RESUMEN
BACKGROUND: The incidence of diabetic kidney disease (DKD) continues to rapidly increase, with limited available treatment options. One of the hallmarks of DKD is persistent inflammation, but the underlying molecular mechanisms of early diabetic kidney injury remain poorly understood. C-X-C chemokine receptor 2 (CXCR2), plays an important role in the progression of inflammation-related vascular diseases and may bridge between glomerular endothelium and persistent inflammation in DKD. METHODS: Multiple methods were employed to assess the expression levels of CXCR2 and its ligands, as well as renal inflammatory response and endothelial glycocalyx shedding in patients with DKD. The effects of CXCR2 on glycocalyx shedding, and persistent renal inflammation was examined in a type 2 diabetic mouse model with Cxcr2 knockout specifically in endothelial cells (DKD-Cxcr2 eCKO mice), as well as in glomerular endothelial cells (GECs), cultured in high glucose conditions. RESULTS: CXCR2 was associated with early renal decline in DKD patients, and endothelial-specific knockout of CXCR2 significantly improved renal function in DKD mice, reduced inflammatory cell infiltration, and simultaneously decreased the expression of proinflammatory factors and chemokines in renal tissue. In DKD conditions, glycocalyx shedding was suppressed in endothelial Cxcr2 knockout mice compared to Cxcr2 L/L mice. Modulating CXCR2 expression also affected high glucose-induced inflammation and glycocalyx shedding in GECs. Mechanistically, CXCR2 deficiency inhibited the activation of NF-κB signaling, thereby regulating inflammation, restoring the endothelial glycocalyx, and alleviating DKD. CONCLUSIONS: Taken together, under DKD conditions, activation of CXCR2 exacerbates inflammation through regulation of the NF-κB pathway, leading to endothelial glycocalyx shedding and deteriorating renal function. Endothelial CXCR2 deficiency has a protective role in inflammation and glycocalyx dysfunction, suggesting its potential as a promising therapeutic target for DKD treatment.
Asunto(s)
Nefropatías Diabéticas , FN-kappa B , Receptores de Interleucina-8B , Animales , Humanos , Ratones , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Células Endoteliales/metabolismo , Endotelio/metabolismo , Glucosa , Glicocálix/metabolismo , Inflamación/metabolismo , Ratones Noqueados , FN-kappa B/metabolismo , Receptores de Quimiocina/uso terapéutico , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Complicaciones de la Diabetes/genética , Complicaciones de la Diabetes/metabolismoRESUMEN
The glycocalyx is a layer composed of carbohydrate side chains bound to core proteins that lines the vascular endothelium. The integrity of the glycocalyx is essential for endothelial cells' performance and vascular homeostasis. The neuroendocrine and immune systems influence the composition, maintenance, activity and degradation of the endothelial glycocalyx. The female organism has unique characteristics, and estrogen and progesterone, the main female hormones are essential to the development and physiology of the reproductive system and to the ability to develop a fetus. Female sex hormones also exert a wide variety of effects on other organs, including the vascular endothelium. They upregulate nitric oxide synthase expression and activity, decrease oxidative stress, increase vasodilation, and protect from vascular injury. This review will discuss how female hormones and pregnancy, which prompts to high levels of estrogen and progesterone, modulate the endothelial glycocalyx. Diseases prevalent in women that alter the glycocalyx, and therapeutic forms to prevent glycocalyx degradation and potential treatments that can reconstitute its structure and function will also be discussed.
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Glicocálix , Progesterona , Embarazo , Humanos , Femenino , Progesterona/metabolismo , Progesterona/farmacología , Glicocálix/metabolismo , Células Endoteliales/metabolismo , Vasodilatación , Estrógenos/metabolismo , Estrógenos/farmacologíaRESUMEN
BACKGROUND: The pathophysiology of cardiac arrest (CA) involves over-activation of systemic inflammatory responses, relative adrenal insufficiency, and glycocalyx damage. Corticosteroids have beneficial effects in preventing the perturbation of the endothelial glycocalyx. OBJECTIVES: The aim of this systematic review was to determine the efficacy of glucocorticoids in patients with cardiac arrest. METHODS: We searched PubMed, Scopus, ISI Web of Science, Google Scholar, and Cochrane central register for relevant clinical trials and cohort studies until September 2019. RESULTS: We retrieved 7 peer-reviewed published studies for the systematic review. Two studies were clinical trials evaluating 147 patients, while five illustrated cohort design, evaluating 196,192 patients. In total, 196,339 patients were assessed. There was limited evidence and conflicting results to establish a correlation between glucocorticoids and the survival of patients suffering from cardiac arrest. However, the links between these medications and survival-to-admission, survival-to discharge, and 1-year survival rates were strong and consistent in observational studies. CONCLUSION: The clinical evidence regarding the efficacy and safety of glucocorticoids in CA is limited to observational studies with inconsistent methodology and few clinical trials with a small sample size. Nevertheless, it seems that glucocorticoid supplementation during and after cardiopulmonary resuscitation (CPR) may have beneficial effects in terms of survival-to-admission, survival to discharge, 1-year survival rates, and an improved return of spontaneous circulation (ROSC) rate, especially in patients with hemodynamic instability and cardiovascular diseases (i.e., refractory hemodynamic shock). Future studies with high-quality, large-scale, long-term intervention and precise baseline characteristics are needed to evaluate the exact effective dose, duration, and efficacy of glucocorticoids in CA.
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Reanimación Cardiopulmonar , Paro Cardíaco , Corticoesteroides , Glucocorticoides/uso terapéutico , Paro Cardíaco/tratamiento farmacológico , Hospitalización , HumanosRESUMEN
Ricin toxin isolated from the castor bean (Ricinus communis) is one of the most potent and lethal molecules known. While the pathophysiology and clinical consequences of ricin poisoning by the parenteral route, i.e., intramuscular penetration, have been described recently in various animal models, the preceding mechanism underlying the clinical manifestations of systemic ricin poisoning has not been completely defined. Here, we show that following intramuscular administration, ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages. Increased levels of circulating VEGF and decreased expression of vascular VE-cadherin caused blood vessel impairment, thereby promoting hyperpermeability in various organs. Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication, indicating that the vascular glycocalyx of both mice and swine underwent extensive damage. Finally, by using side-stream dark field intravital microscopy imaging, we determined that ricin poisoning leads to microvasculature malfunctioning, as manifested by aberrant blood flow and a significant decrease in the number of diffused microvessels. These findings, which suggest that glycocalyx shedding and microcirculation dysfunction play a major role in the pathology of systemic ricin poisoning, may serve for the formulation of specifically tailored therapies for treating parenteral ricin intoxication.
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Células Endoteliales/efectos de los fármacos , Glicocálix/efectos de los fármacos , Ricina/toxicidad , Ricinus/química , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Relación Dosis-Respuesta a Droga , Células Endoteliales/citología , Células Endoteliales/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Glicocálix/química , Glicocálix/metabolismo , Heparitina Sulfato/química , Heparitina Sulfato/metabolismo , Humanos , Ácido Hialurónico/química , Ácido Hialurónico/metabolismo , Hidrólisis , Inyecciones Intramusculares , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones , Microcirculación/efectos de los fármacos , Ricina/aislamiento & purificación , Bazo/efectos de los fármacos , Bazo/metabolismo , Bazo/patología , Porcinos , Sindecano-1/química , Sindecano-1/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: Severe burns cause hypermetabolic and inflammatory responses are treated with significant volume resuscitation. This study aimed to evaluate correlations between glycocalyx metabolites and the burn size as well as certain clinical parameters such as administered fluid volumes. STUDY DESIGN: Severely burned patients with a total body surface area (TBSA) burned smaller and larger than 20% were included. Clinical parameters including length of stay, mortality, fluid administration and Sequential Organ Failure Assessment (SOFA) score as well as syndecan and heparansulfate, as laboratory parameters for endothelial damage, were obtained. RESULTS: A total of 39 patients (32 males, 7 females) with a mean age at burn of 45 ± 21 years were included. Syndecan levels decreased and heparansulfate levels increased over time. In both heparansulfate and syndecan, there was no significant difference between burns smaller and larger than 20% TBSA at any time point. Syndecan levels at 24 h after burn correlated significantly with IL-10 levels at admission (R = 0.58 and p < 0.05). There were significant linear correlations of %TBSA and cumulative administration of fluids after 24 h on syndecan levels after 48 h. Correlations between clinical parameters and syndecan or heparansulfate levels over time were not found. CONCLUSIONS: This study shows that even though there are moderate correlations with burn size and administered fluid volume, levels of syndecan and heparansulfate are not predictive for clinical outcomes of burned patients in our cohort. Further studies with higher numbers evaluating the effect of large burns on glycocalyx shedding over a longer period of time are needed. Showing significant glycocalyx shedding in large burn including potentially correlations with clinical outcomes may yield new therapeutic targets.
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Quemaduras/complicaciones , Endotelio/metabolismo , Glicocálix/metabolismo , Adulto , Análisis de Varianza , Superficie Corporal , Quemaduras/metabolismo , Quemaduras/fisiopatología , Endotelio/lesiones , Femenino , Fluidoterapia/métodos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resucitación/métodosRESUMEN
Severe malaria is mostly caused by Plasmodium falciparum, resulting in considerable, systemic inflammation and pronounced endothelial activation. The endothelium forms an interface between blood and tissue, and vasculopathy has previously been linked with malaria severity. We studied the extent to which the endothelial glycocalyx that normally maintains endothelial function is involved in falciparum malaria pathogenesis by using incident dark-field imaging in the buccal mucosa. This enabled calculation of the perfused boundary region, which indicates to what extent erythrocytes can permeate the endothelial glycocalyx. The perfused boundary region was significantly increased in severe malaria patients and mirrored by an increase of soluble glycocalyx components in plasma. This is suggestive of a substantial endothelial glycocalyx loss. Patients with severe malaria had significantly higher plasma levels of sulfated glycosaminoglycans than patients with uncomplicated malaria, whereas other measured glycocalyx markers were raised to a comparable extent in both groups. In severe malaria, the plasma level of the glycosaminoglycan hyaluronic acid was positively correlated with the perfused boundary region in the buccal cavity. Plasma hyaluronic acid and heparan sulfate were particularly high in severe malaria patients with a low Blantyre coma score, suggesting involvement in its pathogenesis. In vivo imaging also detected perivascular hemorrhages and sequestering late-stage parasites. In line with this, plasma angiopoietin-1 was decreased while angiopoietin-2 was increased, suggesting vascular instability. The density of hemorrhages correlated negatively with plasma levels of angiopoietin-1. Our findings indicate that as with experimental malaria, the loss of endothelial glycocalyx is associated with vascular dysfunction in human malaria and is related to severity.
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Endotelio Vascular/patología , Glicocálix/patología , Malaria Falciparum/patología , Mucosa Bucal/patología , Hemorragia Bucal/patología , Angiopoyetina 1/sangre , Angiopoyetina 2/sangre , Biomarcadores/sangre , Niño , Preescolar , Endotelio Vascular/fisiopatología , Femenino , Glicosaminoglicanos/sangre , Humanos , Lactante , Malaria Falciparum/sangre , Malaria Falciparum/diagnóstico por imagen , Malaria Falciparum/fisiopatología , Masculino , Mucosa Bucal/irrigación sanguínea , Mucosa Bucal/diagnóstico por imagen , Mucosa Bucal/fisiopatología , Hemorragia Bucal/sangre , Hemorragia Bucal/diagnóstico por imagen , Hemorragia Bucal/fisiopatologíaRESUMEN
To determine (a) whether chronic heart failure with reduced ejection fraction (HFrEF) is associated with increased glycocalyx shedding; (b) whether glycocalyx shedding in HFrEF with left ventricular dyssynchrony is related to inflammation, endothelial dysfunction and/or redox stress and is ameliorated by cardiac resynchronisation therapy. Glycocalyx shedding has been reported to be increased in heart failure and is a marker of increased mortality. Its role in dyssynchronous systolic heart failure and the effects of cardiac resynchronisation therapy (CRT) are largely unknown. Twenty-six patients with dyssynchronous HFrEF were evaluated before and 6 months after CRT insertion. Echocardiographic septal to posterior wall delay (SPWD) assessed intra-ventricular mechanical dyssynchrony, and quality of life, integrity of nitric oxide (NO) signalling, inflammatory and redox-related biomarkers were measured. Glycocalyx shedding was quantitated via plasma levels of the glycocalyx component, syndecan-1. Syndecan-1 levels pre-CRT were inversely correlated with LVEF (r = - 0.45, p = 0.02) and directly with SPWD (r = 0.44, p = 0.02), QOL (r = 0.39, p = 0.04), plasma NT-proBNP (r = 0.43, p = 0.02), and the inflammatory marker, symmetric dimethylarginine (SDMA) (r = 0.54, p = 0.003). On multivariate analysis, syndecan-1 levels were predicted by SPWD and SDMA (ß = 0.42, p = 0.009 and ß = 0.54, p = 0.001, respectively). No significant correlation was found between syndecan-1 levels and other markers of endothelial dysfunction/inflammatory activation. Following CRT there was no significant change in syndecan-1 levels. In patients with dyssynchronous HFrEF, markers of glycocalyx shedding are associated with the magnitude of mechanical dyssynchrony and elevation of SDMA levels and inversely with LVEF. However, CRT does not reverse this process.
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Terapia de Resincronización Cardíaca , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Glicocálix/metabolismo , Insuficiencia Cardíaca Sistólica/terapia , Sindecano-1/sangre , Disfunción Ventricular Izquierda/terapia , Anciano , Biomarcadores/sangre , Enfermedad Crónica , Endotelio Vascular/fisiopatología , Femenino , Insuficiencia Cardíaca Sistólica/sangre , Insuficiencia Cardíaca Sistólica/diagnóstico , Insuficiencia Cardíaca Sistólica/fisiopatología , Humanos , Masculino , Volumen Sistólico , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular IzquierdaRESUMEN
Limited information exists regarding endothelial dysfunction following burn injury. This project aims to evaluate whether thermal injury results in shedding of the endothelial glycocalyx in a manner quantitatively proportional to injury severity, and whether theloss of intact glycocalyx is measurable in end organs. C57BL/6 mice were grouped as uninjured controls, 10% or 25% Total Body Surface Area (TBSA) scald burns. Blood and tissue sampling was performed over a specific time course. Plasma levels of shed syndecan-1, a marker of glycocalyx damage, were quantified by ELISA. Lung and spleen sections were stained with immunofluorescent anti-syndecan-1 antibodies to evaluate intact glycocalyx. Plasma syndecan-1 levels were higher in injured versus uninjured animals. Normalized levels of syndecan-1 in burned mice were significantly increased compared to hour 0 (p<0.05) at hours 4 and 8 post-injury in the 10% TBSA, and at hour 4 in the 25% TBSA group. Levels in the 10% and 25% TBSA groups peaked at hour 4 with fold change of 2.3 and 2.4 respectively. There was less pulmonary syndecan-1 immunostaining in burned animals compared to controls, and the levels inversely correlated with systemic shed syndecan- 1, beginning at hour 4 in the 10% TBSA injury group and at all time points in the 25% TBSA injury group, (0.27±0.06 and 0.14±0.04 respectively for hour 4). Similarly, there was less spleen syndecan-1 immunostaining in burned animals compared to controls at all time points. Burn injury causes shedding of syndecan-1 in a murine model, with levels correlated to injury severity and loss of the glycocalyx in lung and spleen. This work provides further insight into quantification and temporality of glycocalyx damage and systemic response to burn.
Les données concernant la dysfonction endothéliale après brûlure sont parcellaires. Les buts de cette étude étaient d'établir une corrélation entre la perte de glycocalyx et la gravité de la brûlure et si cette perte était mesurable au niveau des organes. Des souris C57BL/6 ont été réparties en groupes contrôle, brûlure 10% et brûlure 25% de SCT. Des prélèvements de sang et de tissus ont été réalisés à intervalles prédéterminés. Les taux plasmatiques de syndecan 1 (S1), marqueur de lésion du glycocalyx, ont été mesuré par méthode ELISA. Des échantillons de poumon et de rate ont été mis en présence d'anticorps anti S1, afin d'évaluer le glycocalyx intact. Les taux plasmatiques de S1 étaient plus élevés que ceux du groupe contrôle. Chez les souris brûlées sur 10% de SCT, les taux de S1 à 4h et 8 h étaient supérieurs au taux avant brûlure, ceci n'étant observé qu'à h4 chez les souris brûlées sur 25% de SCT. Le pic de S1 se produisait à h4, avec un rapport de x2,3 (10%) et x2,4 (25%) par rapport à la valeur de base. A partir de h4, on observait une baisse de complexes S1-antiS1 dans les poumons des souris brûlées sur 10% (0,27 +/- 0,06), inversement corrélée aux taux plasmatiques de S1. Cette observation se répétait lors de tous les dosages chez les 25% (0,14 +/- 0,04 à h4). Les mêmes constatations étaient faites sur les échantillons de rate. La brûlure cause des lésions du glycocalyx, parallèles à sa gravité. Ces travaux ouvrent le champ à des recherches futures sur les lésions du glycocalyx et la réponse inflammatoire aux brûlures.
RESUMEN
BACKGROUND: Acute myocardial infarction (AMI) and other forms of myocardial acute oxidative stress are associated with variable "shedding" of the endothelial glycocalyx (GCS) which can be quantitated ex vivo by release into plasma of glycocalyx components such as Syndecan-1 (SD-1). Previous studies have implicated release of both catecholamines and BNP as potential accentuating factors in GCS: since these are prominent aspects of the pathogenesis of Takotsubo cardiomyopathy (TTC), we hypothesised that TTC is associated with increased GCS and the extent of GCS is predictable on the basis of NT-proBNP and catecholamine releases. METHODS: SD-1 concentrations were measured in 48 TTC patients acutely and after 3months, and compared with those in 12 healthy controls, and 17 patients with AMI. Correlations were sought between SD-1 levels markers of severity of TTC episodes in individual patients. RESULTS: Acute SD-1 concentrations in TTC patients were elevated significantly (p<0.0001, 1-way ANOVA) compared to control values. There were no significant correlations between SD-1 concentrations and any markers of severity of acute TTC episodes, such as NT-proBNP or catecholamine release. Over 3months, SD-1 concentrations fell significantly (p=0.0002) to approximately the same values as in control subjects. CONCLUSIONS: TTC is associated acutely with a marked increase in GCS. Potentially, GCS might contribute to increased coronary vascular permeability in TTC, thus dissociating development of myocardial oedema from severity of associated inflammation. Prevention of GCS represents a potential therapeutic option in TTC.
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Micropartículas Derivadas de Células/metabolismo , Glicocálix/metabolismo , Sindecano-1/sangre , Cardiomiopatía de Takotsubo/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Endotelio Vascular/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Cardiomiopatía de Takotsubo/diagnóstico , Factores de TiempoRESUMEN
BACKGROUND: On-pump cardiac surgery triggers a significant postoperative systemic inflammatory response, sometimes resulting in multiple-organ dysfunction associated with poor clinical outcome. Extracorporeal cytokine elimination with a novel haemoadsorption (HA) device (CytoSorb®) promises to attenuate inflammatory response. This study primarily assesses the efficacy of intraoperative HA during cardiopulmonary bypass (CPB) to reduce the proinflammatory cytokine burden during and after on-pump cardiac surgery, and secondarily, we aim to evaluate effects on postoperative organ dysfunction and outcomes in patients at high risk. METHODS/DESIGN: This will be a single-centre randomised, two-arm, patient-blinded trial of intraoperative HA in patients undergoing on-pump cardiac surgery. Subjects will be allocated to receive either CPB with intraoperative HA or standard CPB without HA. The primary outcome is the difference in mean interleukin 6 (IL-6) serum levels between the two study groups on admission to the intensive care unit. A total number of 40 subjects was calculated as necessary to detect a clinically relevant 30 % reduction in postoperative IL-6 levels. Secondary objectives evaluate effects of HA on markers of inflammation up to 48 hours postoperatively, damage to the endothelial glycocalyx and effects on clinical scores and parameters of postoperative organ dysfunction and outcomes. DISCUSSION: In this pilot trial we try to assess whether intraoperative HA with CytoSorb® can relevantly reduce postoperative IL-6 levels in patients undergoing on-pump cardiac surgery. Differences in secondary outcome variables between the study groups may give rise to further studies and may lead to a better understanding of the mechanisms of haemoadsorption. TRIAL REGISTRATION: German Clinical Trials Register number DRKS00007928 (Date of registration 3 Aug 2015).