.2022.105843] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 04/29/2022] [Accepted: 05/25/2022] [Indexed: 01/01/2023]
Abstract
The endothelial glycocalyx (eGlx) is a critically important structure lining the luminal surface of endothelial cells. There is increasing evidence, in human patients and animal models, for its crucial role in the maintenance of health. Moreover, its damage is associated with the pathogenesis of multiple disease states. This review provides readers with an overview of the eGlx; summarising its structure, essential functions, and evidence for its role in disease. We highlight the lack of studies regarding the eGlx in cats and dogs, particularly in naturally occurring diseases. Importantly, we discuss techniques to aid its study, which can be applied to veterinary species. Finally, we present targeted therapies aimed at preserving, and in some cases, restoring damaged eGlx.
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Affiliation(s)
- Sara J Lawrence-Mills
- Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK; current affiliation The Royal Veterinary College, University of London, North Mimms, UK.
| | - David Hughes
- Bristol Veterinary School, University of Bristol, Langford, UK
| | | | - Matthew Butler
- Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK
| | - Chris Neal
- Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK
| | - Rebecca R Foster
- Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK
| | - Gavin I Welsh
- Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK
| | - Natalie Finch
- Bristol Renal, Bristol Medical School, University of Bristol, Bristol, UK; Bristol Veterinary School, University of Bristol, Langford, UK; Langford Vets, Langford House, Langford, UK
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29
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Fernández-Sarmiento J, Molina CF, Salazar-Pelaez LM, Flórez S, Alarcón-Forero LC, Sarta M, Hernández-Sarmiento R, Villar JC. Biomarkers of Glycocalyx Injury and Endothelial Activation are Associated with Clinical Outcomes in Patients with Sepsis: A Systematic Review and Meta-Analysis. J Intensive Care Med 2022; 38:95-105. [PMID: 35722738 DOI: 10.1177/08850666221109186] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Sepsis is one of the main causes of morbidity and mortality worldwide. Microcirculatory impairment, especially damage to the endothelium and glycocalyx, is often not assessed. The objective of this systematic review and meta-analysis was to summarize the available evidence of the risk of unsatisfactory outcomes in patients with sepsis and elevated glycocalyx injury and endothelial activation biomarkers. DESIGN A systematic search was carried out on PubMed/MEDLINE, Embase, Cochrane and Google Scholar up to December 31, 2021, including studies in adults and children with sepsis which measured glycocalyx injury and endothelial activation biomarkers within 48 hours of hospital admission. The primary outcome was the risk of mortality from all causes and the secondary outcomes were the risk of developing respiratory failure (RF) and multiple organ dysfunction syndrome (MODS) in patients with elevations of these biomarkers. MEASUREMENTS AND MAIN RESULTS A total of 17 studies (3,529 patients) were included: 11 evaluated syndecan-1 (n=2,397) and 6 endocan (n=1,132). Syndecan-1 was higher in the group of patients who died than in those who survived [255 ng/mL (IQR: 139-305) vs. 83 ng/mL (IQR:40-111); p=0.014]. Patients with elevated syndecan-1 had a greater risk of death (OR 2.32; 95% CI 1.89, 3.10: p<0.001), MODS (OR 3.3; 95% CI 1.51, 7.25: p=0.003;), or RF (OR 7.53; 95% CI 1.86-30.45: p=0.005). Endocan was higher in patients who died [3.1 ng/mL (IQR 2.3, 3.7) vs. 1.62 ng/mL (IQR 1.2, 5.7); OR 9.53; 95% CI 3.34, 27.3; p<0.001], who had MODS (OR 8.33; 95% CI 2.07, 33.58; p=0.003) and who had RF (OR 9.66; 95% CI 2.26, 43.95; p=0.002). CONCLUSION Patients with sepsis and abnormal glycocalyx injury and endothelial activation biomarkers have a greater risk of developing respiratory failure, multiple organ failure, and death. Microcirculatory impairment should be routinely evaluated in patients with sepsis, using biomarkers to stratify risk groups.
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Affiliation(s)
- Jaime Fernández-Sarmiento
- Department of Pediatrics and Intensive Care, 42705Fundación Cardioinfantil-Instituto de Cardiología, Universidad de La Sabana, Bogotá, Colombia.,113097Universidad CES Graduate School, Medellín, Colombia
| | | | | | - Steffanie Flórez
- Department of Pediatrics and Intensive Care, 42705Fundación Cardioinfantil-Instituto de Cardiología, Universidad de La Sabana, Bogotá, Colombia
| | - Laura Carolina Alarcón-Forero
- Department of Pediatrics and Intensive Care, 42705Fundación Cardioinfantil-Instituto de Cardiología, Universidad de La Sabana, Bogotá, Colombia
| | - Mauricio Sarta
- Department of Pediatrics and Intensive Care, Universidad del Rosario, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
| | - Ricardo Hernández-Sarmiento
- Department of Pediatrics and Intensive Care, 42705Fundación Cardioinfantil-Instituto de Cardiología, Universidad de La Sabana, Bogotá, Colombia
| | - Juan Carlos Villar
- Departament of Research, Fundación Cardioinfantil-Instituto de Cardiología, Bogotá, Colombia
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30
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Sun T, Wang Y, Wu X, Cai Y, Zhai T, Zhan Q. Prognostic Value of Syndecan-1 in the Prediction of Sepsis-Related Complications and Mortality: A Meta-Analysis. Front Public Health 2022; 10:870065. [PMID: 35480580 PMCID: PMC9035829 DOI: 10.3389/fpubh.2022.870065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 02/22/2022] [Indexed: 12/11/2022] Open
Abstract
Aim Syndecan-1 (SDC-1) has been shown to have a high predictive value for sepsis development, though uncertainty around these results exists. The aim of this meta-analysis was to assess the prognostic ability of SDC-1 in predicting sepsis-related complications and mortality. Methods We searched PubMed, EMBASE, Cochrane Library, and Google Scholar databases from January 01, 1990, to March 17, 2021, to identify eligible studies. The search terms used were “SDC-1,” “sepsis,” “severe sepsis,” and “septic shock,” and a meta-analysis was performed using the RevMan 5.4 software. Results Eleven studies with a total of 2,318 enrolled patients were included. SDC-1 concentrations were significantly higher in the composite poor outcome group [standardized mean difference (SMD) = 0.55; 95% CI: 0.38–0.72; P < 0.001] as well as in deceased patients (SMD = 0.53; 95% CI: 0.40–0.67; P < 0.001), patients with septic shock (SMD = 0.81; 95% CI: 0.36–1.25; P < 0.001), and patients with acute kidney injury (SMD = 0.48; 95% CI: 0.33–0.62; P < 0.001). Statistical significance was also found in the subgroup analysis when stratified by different sepsis diagnostic criteria. Conclusion Baseline SDC-1 levels may be a useful predictor of sepsis-related complications and mortality. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021246344, PROSPERO, identifier: CRD42021246344.
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Affiliation(s)
- Ting Sun
- Capital Medical University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Yuqiong Wang
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Xiaojing Wu
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Ying Cai
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Tianshu Zhai
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Qingyuan Zhan
- Capital Medical University China-Japan Friendship School of Clinical Medicine, Beijing, China
- Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
- *Correspondence: Qingyuan Zhan
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31
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Cartotto R, Burmeister DM, Kubasiak JC. Burn Shock and Resuscitation: Review and State of the Science. J Burn Care Res 2022; 43:irac025. [PMID: 35218662 DOI: 10.1093/jbcr/irac025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Indexed: 12/31/2022]
Abstract
Burn shock and acute fluid resuscitation continue to spark intense interest and debate among burn clinicians. Following a major burn injury, fluid resuscitation of burn shock is life-saving, but paradoxically can also be a source of increased morbidity and mortality because of the unintended consequence of systemic edema formation. Considerable research over the past two decades has been devoted to understanding the mechanisms of edema formation, and to develop strategies to curb resuscitation fluids and limit edema development. Recognition of burn endotheliopathy - injury to the endothelium's glycocalyx layer- is one of the most important recent developments in our understanding of burn shock pathophysiology. Newer monitoring approaches and resuscitation endpoints, along with alternative resuscitation strategies to crystalloids alone, such as administration of albumin, or plasma, or high dose ascorbic acid, have had mixed results in limiting fluid creep. Clear demonstration of improvements in outcomes with all of these approaches remains elusive. This comprehensive review article on burn shock and acute resuscitation accompanies the American Burn Association's State of the Science meeting held in New Orleans, LA on November 2-3, 2021 and the Proceedings of that conference published in this journal.
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Affiliation(s)
- Robert Cartotto
- Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, and University of Toronto, Canada
| | - David M Burmeister
- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland and United States Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas USA
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32
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Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review. Clin Pharmacokinet 2022; 61:593-617. [PMID: 35218003 PMCID: PMC9095522 DOI: 10.1007/s40262-021-01102-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2021] [Indexed: 02/07/2023]
Abstract
The pathophysiology of sepsis alters drug pharmacokinetics, resulting in inadequate drug exposure and target-site concentration. Suboptimal exposure leads to treatment failure and the development of antimicrobial resistance. Therefore, we seek to optimize antimicrobial therapy in sepsis by selecting the right drug and the correct dosage. A prerequisite for achieving this goal is characterization and understanding of the mechanisms of pharmacokinetic alterations. However, most infections take place not in blood but in different body compartments. Since tissue pharmacokinetic assessment is not feasible in daily practice, we need to tailor antibiotic treatment according to the specific patient’s pathophysiological processes. The complex pathophysiology of sepsis and the ineffectiveness of current targeted therapies suggest that treatments guided by biomarkers predicting target-site concentration could provide a new therapeutic strategy. Inflammation, endothelial and coagulation activation markers, and blood flow parameters might be indicators of impaired tissue distribution. Moreover, hepatic and renal dysfunction biomarkers can predict not only drug metabolism and clearance but also drug distribution. Identification of the right biomarkers can direct drug dosing and provide timely feedback on its effectiveness. Therefore, this might decrease antibiotic resistance and the mortality of critically ill patients. This article fills the literature gap by characterizing patient biomarkers that might be used to predict unbound plasma-to-tissue drug distribution in critically ill patients. Although all biomarkers must be clinically evaluated with the ultimate goal of combining them in a clinically feasible scoring system, we support the concept that the appropriate biomarkers could be used to direct targeted antibiotic dosing.
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33
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Molema G, Zijlstra JG, van Meurs M, Kamps JAAM. Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury. Nat Rev Nephrol 2022; 18:95-112. [PMID: 34667283 DOI: 10.1038/s41581-021-00489-1] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2021] [Indexed: 12/29/2022]
Abstract
Microvascular endothelial cells in the kidney have been a neglected cell type in sepsis-induced acute kidney injury (sepsis-AKI) research; yet, they offer tremendous potential as pharmacological targets. As endothelial cells in distinct cortical microvascular segments are highly heterogeneous, this Review focuses on endothelial cells in their anatomical niche. In animal models of sepsis-AKI, reduced glomerular blood flow has been attributed to inhibition of endothelial nitric oxide synthase activation in arterioles and glomeruli, whereas decreased cortex peritubular capillary perfusion is associated with epithelial redox stress. Elevated systemic levels of vascular endothelial growth factor, reduced levels of circulating sphingosine 1-phosphate and loss of components of the glycocalyx from glomerular endothelial cells lead to increased microvascular permeability. Although coagulation disbalance occurs in all microvascular segments, the molecules involved differ between segments. Induction of the expression of adhesion molecules and leukocyte recruitment also occurs in a heterogeneous manner. Evidence of similar endothelial cell responses has been found in kidney and blood samples from patients with sepsis. Comprehensive studies are needed to investigate the relationships between segment-specific changes in the microvasculature and kidney function loss in sepsis-AKI. The application of omics technologies to kidney tissues from animals and patients will be key in identifying these relationships and in developing novel therapeutics for sepsis.
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Affiliation(s)
- Grietje Molema
- Dept. Pathology and Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
| | - Jan G Zijlstra
- Dept. Critical Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Matijs van Meurs
- Dept. Pathology and Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Dept. Critical Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jan A A M Kamps
- Dept. Pathology and Medical Biology, Medical Biology section, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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34
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Rizzo AN, Haeger SM, Oshima K, Yang Y, Wallbank AM, Jin Y, Lettau M, McCaig LA, Wickersham NE, McNeil JB, Zakharevich I, McMurtry SA, Langouët-Astrié CJ, Kopf KW, Voelker DR, Hansen KC, Shaver CM, Kerchberger VE, Peterson RA, Kuebler WM, Ochs M, Veldhuizen RA, Smith BJ, Ware LB, Bastarache JA, Schmidt EP. Alveolar epithelial glycocalyx degradation mediates surfactant dysfunction and contributes to acute respiratory distress syndrome. JCI Insight 2022; 7:154573. [PMID: 34874923 PMCID: PMC8855818 DOI: 10.1172/jci.insight.154573] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/03/2021] [Indexed: 12/03/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in patients with ARDS. Using mass spectrometry of airspace fluid noninvasively collected from mechanically ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation. Male patients had increased shedding, which correlated with airspace concentrations of matrix metalloproteinases. Selective epithelial glycocalyx degradation in mice was sufficient to induce surfactant dysfunction, a key characteristic of ARDS, leading to microatelectasis and decreased lung compliance. Rapid colorimetric quantification of airspace glycosaminoglycans was feasible and could provide point-of-care prognostic information to clinicians and/or be used for predictive enrichment in clinical trials.
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Affiliation(s)
- Alicia N. Rizzo
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine
| | - Sarah M. Haeger
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine
| | - Kaori Oshima
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine
| | - Yimu Yang
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine
| | | | - Ying Jin
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine,,Department of Biostatistics and Informatics, School of Public Health, University of Colorado, Aurora, Colorado, USA
| | - Marie Lettau
- Institute of Functional Anatomy, Charité-Universitätsmedizin, Berlin, Germany
| | - Lynda A. McCaig
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
| | - Nancy E. Wickersham
- Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - J. Brennan McNeil
- Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Igor Zakharevich
- Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, Colorado, USA
| | - Sarah A. McMurtry
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine
| | | | - Katrina W. Kopf
- Department of Medicine, National Jewish Health, Denver, Colorado, USA
| | - Dennis R. Voelker
- Department of Medicine, National Jewish Health, Denver, Colorado, USA
| | - Kirk C. Hansen
- Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, Colorado, USA
| | - Ciara M. Shaver
- Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - V. Eric Kerchberger
- Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Ryan A. Peterson
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine,,Department of Biostatistics and Informatics, School of Public Health, University of Colorado, Aurora, Colorado, USA
| | | | - Matthias Ochs
- Institute of Functional Anatomy, Charité-Universitätsmedizin, Berlin, Germany
| | - Ruud A.W. Veldhuizen
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
| | - Bradford J. Smith
- Department of Bioengineering, and,Division of Pulmonary and Sleep Medicine, Department of Pediatrics, University of Colorado, Aurora, Colorado, USA
| | - Lorraine B. Ware
- Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Julie A. Bastarache
- Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Eric P. Schmidt
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine,,Department of Medicine, Denver Health Medical Center, Denver, Colorado, USA
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35
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Masola V, Greco N, Gambaro G, Franchi M, Onisto M. Heparanase as active player in endothelial glycocalyx remodeling. Matrix Biol Plus 2022; 13:100097. [PMID: 35036899 PMCID: PMC8749438 DOI: 10.1016/j.mbplus.2021.100097] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
The surface of all animal cells is coated with a layer of carbohydrates linked in various ways to the outer side of the plasma membrane. These carbohydrates are mainly bound to proteins in the form of glycoproteins and proteoglycans and together with the glycolipids constitute the so-called glycocalyx. In particular, the endothelial glycocalyx that covers the luminal layer of the endothelium is composed of glycosaminoglycans (heparan sulphate -HS and hyaluronic acid -HA), proteoglycans (syndecans and glypicans) and adsorbed plasma proteins. Thanks to its ability to absorb water, this structure contributes to making the surface of the vessels slippery but at the same time acts by modulating the mechano-transduction of the vessels, the vascular permeability and the adhesion of leukocytes in thus regulating several physiological and pathological events. Among the various enzymes involved in the degradation of the glycocalyx, heparanase (HPSE) has been shown to be particularly involved. This enzyme is responsible for the cutting of heparan sulfate (HS) chains at the level of the proteoglycans of the endothelial glycocalyx whose dysfunction appears to have a role in organ fibrosis, sepsis and viral infection. In this mini-review, we describe the mechanisms by which HPSE contributes to glycocalyx remodeling and then examine the role of glycocalyx degradation in the development of pathological conditions and pharmacological strategies to preserve glycocalyx during disease pathogenesis.
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Affiliation(s)
- Valentina Masola
- Renal Unit, Dept. of Medicine, University Hospital of Verona, Verona, Italy.,Dept. of Biomedical Sciences, University of Padova, Padua, Italy
| | - Nicola Greco
- Dept. of Biomedical Sciences, University of Padova, Padua, Italy
| | - Giovanni Gambaro
- Renal Unit, Dept. of Medicine, University Hospital of Verona, Verona, Italy
| | - Marco Franchi
- Dept. of Life Quality Sciences, University of Bologna, Rimini, Italy
| | - Maurizio Onisto
- Dept. of Biomedical Sciences, University of Padova, Padua, Italy
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36
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Association between plasma glycocalyx component levels and poor prognosis in severe influenza type A (H1N1). Sci Rep 2022; 12:163. [PMID: 34997090 PMCID: PMC8741814 DOI: 10.1038/s41598-021-04146-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 11/29/2021] [Indexed: 11/08/2022] Open
Abstract
Influenza A virus infection causes a series of diseases, but the factors associated with disease severity are not fully understood. Disruption of the endothelial glycocalyx contributes to acute lung injury in sepsis, but has not been well studied in H1N1 influenza. We aim to determine whether the plasma glycocalyx components levels are predictive of disease severity in H1N1 influenza. This prospective observational study included 53 patients with influenza A (H1N1) during the influenza season, and 30 healthy controls in our hospital. Patients were grouped by severity and survival. We collected clinical data and blood samples at admission. Inflammatory factors (tumor necrosis factor-α, interleukin-6, interleukin-10) and endothelial glycocalyx components (syndecan-1, hyaluronan, heparan sulfate) were measured. The plasma levels of syndecan-1, hyaluronan, and heparan sulfate were significantly higher in patients with severe influenza A (H1N1) than in mild cases. Syndecan-1 and hyaluronan were positively correlated with disease severity, which was indicated by the APACHE II and SOFA scores and lactate levels, and negatively correlated with albumin levels. At a cutoff point ≥ 173.9 ng/mL, syndecan-1 had a 81.3% sensitivity and 70.3% specificity for predicting of 28-day mortality. Kaplan–Meier analysis demonstrated a strong association between syndecan-1 levels and 28-day mortality (log-rank 11.04, P = 0.001). Elevated plasma levels of syndecan-1 has a potential role in systemic organ dysfunction and may be indicative of disease severity in patients with influenza A (H1N1).
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37
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Analysis of Normal Levels of Free Glycosaminoglycans in Urine and Plasma in Adults. J Biol Chem 2022; 298:101575. [PMID: 35007531 PMCID: PMC8888457 DOI: 10.1016/j.jbc.2022.101575] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/05/2022] [Accepted: 01/06/2022] [Indexed: 01/18/2023] Open
Abstract
Plasma and urine glycosaminoglycans (GAGs) are long, linear sulfated polysaccharides that have been proposed as potential noninvasive biomarkers for several diseases. However, owing to the analytical complexity associated with the measurement of GAG concentration and disaccharide composition (the so-called GAGome), a reference study of the normal healthy GAGome is currently missing. Here, we prospectively enrolled 308 healthy adults and analyzed their free GAGomes in urine and plasma using a standardized ultra-high-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry method together with comprehensive demographic and blood chemistry biomarker data. Of 25 blood chemistry biomarkers, we mainly observed weak correlations between the free GAGome and creatinine in urine and hemoglobin or erythrocyte counts in plasma. We found a higher free GAGome concentration – but not a more diverse composition - in males. Partitioned by gender, we also established reference intervals for all detectable free GAGome features in urine and plasma. Finally, we carried out a transference analysis in healthy individuals from two distinct geographical sites, including data from the Lifelines Cohort Study, which validated the reference intervals in urine. Our study is the first large-scale determination of normal free GAGomes reference intervals in plasma and urine and represents a critical resource for future physiology and biomarker research.
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38
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Endothelial glycocalyx degradation during sepsis: Causes and consequences. Matrix Biol Plus 2021; 12:100094. [PMID: 34917925 PMCID: PMC8668992 DOI: 10.1016/j.mbplus.2021.100094] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/21/2021] [Accepted: 11/23/2021] [Indexed: 12/23/2022] Open
Abstract
The endothelial glycocalyx is a ubiquitous intravascular structure essential for vascular homeostasis. During sepsis, the glycocalyx is degraded via the collective action of a variety of redundant sheddases, the regulation of which remains the focus of active investigation. Septic loss of the glycocalyx imparts both local vascular injury (leading to acute respiratory distress syndrome and acute kidney injury) as well as the systemic consequences of circulating glycosaminoglycan fragments (leading to cognitive dysfunction). Glycocalyx degradation during sepsis is potentially shaped by clinically-modifiable factors, suggesting opportunities for therapeutic intervention to mitigate the end-organ consequences of sepsis. The glycocalyx is a ubiquitous structure found on endothelial cells that extends into the vascular lumen. It is enriched in proteoglycans, which are proteins attached to the glycosaminoglycans heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid. In health and disease, the endothelial glycocalyx is a central regulator of vascular permeability, inflammation, coagulation, and circulatory tonicity. During sepsis, a life-threatening syndrome seen commonly in hospitalized patients, the endothelial glycocalyx is degraded, significantly contributing to its many clinical manifestations. In this review we discuss the intrinsically linked mechanisms responsible for septic endothelial glycocalyx destruction: glycosaminoglycan degradation and proteoglycan cleavage. We then examine the consequences of local endothelial glycocalyx loss to several organ systems and the systemic consequences of shed glycocalyx constituents. Last, we explore clinically relevant non-modifiable and modifiable factors that exacerbate or protect against endothelial glycocalyx shedding during sepsis.
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Key Words
- ADAM, A Disintegrin and Metalloproteinase
- ANP, Atrial Natriuretic Peptide
- ARDS, Acute respiratory distress syndrome
- Ang2, Angiopoietin-2
- DAMP, Damage-associated Molecular Pattern
- Endothelial glycocalyx
- FFP, Fresh Frozen Plasma
- GAG, Glycosaminoglycan
- Glycosaminoglycans
- HPSE-1/2, Heparanase-1/2
- LPS, Lipopolysaccharide
- MMP, Matrix Metalloproteinase
- PG, Proteoglycan
- Proteoglycans
- Sepsis
- TIMP, Tissue inhibitors of matrix metalloproteinase
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39
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Banerjee S, Mwangi JG, Stanley TK, Mitra R, Ebong EE. Regeneration and Assessment of the Endothelial Glycocalyx To Address Cardiovascular Disease. Ind Eng Chem Res 2021. [DOI: 10.1021/acs.iecr.1c03074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Selina Banerjee
- Department of Chemical Engineering, Northeastern University, Boston, Massachusetts 02115, United States
| | - John G. Mwangi
- Department of Biology, Northeastern University, Boston, Massachusetts 02115, United States
| | - Theodora K. Stanley
- Department of Health Sciences, Northeastern University, Boston, Massachusetts 02115, United States
| | - Ronodeep Mitra
- Department of Chemical Engineering, Northeastern University, Boston, Massachusetts 02115, United States
| | - Eno E. Ebong
- Department of Chemical Engineering, Northeastern University, Boston, Massachusetts 02115, United States
- Department of Health Sciences, Northeastern University, Boston, Massachusetts 02115, United States
- Department of Bioengineering, Northeastern University, Boston, Massachusetts 02115, United States
- Department of Neuroscience, Albert Einstein College of Medicine, New York, New York 10461, United States
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40
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Bush MA, Anstey NM, Yeo TW, Florence SM, Granger DL, Mwaikambo ED, Weinberg JB. Vascular Dysfunction in Malaria: Understanding the Role of the Endothelial Glycocalyx. Front Cell Dev Biol 2021; 9:751251. [PMID: 34858979 PMCID: PMC8631294 DOI: 10.3389/fcell.2021.751251] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/27/2021] [Indexed: 01/18/2023] Open
Abstract
Malaria caused by Plasmodium falciparum results in over 400,000 deaths annually, predominantly affecting African children. In addition, non-falciparum species including vivax and knowlesi cause significant morbidity and mortality. Vascular dysfunction is a key feature in malaria pathogenesis leading to impaired blood perfusion, vascular obstruction, and tissue hypoxia. Contributing factors include adhesion of infected RBC to endothelium, endothelial activation, and reduced nitric oxide formation. Endothelial glycocalyx (eGC) protects the vasculature by maintaining vessel integrity and regulating cellular adhesion and nitric oxide signaling pathways. Breakdown of eGC is known to occur in infectious diseases such as bacterial sepsis and dengue and is associated with adverse outcomes. Emerging studies using biochemical markers and in vivo imaging suggest that eGC breakdown occurs during Plasmodium infection and is associated with markers of malaria disease severity, endothelial activation, and vascular function. In this review, we describe characteristics of eGC breakdown in malaria and discuss how these relate to vascular dysfunction and adverse outcomes. Further understanding of this process may lead to adjunctive therapy to preserve or restore damaged eGC and reduce microvascular dysfunction and the morbidity/mortality of malaria.
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Affiliation(s)
- Margaret A Bush
- Duke University School of Nursing and Durham VA Medical Centers, Durham, NC, United States
| | - Nicholas M Anstey
- Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia
| | - Tsin W Yeo
- Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,National Centre for Infectious Diseases, Tan Tock Seng Hospital, Singapore, Singapore
| | | | - Donald L Granger
- School of Medicine, University of Utah and Salt Lake City VA Medical Centers, Salt Lake City, UT, United States
| | | | - J Brice Weinberg
- Duke University School of Medicine and Durham VA Medical Centers, Durham, NC, United States
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41
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Drost CC, Rovas A, Kümpers P. Protection and rebuilding of the endothelial glycocalyx in sepsis - Science or fiction? Matrix Biol Plus 2021; 12:100091. [PMID: 34877522 PMCID: PMC8633034 DOI: 10.1016/j.mbplus.2021.100091] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/14/2021] [Accepted: 10/26/2021] [Indexed: 12/17/2022] Open
Abstract
The endothelial glycocalyx (eGC), a delicate carbohydrate-rich structure lining the luminal surface of the vascular endothelium, is vital for maintenance of microvascular homeostasis. In sepsis, damage of the eGC triggers the development of vascular hyperpermeability with consecutive edema formation and organ failure. While there is evidence that protection or rebuilding of the eGC might counteract sepsis-induced vascular leakage and improve outcome, approved therapeutics are not yet available. This narrative review aims to outline possible therapeutic strategies to ameliorate organ dysfunction caused by eGC impairment.
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Affiliation(s)
- Carolin Christina Drost
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
| | - Alexandros Rovas
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
| | - Philipp Kümpers
- Department of Medicine D, Division of General Internal and Emergency Medicine, Nephrology, and Rheumatology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany
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42
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Bangalore H, Carter MJ, Parmar K, Austin C, Shankar-Hari M, Hunt BJ, Tibby SM. Degradation of the Endothelial Glycocalyx Contributes to Metabolic Acidosis in Children Following Cardiopulmonary Bypass Surgery. Pediatr Crit Care Med 2021; 22:e571-e581. [PMID: 33950888 DOI: 10.1097/pcc.0000000000002746] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Cardiopulmonary bypass surgery is complicated by metabolic acidosis, microvascular dysfunction, and capillary leak. The glycocalyx-a layer of proteins and sugars lining the vascular endothelium-is degraded during cardiopulmonary bypass. We aimed to describe the kinetics of glycocalyx degradation during and following cardiopulmonary bypass. We hypothesized that cleavage of negatively charged fragments of the glycocalyx would directly induce metabolic acidosis through changes in the strong ion gap (defined using Stewart's physicochemical approach to acid-base chemistry). We also investigated whether glycocalyx degradation was associated with failure of endothelial function and cardiovascular dysfunction. DESIGN Single-center prospective cohort study. SETTING Twenty-two bed surgical/medical PICU. PATIENTS Twenty-seven term infants and children requiring cardiopulmonary bypass surgery for the correction/palliation of congenital heart disease. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We recruited 27 patients, 5 days to 57 months old. We prospectively sampled plasma prior to, during, and following cardiopulmonary bypass at predefined time points. We measured plasma concentrations of interleukin-6 (inflammatory marker), heparan sulfate (negatively charged glycocalyx glycosaminoglycan), and syndecan-1 (neutrally charged glycocalyx protein). We defined the following outcome measures: metabolic acidosis (strong ion gap), renal dysfunction (fold change in creatinine), capillary leak (fluid bolus volume), cardiovascular dysfunction (Vasoactive Inotropic Score), and length of ventilation. In linear regression models, maximum measured heparan sulfate concentration (negatively charged) was associated with metabolic acidosis (p = 0.016), renal dysfunction (p = 0.009), and length of ventilation (p = 0.047). In contrast, maximum measured syndecan-1 concentration (neutrally charged) was not associated with these clinical endpoints (p > 0.30 for all). CONCLUSIONS Our data show that metabolic acidosis (increased strong ion gap) is associated with plasma concentration of heparan sulfate, a negatively charged glycosaminoglycan cleaved from the endothelial glycocalyx during cardiopulmonary bypass. In addition, cleavage of heparan sulfate was associated with renal dysfunction, capillary leak, and global markers of cardiovascular dysfunction. These data highlight the importance of designing translational therapies to protect the glycocalyx in cardiopulmonary bypass.
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Affiliation(s)
- Harish Bangalore
- Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Michael J Carter
- Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, St Thomas' Hospital, London, United Kingdom
| | - Kiran Parmar
- Thrombosis and Vascular Biology Research Group, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Conal Austin
- Department of Cardiology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
- Institute of Women and Children's Health, King's College London, St Thomas' Hospital, London, United Kingdom
| | - Manu Shankar-Hari
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
- Department of Intensive Care, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Beverley J Hunt
- Thrombosis and Vascular Biology Research Group, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Shane M Tibby
- Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
- Department of Women and Children's Health, School of Life Course Sciences, King's College London, St Thomas' Hospital, London, United Kingdom
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Queisser KA, Mellema RA, Middleton EA, Portier I, Manne BK, Denorme F, Beswick EJ, Rondina MT, Campbell RA, Petrey AC. COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction. JCI Insight 2021; 6:147472. [PMID: 34314391 PMCID: PMC8492325 DOI: 10.1172/jci.insight.147472] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.
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Affiliation(s)
| | | | - Elizabeth A. Middleton
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Division of General Internal Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Irina Portier
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
| | - Bhanu Kanth Manne
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
| | - Frederik Denorme
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
| | - Ellen J. Beswick
- Department of Pathology and
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Matthew T. Rondina
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Department of Pathology and
- Division of General Internal Medicine, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA
- Geriatric Research, Education, and Clinical Center and
- Department of Internal Medicine, George E. Wahlen Salt Lake City Veterans Affairs Medical Center, Salt Lake City, Utah, USA
| | - Robert A. Campbell
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
| | - Aaron C. Petrey
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Department of Pathology and
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
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44
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Hu Z, Cano I, D’Amore PA. Update on the Role of the Endothelial Glycocalyx in Angiogenesis and Vascular Inflammation. Front Cell Dev Biol 2021; 9:734276. [PMID: 34532323 PMCID: PMC8438194 DOI: 10.3389/fcell.2021.734276] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/12/2021] [Indexed: 12/21/2022] Open
Abstract
The endothelial glycocalyx is a negatively charged, carbohydrate-rich structure that arises from the luminal surface of the vascular endothelium and is comprised of proteoglycans, glycoproteins, and glycolipids. The glycocalyx, which sits at the interface between the endothelium and the blood, is involved in a wide array of physiological and pathophysiological processes, including as a mechanotransducer and as a regulator of inflammation. Most recently, components of the glycocalyx have been shown to play a key role in controlling angiogenesis. In this review, we briefly summarize the structure and function of the endothelial glycocalyx. We focus on its role and functions in vascular inflammation and angiogenesis and discuss the important unanswered questions in this field.
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Affiliation(s)
- Zhengping Hu
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Issahy Cano
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Patricia A. D’Amore
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
- Department of Pathology, Harvard Medical School, Boston, MA, United States
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45
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Bush MA, Florence SM, Yeo TW, Kalingonji AR, Chen Y, Granger DL, Rubach MP, Anstey NM, Mwaikambo ED, Weinberg JB. Degradation of endothelial glycocalyx in Tanzanian children with falciparum malaria. FASEB J 2021; 35:e21805. [PMID: 34403544 DOI: 10.1096/fj.202100277rr] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 06/25/2021] [Accepted: 07/01/2021] [Indexed: 01/20/2023]
Abstract
A layer of glycocalyx covers the vascular endothelium serving important protective and homeostatic functions. The objective of this study was to determine if breakdown of the endothelial glycocalyx (eGC) occurs during malaria infection in children. Measures of eGC integrity, endothelial activation, and microvascular reactivity were prospectively evaluated in 146 children: 44 with moderately severe malaria (MSM), 42 with severe malaria (SM), and 60 healthy controls (HC). Biochemical measures of eGC integrity included plasma syndecan-1 and total urinary glycosaminoglycans (GAG). Side-stream dark field imaging was used to quantitatively assess integrity of eGC. Plasma angiopoietin-2 (Ang-2) was measured as a marker of endothelial activation and also as a possible mediator of eGC breakdown. Our results show that urinary GAG, syndecan-1, and Ang-2 were elevated in patients with MSM and SM compared with HC. Syndecan-1 and GAG levels correlated significantly with each other and with plasma Ang-2. The eGC breakdown products also inversely correlated significantly with hemoglobin and platelet count. In the MSM group, imaging results provided further evidence for eGC degradation. Although not correlated with markers of eGC degradation, vascular function (assessed by non-invasive near infrared spectroscopy [NIRS]) demonstrated reduced microvascular reactivity, particularly affecting the SM group. Our findings provide further evidence for breakdown of eGC in falciparum malaria that may contribute to endothelial activation and adhesion of parasitized red blood cells, with reduced nitric oxide formation, and vascular dysfunction.
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Affiliation(s)
- Margaret A Bush
- School of Medicine, Duke University and Durham VA Medical Centers, Durham, NC, USA
| | | | - Tsin W Yeo
- Menzies School of Health Research, Charles Darwin University, Darwin, Australia.,Lee Kong Chian School of Medicine, Nanyang Technological University, Republic of Singapore.,National Centre for Infectious Diseases, Tan Tock Seng Hospital, Republic of Singapore
| | | | - Youwei Chen
- School of Medicine, Duke University and Durham VA Medical Centers, Durham, NC, USA
| | - Donald L Granger
- University of Utah and VA Medical Centers, Salt Lake City, UT, USA
| | - Matthew P Rubach
- School of Medicine, Duke University and Durham VA Medical Centers, Durham, NC, USA
| | - Nicholas M Anstey
- Menzies School of Health Research, Charles Darwin University, Darwin, Australia
| | | | - Joe Brice Weinberg
- School of Medicine, Duke University and Durham VA Medical Centers, Durham, NC, USA
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46
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Mutoji KN, Sun M, Nash A, Puri S, Hascall V, Coulson-Thomas VJ. Anti-inflammatory protein TNFα-stimulated gene-6 (TSG-6) reduces inflammatory response after brain injury in mice. BMC Immunol 2021; 22:52. [PMID: 34348643 PMCID: PMC8336266 DOI: 10.1186/s12865-021-00443-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 07/09/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Current research suggests that the glial scar surrounding penetrating brain injuries is instrumental in preserving the surrounding uninjured tissue by limiting the inflammatory response to the injury site. We recently showed that tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6), a well-established anti-inflammatory molecule, is present within the glial scar. In the present study we investigated the role of TSG-6 within the glial scar using TSG-6 null and littermate control mice subjected to penetrating brain injuries. RESULTS Our findings show that mice lacking TSG-6 present a more severe inflammatory response after injury, which was correlated with an enlarged area of astrogliosis beyond the injury site. CONCLUSION Our data provides evidence that TSG-6 has an anti-inflammatory role within the glial scar.
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Affiliation(s)
- Kazadi Nadine Mutoji
- College of Optometry, University of Houston, 4901 Calhoun Road, Houston, TX, 77204-2020, USA
| | - Mingxia Sun
- College of Optometry, University of Houston, 4901 Calhoun Road, Houston, TX, 77204-2020, USA
| | - Amanda Nash
- College of Optometry, University of Houston, 4901 Calhoun Road, Houston, TX, 77204-2020, USA
- Department of Bioengineering, Rice University, Houston, TX, 77030, USA
| | - Sudan Puri
- College of Optometry, University of Houston, 4901 Calhoun Road, Houston, TX, 77204-2020, USA
| | | | - Vivien J Coulson-Thomas
- College of Optometry, University of Houston, 4901 Calhoun Road, Houston, TX, 77204-2020, USA.
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47
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Astapenko D, Ticha A, Hyspler R, Tomasova A, Navratil P, Maly O, Parizkova RC, Cizkova D, Huey SC, Lehmann C, Malbrain MLNG, Cerny V. A porcine model of endothelial glycocalyx damage by enzymatic digestion: A pilot study. Clin Hemorheol Microcirc 2021; 78:325-338. [PMID: 33843666 DOI: 10.3233/ch-211133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND The endothelial glycocalyx (EG) plays a vital role in the physiology and pathophysiology of human microcirculation. Having relevant EG damage model would be important tool for testing new interventions aiming at EG protection and recovery. We describe the first in vivo EG damage model in pig. OBJECTIVE To investigate the course of animal EG damage induced by specific enzymes. MATERIAL AND METHODS Four anesthetized piglets received enzymes: 1g hyaluronidase and 25 IU heparanase I intravenously. Blood and urine samples were collected at baseline and 20/40/60/80/100/120 min for detecting markers of endothelial and EG function. Sublingual microcirculation and EG thickness were assessed by Side-stream Dark Field (SDF) imaging and Perfused Boundary Region (PBR) respectively. EG of the mesentery artery was visualized in fluorescent microscopy. RESULTS Biochemical marker of EG damage syndecan-1 showed temporary increase with return to baseline and was reflected by PBR values. Albumin levels suggested brief period of capillary leakage (decrease in the serum, increase in the urine) with a trend to normalization. Urine glycosaminoglycans peaked at 120 minutes. Microcirculatory perfusion parameter showed significant alteration. Diffusion parameters were altered with no statistical significance. CONCLUSION EG damage induced by specific enzymes was reflected by temporary changes of biochemical makers together with alteration of microcirculation and changes in fluorescent microscopy of EG layer. Our results support to further validate presented model of EG damage on a larger number of animals.
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Affiliation(s)
- David Astapenko
- Department of Anesthesiology, Resuscitation and Intensive Care Medicine, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.,Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic
| | - Alena Ticha
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Radomir Hyspler
- Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic.,Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Adela Tomasova
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Pavel Navratil
- Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic.,Department of Urology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Ondrej Maly
- Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic.,Department of Surgery, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.,Faculty of Military Health Sciences, University of Defense Brno, Brno, Czech Republic
| | - Renata Cerna Parizkova
- Department of Anesthesiology, Resuscitation and Intensive Care Medicine, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.,Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic
| | - Dana Cizkova
- Department of Histology and Embryology, Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic
| | - Shin Chua Huey
- Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic
| | - Christian Lehmann
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada
| | - Manu L N G Malbrain
- Faculty of Engineering, Dept. of Electronics and Informatics, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,International Fluid Academy, Lovenjoel, Belgium
| | - Vladimir Cerny
- Department of Anesthesiology, Resuscitation and Intensive Care Medicine, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.,Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic.,Department of Anesthesiology, Perioperative Medicine and Intensive Care, J.E. Purkinje University, Masaryk Hospital, Usti nad Labem, Czech Republic.,Centrum for Research and Development, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.,Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada
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Karampoor S, Zahednasab H, Farahmand M, Mirzaei R, Zamani F, Tabibzadeh A, Bouzari B, Ajdarkosh H, Nikkhah M, Hashemi MR, Laali A, Keyvani H. A possible pathogenic role of Syndecan-1 in the pathogenesis of coronavirus disease 2019 (COVID-19). Int Immunopharmacol 2021; 97:107684. [PMID: 33932696 PMCID: PMC8052477 DOI: 10.1016/j.intimp.2021.107684] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/13/2021] [Accepted: 04/13/2021] [Indexed: 02/08/2023]
Abstract
A cell-surface heparan proteoglycan called Syndecan-1 (SDC-1) has multiple roles in healthy and pathogenic conditions, including respiratory viral infection. In this study, we explore the dynamic alternation in the levels of SDC-1 in cases with COVID-19. A total of 120 cases definitely diagnosed with COVID-19 were admitted to the Firoozgar Hospital, Tehran, Iran, from December 1, 2020, to January 29, 2021, and included in our study. Also, 58 healthy subjects (HS) were chosen as the control group. Patients were classified into two groups: 1) ICU patients and (63 cases) 2) non-ICU patients (57 cases). The dynamic changes of serum SCD-1, CRP, IL-6, IL-10, IL-18, and Vit D levels a well as the disease activity were investigated in three-time points (T1-T3). Our results indicated that the COVID-19 patients had significantly increased SCD-1, CRP, IL-6, IL-10, and IL-18 levels than in HS, while the Vit D levels in COVID-19 patients were significantly lower than HS. Further analysis demonstrated that the SCD-1, CRP, IL-6, IL-10, and IL-18 levels in ICU patients were significantly higher than in non-ICU patients. Tracking dynamic changes in the above markers indicated that on the day of admission, the SCD-1, CRP, IL-6, IL-10, and IL-18 levels were gradually increased on day 5 (T2) and then gradually decreased on day 10 (T3). ROC curve analysis suggests that markers mentioned above, SDC-1, IL-6, and IL-18 are valuable indicators in evaluating the activity of COVID-19. All in all, it seems that the serum SDC-1 levels alone or combined with other markers might be a good candidate for disease activity monitoring.
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Affiliation(s)
- Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamid Zahednasab
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Mohammad Farahmand
- Department of Medical Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Tabibzadeh
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Behnaz Bouzari
- Department of Pathology, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Nikkhah
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Melika Razavi Hashemi
- Department of Pathology, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Azadeh Laali
- Department of Infectious Disease, School of Medicine, Firoozgar General Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Keyvani
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis. Respir Res 2021; 22:193. [PMID: 34217286 PMCID: PMC8254367 DOI: 10.1186/s12931-021-01793-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 06/30/2021] [Indexed: 12/28/2022] Open
Abstract
Background Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. Methods PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. Results In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. Conclusion PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.
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50
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Endothelial Dysfunction and Neutrophil Degranulation as Central Events in Sepsis Physiopathology. Int J Mol Sci 2021; 22:ijms22126272. [PMID: 34200950 PMCID: PMC8230689 DOI: 10.3390/ijms22126272] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/02/2021] [Accepted: 06/08/2021] [Indexed: 12/29/2022] Open
Abstract
Sepsis is a major health problem worldwide. It is a time-dependent disease, with a high rate of morbidity and mortality. In this sense, an early diagnosis is essential to reduce these rates. The progressive increase of both the incidence and prevalence of sepsis has translated into a significant socioeconomic burden for health systems. Currently, it is the leading cause of noncoronary mortality worldwide and represents one of the most prevalent pathologies both in hospital emergency services and in intensive care units. In this article, we review the role of both endothelial dysfunction and neutrophil dysregulation in the physiopathology of this disease. The lack of a key symptom in sepsis makes it difficult to obtain a quick and accurate diagnosis of this condition. Thus, it is essential to have fast and reliable diagnostic tools. In this sense, the use of biomarkers can be a very important alternative when it comes to achieving these goals. Both new biomarkers and treatments related to endothelial dysfunction and neutrophil dysregulation deserve to be further investigated in order to open new venues for the diagnosis, treatment and prognosis of sepsis.
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