heparitin-sulfate and Systemic-Inflammatory-Response-Syndrome

Tissue and organ transplants between genetically distinct individuals are always or nearly always rejected. The universality and speed of transplant rejection distinguishes this immune response from all others. Although this distinction is incompletely understood, some efforts to shed light on transplant rejection have revealed broader insights, including a relationship between activation of complement in grafted tissues, the metabolism of heparan sulfate proteoglycan and the nature of immune and inflammatory responses that ensue. Complement activation on cell surfaces, especially on endothelial cell surfaces, causes the shedding heparan sulfate, an acidic saccharide, from the cell surface and neighboring extracellular matrix. Solubilized in this way, heparan sulfate can activate leukocytes via toll like receptor-4, triggering inflammatory responses and activating dendritic cells, which migrate to regional lymphoid organs where they spark and to some extent govern cellular immune responses. In this way local ischemia, tissue injury and infection, exert systemic impact on immunity. Whether or in what circumstances this series of events explains the distinct characteristics of the immune response to transplants is still unclear but the events offer insight into the inception of immunity under the sub-optimal conditions accompanying infection and mechanisms by which infection and tissue injury engender systemic inflammation.

Topics: Complement Activation; Complement System Proteins; Dendritic Cells; Endothelial Cells; Extracellular Matrix; Gene Expression Regulation; Graft Rejection; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Leukocytes; Signal Transduction; Systemic Inflammatory Response Syndrome; Tissue Transplantation; Toll-Like Receptor 4

TLRs are usually thought to recognize substances produced by microorganisms and thus, to initiate host defenses. This concept, however, fails to explain some functions of this family of receptors. Recognition of endogenous substances may explain the broader functions of TLRs in physiology and disease. Activation of TLRs by endogenous substances necessitates vigorous control of the function of the receptors. This communication will summarize a line of research, which points to an endogenous agonist for TLR4 and a putative mechanism for controlling the function of that receptor.

Topics: Animals; Heparitin Sulfate; Humans; Sepsis; Systemic Inflammatory Response Syndrome; Toll-Like Receptors

Type II of heparin-associated thrombocytopenia (HAT) is well known, but the cardinal symptom, thrombocytopenia, is rarely adequately considered. Serious and potential lethal complications such as pulmonary embolism, cerebral stroke, or limb gangrene are often falsely regarded as insufficient anticoagulation. Guided diagnosis and therapy are of vital importance for the patient's outcome. Based on the experience of patients with HAT Type II treated in the intensive care unit, a diagnostic and therapeutic approach to the cardinal symptom thrombocytopenia is presented. A recently developed heparin-induced platelet activation assay (HIPAA) seems to be a highly sensitive laboratory test. The first therapeutic principle in case of presumed and diagnosed HAT is the cessation of unfractioned or low-molecular-weight heparins. ORG 10172 (Orgaran), a low-sulfated heparinoid with a low cross-reactivity (10%) to heparins, can be regarded as the most effective anticoagulant in patients with HAT Type II.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Arterial Occlusive Diseases; Chondroitin Sulfates; Dermatan Sulfate; Diagnosis, Differential; Female; Gangrene; Heparin; Heparitin Sulfate; Humans; Middle Aged; Phenprocoumon; Platelet Activation; Platelet Aggregation; Platelet Count; Pulmonary Embolism; Recurrence; Systemic Inflammatory Response Syndrome; Thrombocytopenia; Thromboembolism; Thrombophlebitis

Multisystem inflammatory syndrome in children (MIS-C) represents a rare but severe complication of severe acute respiratory syndrome coronavirus 2 infection affecting children that can lead to myocardial injury and shock. Vascular endothelial dysfunction has been suggested to be a common complicating factor in patients with coronavirus disease 2019 (COVID-19). This study aims to characterize endothelial glycocalyx degradation in children admitted with MIS-C. We collected blood and urine samples and measured proinflammatory cytokines, myocardial injury markers, and endothelial glycocalyx markers in 17 children admitted with MIS-C, ten of which presented with inflammatory shock requiring intensive care admission and hemodynamic support with vasopressors. All MIS-C patients presented signs of glycocalyx deterioration with elevated levels of syndecan-1 in blood and both heparan sulfate and chondroitin sulfate in the urine. The degree of glycocalyx shedding correlated with tumor necrosis factor-α concentration. Five healthy age-matched children served as controls. Patients with MIS-C presented severe alteration of the endothelial glycocalyx that was associated with disease severity. Future studies should clarify if glycocalyx biomarkers could effectively be predictive indicators for the development of complications in adult patients with severe COVID-19 and children with MIS-C. KEY MESSAGES : Children admitted with MIS-C presented signs of endothelial glycocalyx injury with elevated syndecan-1 and heparan sulfate level. Syndecan-1 levels were associated with MIS-C severity and correlated TNF-α concentration. Syndecan-1 and heparan sulfate may represent potential biomarkers for patients with severe COVID-19 or MIS-C.

Topics: Adult; Biomarkers; Child; COVID-19; Glycocalyx; Heparitin Sulfate; Humans; Syndecan-1; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Systemic inflammatory response syndrome (SIRS) is responsible for pancreatitis-associated mortality, but its initiating events are poorly understood. Possible candidates may be endogenous substances, which have previously been shown to mediate inflammatory responses. The aim of this study was to investigate whether SIRS could be exaggerated by heparan sulfate (HS) in acute pancreatitis (AP).. AP was induced in mice by cerulein injection and HS was administered one hour after the final cerulein injection. The severity of pancreatitis was assessed by serum amylase activity, pancreatic edema, and pancreatic myeloperoxidase (MPO) activity. Systemic inflammation was evaluated by assessing lung injury and by measuring serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Cytokine levels were also measured in pancreas and lung tissues.. HS did not worsen the pancreatic injury induced by cerulein. In contrast, HS exacerbated the systemic inflammation as measured by augmented lung MPO activity, increased lung TNF-alpha and IL-6 levels, and elevated serum IL-6 levels.. Our results indicate a potential role for HS in propagating pancreatic inflammation from a local process to a systemic response and thus suggest the possibility that blockade of HS might improve the outcome of SIRS in AP.

Topics: Animals; Biopsy, Needle; Ceruletide; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Heparitin Sulfate; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Pancreatic Function Tests; Pancreatitis, Acute Necrotizing; Peroxidase; Probability; Random Allocation; Sensitivity and Specificity; Statistics, Nonparametric; Survival Analysis; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Systemic inflammatory mediators, including high mobility group box 1 (HMGB1), play an important role in the development of sepsis. Anticoagulants, such as danaparoid sodium (DA), may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesised that DA would act as an inhibitor of systemic inflammation and prevent endotoxin-induced acute lung injury in a rat model.. We used male Wistar rats. Animals in the intervention arm received a bolus of 50 U/kg of DA or saline injected into the tail vein after lipopolysaccharide (LPS) administration. We measured cytokine (tumour necrosis factor (TNF)alpha, interleukin (IL)-6 and IL-10) and HMGB1 levels in serum and lung tissue at regular intervals for 12 h following LPS injection. The mouse macrophage cell line RAW 264.7 was assessed following stimulation with LPS alone or concurrently with DA with identification of HMGB1 and other cytokines in the supernatant.. Survival was significantly higher and lung histopathology significantly improved among the DA (50 U/kg) animals compared to the control rats. The serum and lung HMGB1 levels were lower over time among DA-treated animals. In the in vitro study, administration of DA was associated with decreased production of HMGB1. In the cell signalling studies, DA administration inhibited the phosphorylation of IkappaB.. DA decreases cytokine and HMGB1 levels during LPS-induced inflammation. As a result, DA ameliorated lung pathology and reduces mortality in endotoxin-induced systemic inflammation in a rat model. This effect may be mediated through the inhibition of cytokines and HMGB1.

Topics: Animals; Chondroitin Sulfates; Dermatan Sulfate; Endotoxins; Heparitin Sulfate; HMGB1 Protein; I-kappa B Proteins; Interleukin-10; Interleukin-6; Male; Mice; NF-kappa B; Rats; Rats, Wistar; Respiratory Distress Syndrome; Survival Rate; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Topics: Heparitin Sulfate; History, 20th Century; History, 21st Century; Ligands; Systemic Inflammatory Response Syndrome; Toll-Like Receptor 4; United States

Systemic inflammatory response syndrome (SIRS) is typically associated with trauma, surgery, or acute pancreatitis. SIRS resembles sepsis, triggered by exogenous macromolecules such as LPS acting on Toll-like receptors. What triggers SIRS in the absence of infection, however, is unknown. In this study, we report that a SIRS-like response can be induced in mice by administration of soluble heparan sulfate, a glycosaminoglycan associated with nucleated cells and extracellular matrices, and by elastase, which cleaves and releases heparan sulfate proteoglycans. The ability of heparan sulfate and elastase to induce SIRS depends on functional Toll-like receptor 4, because mutant mice lacking that receptor or its function do not respond. These results provide a molecular explanation for the initiation of SIRS.

Topics: Animals; Cells, Cultured; Coculture Techniques; Female; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Injections, Intralymphatic; Injections, Intraperitoneal; Membrane Glycoproteins; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Pancreatic Elastase; Receptors, Cell Surface; Signal Transduction; Solubility; Spleen; Swine; Systemic Inflammatory Response Syndrome; Toll-Like Receptors; Tumor Necrosis Factor-alpha