Fluid resuscitation is an essential intervention in critically ill patients, and its ultimate goal is to restore tissue perfusion. Critical illnesses are often accompanied by glycocalyx degradation caused by inflammatory reactions, hypoperfusion, shock, and so forth, leading to disturbed microcirculatory perfusion and organ dysfunction. Therefore, maintaining or even restoring the glycocalyx integrity may be of high priority in the therapeutic strategy. Like drugs, however, different resuscitation fluids may have beneficial or harmful effects on the integrity of the glycocalyx. The purpose of this article is to review the effects of different resuscitation fluids on the glycocalyx. Many animal studies have shown that normal saline might be associated with glycocalyx degradation, but clinical studies have not confirmed this finding. Hydroxyethyl starch (HES), rather than other synthetic colloids, may restore the glycocalyx. However, the use of HES also leads to serious adverse events such as acute kidney injury and bleeding tendencies. Some studies have suggested that albumin may restore the glycocalyx, whereas others have suggested that balanced crystalloids might aggravate glycocalyx degradation. Notably, most studies did not correct the effects of the infusion rate or fluid volume; therefore, the results of using balanced crystalloids remain unclear. Moreover, mainly animal studies have suggested that plasma may protect and restore glycocalyx integrity, and this still requires confirmation by high-quality clinical studies.
Animals ; Colloids ; Crystalloid Solutions/therapeutic use* ; Fluid Therapy ; Glycocalyx ; Humans ; Hydroxyethyl Starch Derivatives ; Isotonic Solutions ; Microcirculation ; Resuscitation

OBJECTIVE: The endothelial glycocalyx (eGC) is a dynamic and multicomponent layer of macromolecules found at the surface of vascular endothelium, which is largely underappreciated. It has recently been recognized that eGC is a major regulator of endothelial function and may have therapeutic value in organ injuries. This study aimed to explore the role of the eGC in various pathologic and physiologic conditions, by reviewing the basic research findings pertaining to the detection of the eGC and its clinical significance. We also explored different pharmacologic agents used to protect and rebuild the eGC. DATA SOURCES: An in-depth search was performed in the PubMed database, focusing on research published after 2003 with keywords including eGC, permeability, glycocalyx and injuries, and glycocalyx protection. STUDY SELECTION: Several authoritative reviews and original studies were identified and reviewed to summarize the characteristics of the eGC under physiologic and pathologic conditions as well as the detection and protection of the eGC. RESULTS: The eGC degradation is closely associated with pathophysiologic changes such as vascular permeability, edema formation, mechanotransduction, and clotting cascade, together with neutrophil and platelet adhesion in diverse injury and disease states including inflammation (sepsis and trauma), ischemia-reperfusion injury, shock, hypervolemia, hypertension, hyperglycemia, and high Na as well as diabetes and atherosclerosis. Therapeutic strategies for protecting and rebuilding the eGC should be explored through experimental test and clinical verifications. CONCLUSIONS Disturbance of the eGC usually occurs at early stages of various clinical pathophysiologies which can be partly prevented and reversed by protecting and restoring the eGC. The eGC seems to be a promising diagnostic biomarker and therapeutic target in clinical settings.
Animals ; Databases, Factual ; Endothelium, Vascular ; metabolism ; pathology ; Glycocalyx ; metabolism ; pathology ; Humans ; Shear Strength

OBJECTIVE: This study demonstrated that dexamethasone (DEX) protects the endothelial glycocalyx from damage induced by the inflammatory stimulus tumor necrosis factor-α (TNF-α) during severe acute pancreatitis (SAP), and improves the renal microcirculation. METHODS: Ninety mice were evenly divided into 3 groups (Sham, SAP, and SAP+DEX). The SAP mice model was established by ligature of pancreatic duct and intraperitoneal injection of cerulein. Renal perfusion and function, and morphological changes of the glycocalyx were evaluated by laser Doppler velocimetry, electron microscopy, and histopathology (hematoxylin and eosin (H&E) staining), respectively. Serum levels of syndecan-1 and TNF-α were assessed by enzyme-linked immunosorbent assay (ELISA). The protective effects of dexamethasone on the glycocalyx and renal microcirculation were evaluated. RESULTS: Significantly high levels of serum TNF-α were detected 3 h after the onset of SAP. These levels might induce degradation of the glycocalyx and kidney hypoperfusion, resulting in kidney microcirculation dysfunction. The application of dexamethasone reduced the degradation of the glycocalyx and improved perfusion of kidney. CONCLUSIONS Dexamethasone protects the endothelial glycocalyx from inflammatory degradation possibly initiated by TNF-α during SAP. This is might be a significant discovery that helps to prevent tissue edema and hypoperfusion in the future.
Acute Disease ; Animals ; Dexamethasone/pharmacology* ; Disease Models, Animal ; Edema/metabolism* ; Endothelium, Vascular/metabolism* ; Enzyme-Linked Immunosorbent Assay ; Glycocalyx/drug effects* ; Kidney/drug effects* ; Male ; Mice ; Mice, Inbred C57BL ; Microcirculation ; Pancreatitis/drug therapy* ; Perfusion ; Protective Agents/pharmacology* ; Tumor Necrosis Factor-alpha/metabolism*

The endothelial glycocalyx (EG) is a gel-like layer lining the luminal surface of healthy vascular endothelium. Recently, the EG has gained extensive interest as a crucial regulator of endothelial funtction, including vascular permeability, mechanotransduction, and the interaction between endothelial and circulating blood cells. The EG is degraded by various enzymes and reactive oxygen species upon pro-inflammatory stimulus. Ischemia-reperfusion injury, oxidative stress, hypervolemia, and systemic inflammatory response are responsible for perioperative EG degradation. Perioperative damage of the EG has also been demonstrated, especially in cardiac surgery. However, the protection of the EG and its association with perioperative morbidity needs to be elucidated in future studies. In this review, the present knowledge about EG and its perioperative implication is discussed from an anesthesiologist's perspective.
Blood Cells ; Capillary Permeability ; Endothelium, Vascular ; Glycocalyx* ; Oxidative Stress ; Permeability ; Phenobarbital ; Reactive Oxygen Species ; Reperfusion Injury ; Thoracic Surgery

To explore the effect of ulinastatin on perioperative glycocalyx and lung function in patients undergoing mitral valve replacement surgery.
 Methods: Fourty patients, undergoing mitral valve replacement, were randomly allocated into a control group and an ulinastatin group, which were administrated 50 mL normal saline or 2×104 U/kg ulinastatin at the beginning of cardiopulmonary bypass (CPB), respectively. The radical artery blood was collected at 4 time points: After induction of anesthesia (T0), at 10 min after the start of CPB (T1), 1 h after the end of CPB (T2), and 8 h after operation. The concentration of syndecan-1 and TNF-α in blood was measured. Moreover, the blood gas analysis was preformed and the oxygen index (OI) and difference in alveolar arterial oxygen partial pressure (PA-aO2) were calculated at T0, T2, and T3.
 Results: There were no significant difference between the 2 groups in OI, PA-aO2, and the concentration of syndecan-1 and TNF-α at T0 (P>0.05). The concentration of syndecan-1 and TNF-α was significantly increased at T1 and T2 in the 2 groups, and reached peak at T2. Compared with the control group, the concentration of syndecan-1 and TNF-α was decreased in the ulinastatin group at T1, T2, and T3 (P<0.05). Compared with T0, OI was lower and PA-aO2 was higher at T2 and T3 in both groups, but the 2 indexes were improved in the ulinastatin group compared with those in the control group (P<0.05).
 Conclusion: Ulinastatin can improve the post-operative pulmonary ventilation function in patients with mitral valve replacement. The mechanism may be associated with the inhibition of TNF-α release and the reduction of glycocalyx shedding induced by ulinastatin.
Cardiopulmonary Bypass ; Glycocalyx ; drug effects ; Glycoproteins ; pharmacology ; Heart Valve Prosthesis Implantation ; Humans ; Lung ; drug effects ; Mitral Valve ; surgery ; Oxygen ; blood ; Syndecan-1 ; blood ; Time Factors ; Tumor Necrosis Factor-alpha ; blood

OBJECTIVE: To observe the effect of different doses and timing of normal saline (NS) resuscitation combined with norepinephrine (NE) on endothelial glycocalyx in rabbits with early septic shock. METHODS: Thirty New Zealand male rabbits were randomly divided into sham group, model group, 30 mL and 60 mL timely resuscitation groups (30 mL and 60 mL timely group), and 30 mL delayed resuscitation group (30 mL delayed group) with 6 rabbits in each group. The rabbit model of septic shock was reproduced by cecal ligation and puncture (CLP). The rabbits in sham group were only received abdominal cavity open without cecal and ligation. The rabbits in 30 mL and 60 mL timely groups and 30 mL delayed group were intravenous infused with 30 mL/kg or 60 mL/kg NS immediately or 1 hour after model reproduction for 1 hour, and the mean arterial pressure (MAP) was maintained over 75 mmHg (1 mmHg = 0.133 kPa) compared with intravenous pumping of 0.02-0.05 μg×kg^-1×min^-1 NE followed by 5 mL/h NS infusion till the end of the experiment. The rabbits in sham and model groups were only given 5 mL/h NS. The changes in arterial blood gas before and immediately after resuscitation were observed in three fluid resuscitation groups. The internal jugular vein blood was collected at 0, 3, 6 hours after model reproduction. The levels of syndecan-1 (polysaccharide envelope marker) in plasma were determined by enzyme linked immunosorbent assay (ELISA). The rabbits were sacrificed at 6 hours after model reproduction, and the lung tissue was harvested. Western Blot was used to determine the protein expressions of intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase 2 (MMP-2) and syndecan-1. The positive expression of syndecan-1 in lung tissue was observed by immunohistochemical method. RESULTS: (1) Blood gas analysis: compared with the results before resuscitation, the levels of lactic acid (Lac) after resuscitation in three fluid resuscitation groups were significantly decreased, especially in 30 mL timely group; the central venous blood oxygen saturation (ScvO₂) was significantly increased, especially in 30 mL delayed group. Oxygenation index (PaO₂/FiO₂) was improved in 30 mL timely and 30 mL delayed resuscitation groups, which was decreased in 60 mL delayed group. (2) Plasma marker: compared with sham group, plasma syndecan-1 level in model group was significantly increased with a time-dependent manner. Plasma syndecan-1 levels at 3 hours in 30 mL timely and 30 mL delayed groups were significantly decreased as compared with those of model group (ng/L: 138.0±2.4, 139.7±15.7 vs. 161.5±4.1, both P < 0.05), but it was significantly increased at 6 hours in 30 mL delayed group (ng/L: 213.1±19.4 vs. 206.4±15.5, P < 0.05). The plasma syndecan-1 levels at 3 hours and 6 hours in 60 mL timely group were significantly higher than those in model group (ng/L: 233.0±28.9 vs. 161.5±4.1, 252.3±27.2 vs. 206.4±15.5, both P < 0.05). (3) Protein expression in lung tissue: compared with sham group, the protein expressions of ICAM-1 and MMP-2 in lung tissue of model group were significantly increased, and syndecan-1 protein expression was significantly decreased. After 30 mL timely or 30 mL delayed resuscitation, the protein expressions of ICAM-1 and MMP-2 in lung tissue were significantly decreased, and syndecan-1 protein expression was significantly increased, especially in 30 mL timely group, which showed statistical differences as compared with those of model group (ICAM-1 protein: 0.56±0.09 vs. 1.04±0.05, MMP-2 protein: 0.83±0.15 vs. 1.06±0.06, syndecan-1 protein: 2.09±0.08 vs. 0.99±0.03, all P < 0.05). The change tendency of protein expressions in 60 mL timely group was opposite to the other two resuscitation groups. (4) Immunohistochemistry: the positive expression of syndecan-1 in lung tissues was significant in the sham group, and it was lowered in model group. The positive expression of syndecan-1 was increased after 30 mL timely or 30 mL delayed resuscitation, but further weakened in 60 mL timely group. CONCLUSIONS The dose and timing of resuscitation with NS in septic shock can affect pulmonary vascular endothelial glycocalyx function. The timely resuscitation with 30 mL NS in combination with NE plays a protective effect on endothelial cell and glycocalyx. However, NS resuscitation which was not timely or excessive infusion can make the glycocalyx degradation more obvious, resulting in increased endothelial permeability, microcirculation damaged, thus aggravate lung injury.
Animals ; Fluid Therapy ; Glycocalyx ; Male ; Matrix Metalloproteinase 2 ; Rabbits ; Resuscitation ; Shock, Septic

Hypertension is a complex trait determined by both genetic and environmental factors and is a major public health problem due to its high prevalence and concomitant increase in the risk for cardiovascular disease. With the recent large increase of dietary salt intake in most developed countries, the prevalence of hypertension increases tremendously which is about 30% of the world population. There is substantial evidence that suggests some people can effectively excrete high dietary salt intake without an increase in arterial BP, and another people cannot excrete effectively without an increase in arterial BP. Salt sensitivity of BP refers to the BP responses for changes in dietary salt intake to produce meaningful BP increases or decreases. The underlying mechanisms that promote salt sensitivity are complex and range from genetic to environmental influences. The phenotype of salt sensitivity is therefore heterogeneous with multiple mechanisms that potentially link high salt intake to increases in blood pressure. Moreover, excess salt intake has functional and pathological effects on the vasculature that are independent of blood pressure. Epidemiologic data demonstrate the role of high dietary salt intake in mediating cardiovascular and renal morbidity and mortality. Almost five decades ago, Guyton and Coleman proposed that whenever arterial pressure is elevated, pressure natriuresis enhances the excretion of sodium and water until blood volume is reduced sufficiently to return arterial pressure to control values. According to this hypothesis, hypertension can develop only when something impairs the excretory ability of sodium in the kidney. However, recent studies suggest that nonosmotic salt accumulation in the skin interstitium and the endothelial dysfunction which might be caused by the deterioration of vascular endothelial glycocalyx layer (EGL) and the epithelial sodium channel on the endothelial luminal surface (EnNaC) also play an important role in nonosmotic storage of salt. These new concepts emphasize that sodium homeostasis and salt sensitivity seem to be related not only to the kidney malfunction but also to the endothelial dysfunction. Further investigations will be needed to assess the extent to which changes in the sodium buffering capacity of the skin interstitium and develop the treatment strategy for modulating the endothelial dysfunction.
Arterial Pressure ; Blood Pressure ; Blood Volume ; Cardiovascular Diseases ; Developed Countries ; Epithelial Sodium Channels ; Glycocalyx ; Homeostasis ; Hypertension* ; Kidney* ; Mortality ; Natriuresis ; Negotiating ; Phenobarbital ; Phenotype ; Prevalence ; Public Health ; Skin ; Sodium ; Water

There has long been a controversy on the use of colloids. Many developments have now been made in the theological aspects. The new glycocalyx model and other related studies have shown that the volume expansion effect of colloids is not so superior to crystalloids in many situations. Moreover, the results from several multicenter studies on septic shock patients indicated that hydroxyethyl starch did not improve clinical outcome, but instead, increased the number of serious complications such as death and renal failure. Accordingly, this long debate has been concluded, at least about the use of hydroxyethyl starch colloid on patients with septic shock. Although there is still a lack of studies on perioperative patients, care is also needed when using colloids in their treatment.
Colloids ; Glycocalyx ; Humans ; Renal Insufficiency ; Shock, Septic ; Starch*

PURPOSE: Nodal metastasis is the main prognostic factor in the patients with oral squamous cell carcinoma (OSCC). We investigated the association between tumor-associated lymphatics and OSCC characteristics. METHODS: Thirty-four specimens were used for the immunohistochemical staining with the antibody for vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3, phosphorylated VEGFR-3, D2-40, and matrix metallproteinases (MMPs). We observed the distribution of the lymphangiogenic factors and quantified the degree of expression. We determined lymphatic vessel density (LVD) and lymphatic vessel dilatation with D2-40 immunostaining. We assessed the association of LVD or lymphatic vessel dilatation with tumor progression or tumor differentiation. RESULTS: OSCC cells expressed lymphangiogenic ligands. Lymphangiogenic receptor, VEGFR-3, was expressed and activated in some tumor cells as well as in tumor-associated endothelial cells. LVD was not associated with tumor size or nodal status, but lymphatic vessel dilatation was higher in tumors with nodal metastasis, and also higher in poorly differentiated tumors. In stromal area of OSCC, MMP-1 and MMP-10 were up-regulated and the basement membrane of tumor-associated endothelial cells was destroyed by these collagenases. CONCLUSION: In the primary tumors with nodal metastasis, especially in poorly differentiated OSCC, tumor cells invaded the dilated lymphatic vessels via ruptured sites. MMP-1 and MMP-10 are important in the lysis of the glycocalyx inside the tumor-associated lymphatic endothelial cells.
Basement Membrane ; Carcinoma, Squamous Cell* ; Collagenases ; Dilatation ; Endothelial Cells ; Glycocalyx ; Humans ; Ligands ; Lymphatic Vessels ; Neoplasm Metastasis* ; Receptors, Vascular Endothelial Growth Factor ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor D ; Vascular Endothelial Growth Factor Receptor-3

Styela clava, called non-native tunicate or sea squirt, is habitat which include bays and harbors in Korea and several sites in the sea faced world. We fabricate cellulose membrane nerve conduit (CMNC) from this native sea squirt skin, and evaluate the capacity of promoting peripheral nerve regeneration in the rat sciatic nerve defect model. After processing the pure cellulose membrane from the sea squirt skin as we already published before, CMNC was designed as a non-tubular sheet with 14 mm length and 4 mm width. Total eleven male Spraque-Dawley rats (12 weeks, weighing 250 to 300g) were divided into sham group (n=2), silicone tube grafted control group (n=3) and experimental group (n=6). Each CMNC grafted nerve was evaluated after 4, 8 and 12 weeks in the experimental group, and after 12 weeks, sciatic function was evaluated with sciatic function index (SFI) and gait analysis, and histomorphology of nerve conduit and the innervated tissues of sciatic nerve were all examined using image analyzer and electromicroscopic methods in the all groups. The regenerated axon and nerve sheath were found only in the inner surface of the CMNC after 4 weeks and became more thicker after 8 and 12 weeks. In the TEM study, CMNC grafted group showed more abundant organized myelinated nerve fibers with thickened extracellular matrix than silicone conduit grafted group after 12 weeks. The sciatic function index (SFI) and ankle stance angle (ASA) in the functional evaluation were -47.2+/-3.9, 35.5.+/-4.9.in CMNC grafted group (n=2) and -80.4+/-7.4, 29.2.+/-5.3.in silicone conduit grafted group (n=3), respectively. And the myelinated axon was 41.59% in CMNC group and 9.51% in silicone conduit group to the sham group. The development of a bioactive CMNC to replace autogenous nerve grafts offers a potential and available approach to improved peripheral nerve regeneration. As we already published before, small peptide fragment derived from the basement membrane matrix proteins of squirt skin, which is a kind of anchoring protein composed of glycocalyx, induced the effective axonal regeneration with rapid growth of Schwann cells beneath the inner surface of CMNC. So the possibilities of clinical application as a peripheral nerve regeneration will be able to be suggested.
Animals ; Ankle ; Axons ; Basement Membrane ; Bays ; Cellulose* ; Ecosystem ; Extracellular Matrix ; Gait ; Glycocalyx ; Humans ; Korea ; Male ; Membranes* ; Myelin Sheath ; Nerve Fibers, Myelinated ; Peripheral Nerves* ; Rats ; Regeneration* ; Schwann Cells ; Sciatic Nerve ; Silicones ; Skin ; Transplants ; Urochordata