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1.
Angiogenesis ; 27(3): 411-422, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38598083

RESUMO

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.


Assuntos
COVID-19 , Glicocálix , Interleucina-6 , Sepse , Humanos , COVID-19/patologia , COVID-19/metabolismo , COVID-19/complicações , Glicocálix/metabolismo , Glicocálix/patologia , Interleucina-6/metabolismo , Interleucina-6/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Sepse/patologia , Sepse/metabolismo , Sepse/complicações , Idoso , Estudos Prospectivos , SARS-CoV-2/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Anticorpos Monoclonais Humanizados
2.
Int J Mol Sci ; 24(6)2023 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-36982455

RESUMO

Soluble fms-like tyrosine kinase-1 (sFlt-1) is a secreted protein that binds heparan sulfate expressed on the endothelial glycocalyx (eGC). In this paper we analyze how excess sFlt-1 causes conformational changes in the eGC, leading to monocyte adhesion, a key event triggering vascular dysfunction. In vitro exposure of primary human umbilical vein endothelial cells to excess sFlt-1 decreased eGC height and increased stiffness as determined by atomic force microscopy (AFM). Yet, structural loss of the eGC components was not observed, as indicated by Ulex europaeus agglutinin I and wheat germ agglutinin staining. Moreover, the conformation observed under excess sFlt-1, a collapsed eGC, is flat and stiff with unchanged coverage and sustained content. Functionally, this conformation increased the endothelial adhesiveness to THP-1 monocytes by about 35%. Heparin blocked all these effects, but the vascular endothelial growth factor did not. In vivo administration of sFlt-1 in mice also resulted in the collapse of the eGC in isolated aorta analyzed ex vivo by AFM. Our findings show that excess sFlt-1 causes the collapse of the eGC and favors leukocyte adhesion. This study provides an additional mechanism of action by which sFlt-1 may cause endothelial dysfunction and injury.


Assuntos
Pré-Eclâmpsia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Humanos , Animais , Camundongos , Feminino , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Glicocálix/metabolismo , Endotélio/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Pré-Eclâmpsia/metabolismo
3.
Angiogenesis ; 25(4): 503-515, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35723762

RESUMO

AIMS: Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients. METHODS AND RESULTS: This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p < 0.0001) in COVID-19. CONCLUSION: Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes.


Assuntos
COVID-19 , Sepse , Adulto , Biomarcadores/metabolismo , Humanos , Microcirculação , Proteoma , Proteômica
4.
Arterioscler Thromb Vasc Biol ; 41(10): e468-e479, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34407633

RESUMO

Objective: ApoM enriches S1P (sphingosine-1-phosphate) within HDL (high-density lipoproteins) and facilitates the activation of the S1P1 (S1P receptor type 1) by S1P, thereby preserving endothelial barrier function. Many protective functions exerted by HDL in extravascular tissues raise the question of how S1P regulates transendothelial HDL transport. Approach and Results: HDL were isolated from plasma of wild-type mice, Apom knockout mice, human apoM transgenic mice or humans and radioiodinated to trace its binding, association, and transport by bovine or human aortic endothelial cells. We also compared the transport of fluorescently-labeled HDL or Evans Blue, which labels albumin, from the tail vein into the peritoneal cavity of apoE-haploinsufficient mice with (apoE-haploinsufficient mice with endothelium-specific knockin of S1P1) or without (control mice, ie, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1) endothelium-specific knockin of S1P1. The binding, association, and transport of HDL from Apom knockout mice and human apoM-depleted HDL by bovine aortic endothelial cells was significantly lower than that of HDL from wild-type mice and human apoM-containing HDL, respectively. The binding, uptake, and transport of 125I-HDL by human aortic endothelial cells was increased by an S1P1 agonist but decreased by an S1P1 inhibitor. Silencing of SR-BI (scavenger receptor BI) abrogated the stimulation of 125I-HDL transport by the S1P1 agonist. Compared with control mice, that is, apoE-haploinsufficient mice without endothelium-specific knockin of S1P1, apoE-haploinsufficient mice with endothelium-specific knockin of S1P1 showed decreased transport of Evans Blue but increased transport of HDL from blood into the peritoneal cavity and SR-BI expression in the aortal endothelium. Conclusions: ApoM and S1P1 promote transendothelial HDL transport. Their opposite effect on transendothelial transport of albumin and HDL indicates that HDL passes endothelial barriers by specific mechanisms rather than passive filtration.


Assuntos
Apolipoproteínas M/metabolismo , Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Lipoproteínas HDL/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Transporte Biológico , Bovinos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Permeabilidade , Placa Aterosclerótica , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Receptores de Esfingosina-1-Fosfato/genética
5.
Int J Mol Sci ; 23(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36555160

RESUMO

(1) Damage to the endothelial glycocalyx (eGC), a protective layer lining the endothelial luminal surface, is associated with chronic kidney disease (CKD), which leads to a worsening of cardiovascular outcomes in these patients. Currently, there are no targeted therapeutic approaches. Whether the dietary supplement EndocalyxTM (ECX) protects against endothelial damage caused by uremic toxins is unknown. (2) We addressed this question by performing atomic force microscopy measurements on living endothelial cells. We examined the effect of ECX on eGC thickness at baseline and with pooled serum from hemodialysis patients. ECX was also successfully administered in vivo in mice, in which eGC was assessed using perfused boundary region measurements by intravital microscopy of cremasteric vessels. (3) Both ECX and fucoidan significantly improved baseline eGC thickness. Our data indicate that these effects are dependent on ERK/MAPK and PI3K signaling. After incubation with eGC damaging serum from dialysis patients, ECX increased eGC height. Intravital microscopy in mice revealed a relevant increase in baseline eGC dimensions after feeding with ECX. (4) We identified a dietary supplement containing glycocalyx substrates and fucoidan as potential mediators of eGC preservation in vitro and in vivo. Our findings suggest that fucoidan may be an essential component responsible for protecting the eGC in acute settings. Moreover, ECX might contribute to both protection and rebuilding of the eGC in the context of CKD.


Assuntos
Glicocálix , Insuficiência Renal Crônica , Animais , Camundongos , Células Endoteliais , Fosfatidilinositol 3-Quinases , Diálise Renal , Insuficiência Renal Crônica/tratamento farmacológico , Humanos
6.
Eur Respir J ; 58(6)2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33986029

RESUMO

BACKGROUND: Defective angiogenesis, incomplete thrombus revascularisation and fibrosis are considered critical pathomechanisms of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism. Angiopoietin-2 (ANGPT2) has been shown to regulate angiogenesis, but its importance for thrombus resolution and remodelling is unknown. METHODS: ANGPT2 plasma concentrations were measured in patients with CTEPH (n=68) and acute pulmonary embolism (n=84). Tissue removed during pulmonary endarterectomy (PEA) for CTEPH was analysed (immuno)histologically. A mouse model of inferior vena cava ligation was used to study the kinetics of venous thrombus resolution in wild-type mice receiving recombinant ANGPT2 via osmotic pumps, and in transgenic mice overexpressing ANGPT2 in endothelial cells. RESULTS: Circulating ANGPT2 levels were higher in CTEPH patients compared to patients with idiopathic pulmonary arterial hypertension and healthy controls, and decreased after PEA. Plasma ANGPT2 levels were elevated in patients with pulmonary embolism and diagnosis of CTEPH during follow-up. Histological analysis of PEA specimens confirmed increased ANGPT2 expression, and low levels of phosphorylated TIE2 were observed in regions with early-organised pulmonary thrombi, myofibroblasts and fibrosis. Microarray and high-resolution microscopy analysis could localise ANGPT2 overexpression to endothelial cells, and hypoxia and transforming growth factor-ß1 were identified as potential stimuli. Gain-of-function experiments in mice demonstrated that exogenous ANGPT2 administration and transgenic endothelial ANGPT2 overexpression resulted in delayed venous thrombus resolution, and thrombi were characterised by lower TIE2 phosphorylation and fewer microvessels. CONCLUSION: Our findings suggest that ANGPT2 delays venous thrombus resolution and that overexpression of ANGPT2 contributes to thrombofibrosis and may thus support the transition from pulmonary embolism to CTEPH.


Assuntos
Angiopoietina-2/sangue , Embolia Pulmonar , Trombose , Animais , Doença Crônica , Endarterectomia , Células Endoteliais , Humanos , Camundongos , Camundongos Transgênicos , Embolia Pulmonar/complicações
7.
Kidney Int ; 97(3): 502-515, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32008804

RESUMO

Dysfunctional high-density lipoprotein (d-HDL) in chronic kidney disease is known to have a change in composition towards an endothelial-damaging phenotype, amongst others, via the accumulation of symmetric dimethylarginine. The endothelial glycocalyx, a carbohydrate-rich layer lining the endothelial luminal surface, is a first line defense against vascular diseases including atherosclerosis. Here we conducted a translational, cross-sectional study to determine the role of symmetric dimethylarginine in d-HDL as a mediator of glycocalyx damage. Using confocal and atomic force microscopy, intact HDL from healthy donors was found to maintain the glycocalyx while isolated HDL from hemodialysis patients and exogenous symmetric dimethylarginine caused significant damage to the glycocalyx in endothelial cells in vitro in a dose-dependent manner. Symmetric dimethylarginine triggered glycocalyx deterioration via molecular pathways mediated by toll-like-receptor 2 and matrix metalloprotease-9. Corresponding intravital microscopy revealed that exogenous symmetric dimethylarginine and d-HDL from hemodialysis patients caused glycocalyx breakdown, which subsequently contributed to alterations in leukocyte rolling. Biologically effective HDL, which estimates the functionality of HDL, was calculated from circulating HDL-cholesterol and symmetric dimethylarginine, as described in the literature. Biologically effective HDL was the only parameter that could independently predict glycocalyx damage in vivo. Thus, our data suggest that symmetric dimethylarginine in d-HDL mediates glycocalyx breakdown in chronic kidney disease.


Assuntos
Glicocálix , Insuficiência Renal Crônica , Arginina/análogos & derivados , Estudos Transversais , Células Endoteliais , Humanos , Lipoproteínas HDL
8.
Int Orthop ; 44(1): 31-38, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127365

RESUMO

BACKGROUND: The diagnosis of low-grade periprosthetic joint infections (PJIs) is challenging, because patients may present with unspecific symptoms, false-negative cultures, or marginally elevated values of serum biomarkers like C-reactive protein (CRP). This may lead to the unintended implantation of a revision prosthesis into an infected surgical site with a repeat risk of short-term failure. Conversely, false diagnosis of joint infection may result in multistage revision procedures, which expose the patient to unnecessary surgical procedures and inappropriate antibiotic treatment. Here, we investigated whether synovial biomarkers can preoperatively distinguish between aseptic prosthesis loosening and low-grade joint infection and the most accurate biomarker combinations. METHODS: Inclusion criteria for the study were indication for revision arthroplasty due to aseptic implant failure, acute high-grade infection, or (suspected) low-grade infection. We prospectively collected synovial fluid of patients undergoing revision arthroplasty for quantitative measurement of alpha defensin, CRP, interleukin (IL-6), IL-10, and lipopolysaccharide binding protein (LBP). RESULTS: The classification tree method revealed alpha defensin and CRP as the most suitable biomarker combination to distinguish between aseptic loosening and low-grade joint infection. The combination of CRP > 2.0 mg/L and alpha defensin > 90.000 pg/mL correctly identified nine  of 11 patients with low-grade infection. CONCLUSIONS: Alpha defensin plus CRP seems to be the most helpful combination for pre-operative discrimination of aseptic loosening vs. low-grade joint infection.


Assuntos
Proteína C-Reativa/análise , Falha de Prótese/etiologia , Infecções Relacionadas à Prótese/diagnóstico , Líquido Sinovial/química , alfa-Defensinas/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Relacionadas à Prótese/classificação , Infecções Relacionadas à Prótese/cirurgia
9.
Crit Care ; 22(1): 44, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29477144

RESUMO

Pulmonary inflammation and vascular leakage are hallmarks of acute respiratory distress syndrome (ARDS), a life-threatening condition, for which there is no specific pharmacologic treatment.Recent literature suggests that leaky vessels in pulmonary infection and ARDS may be mediated through dysregulation of a non-redundant endothelial control pathway, the Tie2 receptor and its ligands, the angiopoietins.This Viewpoint summarizes results from cell-based experiments, animal models and clinical studies underlining the potential of Tie2 targeted interventions in reducing infection-mediated pulmonary hyperpermeability.


Assuntos
Angiopoietina-2/análise , Angiopoietina-2/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Angiopoietina-2/sangue , Biomarcadores/análise , Biomarcadores/sangue , Técnicas de Apoio para a Decisão , Humanos , Receptor TIE-2/efeitos dos fármacos , Receptor TIE-2/metabolismo , Sepse/tratamento farmacológico , Sepse/prevenção & controle , TYK2 Quinase/metabolismo
10.
Eur Surg Res ; 58(5-6): 354-368, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29073603

RESUMO

BACKGROUND: Cardiac surgery often causes ischemia and development of a systemic inflammatory response syndrome, which impairs vascular barrier function, normally maintained by the endothelial cell line and the endothelial glycocalyx (EG). The EG normally covers and protects healthy endothelial cells throughout the vasculature. The aim of the present study was to assess the disruption of the cellular part of the microvascular barrier by determining parameters of endothelial cell activation known to influence and reflect cell-cell junctional integrity. Particular attention was placed on angiopoietins and their important effects on endothelial gap junctions. Furthermore, comparative measurements were undertaken in patients undergoing on- and off-pump cardiac surgery, the latter group presumably experiencing less ischemic stress. METHODS: 30 patients undergoing elective coronary artery bypass surgery were assigned to the conventional coronary artery bypass (CCAB) group (n = 15) or the off-pump coronary artery bypass grafting (OPCAB) group (n = 15). Blood samples were obtained for measuring angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial (VE)-cadherin, and endocan at various time points. RESULTS: There were significant increases in all measured parameters in both study groups versus the respective basal values. Maximal increases were as follows: Ang-1: CCAB +220%, OPCAB +166%, p < 0.05 each; Ang-2: CCAB +150%, OPCAB +20%, p < 0.05 each; VE-cadherin: CCAB +87%, OPCAB +66%, p < 0.05 each; endocan: CCAB +323%, OPCAB +72%, p < 0.05 each. CONCLUSION: The present study demonstrates the activation of endothelial cells, shedding of cell-cell contacts and a potential intrinsic counterregulation by Ang-1 and endocan in patients undergoing major cardiac surgery. Quantitatively greater deviations of parameters in the CCAB than in the OPCAB group suggest a relation between the occurrence of ischemia/reperfusion and the extent of endothelial activation.


Assuntos
Ponte de Artéria Coronária sem Circulação Extracorpórea , Endotélio Vascular/fisiopatologia , Idoso , Angiopoietina-1/sangue , Antígenos CD/sangue , Biomarcadores/sangue , Caderinas/sangue , Endotélio Vascular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteoglicanas/sangue , Proteínas de Transporte Vesicular/sangue
11.
BMC Emerg Med ; 17(1): 11, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28330460

RESUMO

BACKGROUND: Appropriate and timely recognition of sepsis is a prerequisite for starting goal-directed therapy bundles. We analyzed the appropriateness of sepsis recognition and documentation with regard to adequacy of therapy and outcome in an internal medicine emergency department (ED). METHODS: This study included 487 consecutive patients ≥18 years of age who presented to a university hospital ED during a 4-week period. Clinical, laboratory, and follow-up data were acquired independently from documentation by ED physicians. The study team independently rated quality of sepsis classification (American College of Chest Physicians/Society of Critical Care Medicine definitions), diagnostic workup, and guideline-adherent therapy in the ED. RESULTS: Of 487 included patients, 110 presented because of infection. Of those, 54 patients matched sepsis criteria, including 20 with organ damage and thus severe sepsis, as rated by the study team. Sepsis was not recognized in 32 of these 54 cases (59%). Multivariate binary logistic regression analysis revealed that higher systolic blood pressure (p <0.05), the ability to stand (p <0.01) and a low number of documented vital signs in the ED discharge letter (p < 0.05) were independent predictors of missed sepsis. Surprisingly, adequate detection of the septic focus (81 vs. 93%, p = 0.17), appropriate fluid administration (86 vs. 87%, p = 0.39), and guideline-adherent antibiotic regimen (95 vs. 100%, p = 0.42) did not differ between cases of recognized and unrecognized sepsis, respectively. Non-recognition affected neither death-censored length of hospital stay (median 7.63 d vs. 7.13 d, p = 0.42) nor a combined endpoint of death or ICU admission to (9 vs. 12%, p = 0.55). CONCLUSIONS: Non-recognition of sepsis in ED patients with serious infections who formally meet organizational sepsis definitions seems to have no deleterious impact on initial therapy adequacy.


Assuntos
Erros de Diagnóstico/estatística & dados numéricos , Serviço Hospitalar de Emergência/normas , Qualidade da Assistência à Saúde/normas , Sepse/diagnóstico , Adulto , Idoso , Comorbidade , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Alemanha , Mortalidade Hospitalar , Humanos , Estimativa de Kaplan-Meier , Tempo de Internação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Qualidade da Assistência à Saúde/estatística & dados numéricos , Estudos Retrospectivos , Sepse/classificação , Sepse/epidemiologia , Sepse/terapia , Índice de Gravidade de Doença , Estatísticas não Paramétricas
12.
Clin Infect Dis ; 61(3): 332-41, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25870326

RESUMO

BACKGROUND: Late-onset chronic (low-grade) periprosthetic joint infections are often accompanied by unspecific symptoms, false-negative cultures or nonspecific low values of serum biomarkers. This may lead to the unintended implantation of a revision prosthesis into an infected surgical site with the risk of short-term failure developing again. Conversely, false diagnosis of joint infection may result in multistage revision procedures, which expose the patient to unnecessary surgical procedures and inappropriate antibiotic treatment. Here, we investigated whether circulating biomarkers can preoperatively distinguish between aseptic prosthesis loosening and low-grade joint infection, and which biomarker combinations are most accurate. METHODS: Inclusion criteria for the study were indication for revision arthroplasty due to aseptic implant failure, acute high-grade infection, or (suspected) low-grade infection. C-reactive protein (CRP), procalcitonin, tumor necrosis factor α, interleukin 6 (IL-6), interleukin 10, and lipopolysaccharide binding protein were assessed preoperatively in the serum of 98 adult patients. RESULTS: The classification tree method revealed IL-6 and CRP as the most suitable biomarker combination for the discrimination of aseptic loosening vs low-grade joint infection. The combination of IL-6 >5.12 pg/mL and CRP >0.3 mg/dL correctly identified 15 of 16 patients as having low-grade infection (94%) whereas just one patient was aseptic (6%). CONCLUSIONS: This is the first comprehensive prospective clinical study to our knowledge investigating the significance of a combined biomarker approach in differentiating between aseptic prosthesis loosening and low-grade joint infection. CRP plus IL-6 seems to be the most helpful combination for preoperative discrimination of aseptic loosening vs low-grade joint infection.


Assuntos
Biomarcadores/sangue , Prótese de Quadril/efeitos adversos , Prótese do Joelho/efeitos adversos , Falha de Prótese , Infecções Relacionadas à Prótese/diagnóstico , Sepse/diagnóstico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Relacionadas à Prótese/sangue , Infecções Relacionadas à Prótese/epidemiologia , Curva ROC , Sepse/sangue , Sepse/epidemiologia
13.
Mediators Inflamm ; 2015: 670248, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26858516

RESUMO

Escherichia coli O104:H4-associated hemolytic uremic syndrome (HUS) is characterized by Shiga toxin-induced vascular damage. As indicated by recent studies, dysregulation of the angiopoietin (Angpt)/Tie2 ligand receptor system may be crucial for endothelial dysfunction in HUS. Early Angpt-2 levels quantified in 48 adult HUS patients were predictive for a complicated clinical course, in particular for need of hemodialysis and mechanical ventilation as well as occurrence of seizures. In vitro challenge of human umbilical vein endothelial cells with patients' sera indicated an injurious mediator role of Angpt-2 opening future perspectives for mitigating endothelial activation in HUS.


Assuntos
Angiopoietina-2/metabolismo , Síndrome Hemolítico-Urêmica/etiologia , Receptor TIE-2/metabolismo , Escherichia coli Shiga Toxigênica , Adulto , Angiopoietina-2/análise , Estudos de Coortes , Endotélio Vascular/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação
14.
Crit Care Med ; 40(5): 1499-505, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22430236

RESUMO

OBJECTIVE: Angiopoietin-2, an antagonistic ligand of the endothelial Tie2 receptor, has been identified as a gatekeeper of endothelial activation. We examined whether the release of Angiopoietin-2 correlates with surrogates of organ dysfunction and outcome in patients with acute liver failure. DESIGN: Retrospective clinical and immunohistological study. SETTING: Intensive care unit of a university hospital. PATIENTS: Thirty-seven patients with acute liver failure and 20 healthy control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Angiopoietin-2 levels were measured in sera from 37 patients with acute liver failure on admission and from 20 healthy control subjects. Median age of patients with acute liver failure was 34 yrs, 29 were female, and 21 developed encephalopathy grade 3 or greater. Nine patients survived to day 28 without transplantation, five died without transplantation, and 23 received a transplant. Median (interquartile range) Angiopoietin-2 serum concentrations steadily increased across the following groups: healthy control subjects (1.4 [0.9-1.7] ng/mL), patients with transplant-free recovery (10.0 [4.7-12.1] ng/mL), and patients who reached the composite end point of death or emergency liver transplantation (16.8 [11.3-39.5] ng/mL). Angiopoietin-2 release correlated strongly with surrogate markers of organ dysfunction and disease severity measures (lactate, platelet count, Sequential Organ Failure Assessment score, and Simplified Acute Physiology Score III). Angiopoietin-2 levels were higher in patients with acute kidney injury and patients on mechanical ventilation. Furthermore, Angiopoietin-2 levels were closely associated with Bilirubin-Lactate-Etiology score but not with other liver-specific markers. Unadjusted and adjusted Cox's proportional hazards analyses identified Angiopoietin-2 as a predictor of the composite end point of death or transplantation. Finally, immunohistological studies showed that Angiopoietin-2 protein was upregulated in acute liver failure explants compared with matched liver biopsies obtained at baseline. CONCLUSIONS: Collectively, our data show that circulating Angiopoietin-2, which potentially originates from the injured liver, correlates with several features of multiple organ dysfunction syndrome and independently predicts outcome. Tie2 agonists may have potential as an endothelium-targeted therapy to ameliorate multiple organ dysfunction syndrome and improve outcome in acute liver failure.


Assuntos
Angiopoietina-2/sangue , Falência Hepática Aguda/sangue , Adulto , Angiopoietina-2/fisiologia , Biomarcadores/sangue , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Humanos , Fígado/metabolismo , Falência Hepática Aguda/fisiopatologia , Masculino , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/fisiopatologia , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas
15.
Cytokine ; 60(2): 352-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22770562

RESUMO

INTRODUCTION: Endothelial activation leading to vascular barrier dysfunction and organ failure is a well-recognized complication of cardiovascular surgery with cardiopulmonary bypass (CPB). The endothelial-specific angiopoietin-Tie2 ligand-receptor system has been identified as a non-redundant regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to the Tie2 receptor antagonizes Tie2 signaling and renders the endothelial barrier responsive to pro-inflammatory cytokines. We aimed to study the time course and potential triggering factors of Ang-2 release after CPB, as well as the association of Ang-2 changes with surrogates of increased vascular permeability, organ dysfunction, and outcome. METHODS: Serum levels of Ang-2 from 25 adult patients (140 screened) were measured before and at 0, 12, and 24h following CPB procedure by in-house immuno-luminometric assay (ILMA), and compared with indices of organ dysfunction, duration of mechanical ventilation (MV), length of stay (LOS) in the intensive care unit (ICU), and hospital mortality. The effect of Ang-2 was studied in vitro by incubating high Ang-2 patient serum with endothelial cells (EC). RESULTS: Ang-2 levels steadily increased from 2.6 ± 2.4 ng/mL at 0 h up to 7.3 ± 4.6 ng/mL at 24h following CPB (P<0.001). The release of Ang-2 correlated with the duration of CPB, aortic cross-clamp time, and post-CPB lactate levels. Changes in Ang-2 during follow-up correlated with partial pressure of oxygen in arterial blood (PaO(2))/fraction of inspired oxygen (FiO(2)) ratio, alveolar-arterial oxygen tension difference (AaDO(2)), hemodynamics, fluid balance, and disease severity measures. Ang-2 levels at 12h predicted the duration of MV, ICU-LOS, and hospital mortality. High Ang-2 patient sera disrupted EC architecture in vitro, an effect reversed by treatment with the competitive Tie2 ligand angiopoietin-1 (Ang-1). CONCLUSIONS: Collectively, our results suggest that Ang-2 is a putative mediator of endothelial barrier dysfunction after CPB. These findings suggest that targeting the Ang/Tie2 pathway may mitigate organ dysfunction and improve outcome in patients undergoing CPB.


Assuntos
Angiopoietina-2/sangue , Ponte Cardiopulmonar/efeitos adversos , Endotélio/metabolismo , Endotélio/fisiopatologia , Adulto , Idoso , Capilares/patologia , Capilares/fisiopatologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio/patologia , Feminino , Imunofluorescência , Humanos , Hipóxia/sangue , Hipóxia/patologia , Hipóxia/fisiopatologia , Estimativa de Kaplan-Meier , Masculino , Microscopia Confocal , Respiração Artificial , Resultado do Tratamento
16.
Front Immunol ; 13: 916512, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757776

RESUMO

Coronavirus disease 2019 (COVID-19) is a systemic disease associated with injury (thinning) of the endothelial glycocalyx (eGC), a protective layer on the vascular endothelium. The aim of this translational study was to investigate the role of the eGC-degrading enzyme heparanase (HPSE), which is known to play a central role in the destruction of the eGC in bacterial sepsis. Excess activity of HPSE in plasma from COVID-19 patients correlated with several markers of eGC damage and perfused boundary region (PBR, an inverse estimate of glycocalyx dimensions of vessels with a diameter 4-25 µm). In a series of translational experiments, we demonstrate that the changes in eGC thickness of cultured cells exposed to COVID-19 serum correlated closely with HPSE activity in concordant plasma samples (R = 0.82, P = 0.003). Inhibition of HPSE by a nonanticoagulant heparin fragment prevented eGC injury in response to COVID-19 serum, as shown by atomic force microscopy and immunofluorescence imaging. Our results suggest that the protective effect of heparin in COVID-19 may be due to an eGC-protective off-target effect.


Assuntos
COVID-19 , Glucuronidase , Glicocálix , COVID-19/metabolismo , COVID-19/patologia , Glucuronidase/metabolismo , Glicocálix/metabolismo , Glicocálix/patologia , Heparina/farmacologia , Humanos
17.
Crit Care Med ; 39(1): 184-6, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21057310

RESUMO

OBJECTIVE: The objective of this study was to test the ability of myoglobin removal of a novel, high-permeability polysulphone dialyzer in acute kidney injury as a result of rhabdomyolysis. SETTING: Intensive care unit of a tertiary care hospital. PATIENTS: Six patients (one female; aged 24, 36, 41, 55, 63, and 65 yrs) with oligoanuric acute kidney injury resulting from rhabdomyolysis. INTERVENTIONS: Extended dialysis was performed using a single-pass batch dialysis system and a novel polysulphone high-flux dialyzer (effective surface area 1.8 m; inner lumen 220 µm; wall thickness 35 µm; allowing elimination of substances with a molecular weight of up to 30 kDa). MEASUREMENTS AND MAIN RESULTS: Samples were collected at prefilter and postfilter sites as well as from the collected spent dialysate. The dialyzer clearance was calculated from concentrations before and directly after the dialysis membrane, the blood flow, and the ultrafiltration rate. The total amount of the myoglobin removed was measured directly as the whole dialysate was preserved. A median myoglobin clearance of 90.5 mL/min (range, 52.4-126.3 mL/min) was achieved, resulting in a median myoglobin removal per treatment hour of 0.54 g (range, 0.15-2.21 g). CONCLUSIONS: Extended dialysis with a high-flux, high-permeability membrane allowed effective elimination of myoglobin with a clearance of myoglobin that surpassed all previously reported dialysis techniques. This membrane may be advantageous in preventing acute kidney injury or avoiding complete loss of kidney function in patients with rhabdomyolysis. Further studies are needed to determine whether improving renal recovery or mortality in patients with acute kidney injury resulting from rhabdomyolysis is possible.


Assuntos
Injúria Renal Aguda/terapia , Hemofiltração/instrumentação , Membranas Artificiais , Mioglobina/metabolismo , Rabdomiólise/complicações , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Adulto , Idoso , Permeabilidade Capilar , Creatinina/sangue , Cuidados Críticos/métodos , Estado Terminal/mortalidade , Estado Terminal/terapia , Feminino , Seguimentos , Hemofiltração/métodos , Humanos , Unidades de Terapia Intensiva , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Mioglobina/análise , Rabdomiólise/diagnóstico , Estudos de Amostragem , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
18.
Eur Heart J ; 31(18): 2291-300, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20601390

RESUMO

AIMS: To determine the diagnostic utility of circulating angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) as potential biomarkers of disease severity or response to treatment in idiopathic pulmonary arterial hypertension (IPAH). Imbalances in angiogenic factors including vascular endothelial cell growth factor (VEGF) and the angiopoetin-Tie2 receptor system have been implicated in the pathogenesis of IPAH. METHODS AND RESULTS: Plasma Ang-1, Ang-2, soluble Tie2 (sTie2), and VEGF were determined by in-house immunoassays in two cohorts of IPAH patients: a retrospective cohort (n = 81) and a prospective cohort (n = 25). Ten patients with normal pulmonary artery pressures and 14 apparently healthy subjects served as controls. Plasma levels of all angiogenic factors were elevated in IPAH patients compared with controls (all P < 0.005). Angiopoietin-2, but not Ang-1, sTie2, and VEGF correlated with cardiac index (r = -0.53, P < 0.001), pulmonary vascular resistance (PVR) (r= 0.60, P < 0.001), and mixed venous oxygen saturation (SvO(2)) (r= -0.63, P < 0.001). In multivariate analysis, elevated Ang-2 was an independent risk factor of mortality (P = 0.004). The patients in the prospective cohort were studied longitudinally at baseline and 3 months after initiation of therapy. Changes in Ang-2 after initiation of therapy correlated with changes in mean right atrial pressure (r = 0.6, P = 0.008), PVR (r = 0.51, P = 0.04), and inversely related to changes in SvO(2) (r = -0.75, P < 0.001). Histological studies showed that the expression of Ang-2 mRNA and protein was up-regulated in plexiform lesions from IPAH lung tissue samples. CONCLUSION: Ang-2 may be involved in the pathogenesis of IPAH, and plasma Ang-2 might serve as a promising new biomarker of disease severity and response to treatment in patients with IPAH.


Assuntos
Angiopoietina-1/sangue , Angiopoietina-2/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/terapia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/sangue
19.
Ann Hematol ; 89(5): 459-67, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20054548

RESUMO

Angiogenesis plays an important role in the growth and viability of hematologic malignancies. Emerging data suggest a crucial involvement of the endothelial-specific Tie2 receptor and its antagonistic ligand Angiopoietin-2 (Ang-2) in this process. The purpose of this study was to elucidate whether the soluble domain of the Tie2 receptor (sTie2)predicts outcome in patients with acute myeloid leukemia(AML) undergoing allogeneic hematopoietic stem cell transplantation(HSCT). Serum levels of sTie2 and Ang-2 were measured by ELISA in 181 AML patients before conditioning for HSCT. The median follow-up time was 22 months after HSCT. Pre-HSCT sTie2 levels were significantly higher inpatients (median 2.2 (range 1.8-3.0) ng/mL) compared to healthy controls (1.3 (0.9-1.6); p<0.0001). Elevated sTie2 levels were independently associated with active AML but did not relate to cytogenetics/mutational status before transplantation. Logistic regression analysis identified elevated sTie2 (odds ratio (OR) 3.07 (95% confidence interval(CI; 1.56-6.04), p=0.001) as a strong predictor for disease relapse and poor overall survival after HSCT. In a multimarker approach the highest risk for relapse was observed inpatients with both elevated sTie2 and elevated Ang-2 (OR 4.07, (95% CI 1.79-9.25) p<0.0001), as well as patients with both elevated Ang-2 and elevated bone marrow blast count (OR 4.16, (95% CI 1.88-7.36) p<0.0001). Elevated serum sTie2 levels were related to active leukemia,correlated with the percentage of leukemic blasts in the bone marrow, and independently predicted relapse in AML patients after allogeneic HSCT. Furthermore, our data indicate that Tie2 shedding and Ang-2 release seem to reflect overlapping, but nevertheless distinctive features in leukemia-associated neoangiogenesis.


Assuntos
Biomarcadores Tumorais/sangue , Crise Blástica/sangue , Endotélio Vascular/citologia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/cirurgia , Receptor TIE-2/sangue , Adulto , Estudos de Coortes , Endotélio Vascular/metabolismo , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Estrutura Terciária de Proteína , Taxa de Sobrevida/tendências , Transplante Homólogo , Resultado do Tratamento , Carga Tumoral/fisiologia
20.
Nephrol Dial Transplant ; 25(8): 2571-6, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20179005

RESUMO

BACKGROUND: Angiopoietin-2 (Ang-2) is an antagonistic ligand of the endothelial-specific Tie2 receptor. Patients on dialysis have markedly elevated Ang-2 levels, and those correlate with their atherosclerotic burden. The aim of the current study was to investigate the relationship between the circulating levels of Ang-2 and renal function throughout all stages of chronic kidney disease (CKD). In addition, we aimed to detect a potential link between the nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) and the Ang-2 levels. METHODS: Glomerular filtration rate (GFR) was assessed by the inulin clearance technique ((i)GFR) and compared to serum Ang-2 (immunoluminometric assay) and ADMA levels (liquid chromatography-electrospray tandem mass spectrometry) in 44 untreated non-smokers at the different stages of CKD 1-4. Ang-2 was also measured in 19 patients on dialysis (CKD stage 5). In addition, the Ang-2 and (c)GFR (cystatin C) measurements were taken in 15 healthy individuals before and 72 h after kidney donation. RESULTS: The median Ang-2 levels steadily increased across the following groups: healthy controls: 0.77 (0.32-1.08) ng/mL; CKD 1: 0.83 (0.67-1.09) ng/mL; CKD 2: 0.93 (0.74-1.15) ng/mL; CKD 3: 1.13 (0.87-1.49) ng/mL; CKD 4: 1.75 (1.23-2.61) ng/mL; and CKD 5: 4.87 (3.22-7.59) ng/mL, respectively (non-parametric ANOVA P < 0.0001). Ang-2 was associated with the degree of CKD as evidenced by an inverse correlation with the (i)GFR (r = -0.509, P < 0.0001) and positive correlations with homocysteine (r = 0.365, P = 0.015) and phosphate (r = 0.53, P < 0.0001). Additionally, Ang-2 correlated with the ADMA levels (r = 0.35, P = 0.01). We detected a close inverse correlation between the mean changes in GFR and circulating Ang-2 at 72 h after kidney donation (r = -0.54, P = 0.03). CONCLUSIONS: Circulating Ang-2, a putative marker and potential mediator of accelerated atherosclerosis, is inversely related to GFR and increases with advanced CKD. The correlation between Ang-2 and ADMA points towards the hypothesis that the ADMA-driven NO deficiency might trigger Ang-2 release and account for the Ang-2 increase in CKD patients.


Assuntos
Angiopoietina-2/sangue , Progressão da Doença , Nefropatias/sangue , Nefropatias/fisiopatologia , Adulto , Idoso , Arginina/análogos & derivados , Arginina/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Nefropatias/complicações , Masculino , Pessoa de Meia-Idade , Nefrectomia , Fatores de Risco , Doadores de Tecidos
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