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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vascular endothelium plays an important role in regulating immune and inflammatory responses to resist pathogens infection. Although it has been known that lipopolysaccharide (LPS) is a critical inducer of sepsis or endotoxemia, the systematic responses of LPS-stimulation in endothelial cells (ECs) are still unclear. The present study aims to analyze the late-phase responses of LPS-induced rat aortic ECs by using systematic biology approaches, including rat cDNA microarray, 2-DE and MALDI-TOF MS/MS, and cytokine protein array. Furthermore, to improve the efficiency of analysis of the bulk systematic data of rat, we designed a set of bioinformatic tools to convert and integrate these rat data into the corresponding human genes or proteins IDs based on BioCarta, KEGG, and Gene Ontology databases. Using the systematic analysis, it was shown that LPS could promote some signaling or metabolic pathways as well as pathophysiologic phenomena of proliferation, atherogenesis, inflammation, and apoptosis through activated nuclear factor-kappaB pathway in ECs. Interestingly, ECs also activated the mediators of anti-inflammation, antiapoptosis, and antioxidation to protect themselves. Moreover, the expressions of altered genes, proteins, and their involvement in the hypothetical signaling pathway can provide further understanding of inflammation associated responses in ECs.
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PMID:Lipopolysaccharide-stimulated responses in rat aortic endothelial cells by a systems biology approach. 1710 15

Microparticles (MP) derived from vascular endothelium or circulating blood cells circulate in the peripheral blood. They originate from blebbing and shedding from cell membrane surfaces in physiological and pathological conditions and are present in low concentrations in normal plasma. Increased levels are generated by a number of mechanisms including platelet activation, direct vascular endothelial damage, thrombin activity on the cell surface, C5b-9 activation, and PF4-heparin-antibody interaction. Several techniques are currently used to study the generation and nature of circulating microparticles. In particular, the genesis and role of microparticles, derived from platelets, endothelial cells and monocytes, in sepsis (especially meningococcal-induced), heparin-induced thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), aplastic anaemia, paroxysmal nocturnal haemoglobinuria (PNH) and sickle cell disease (SCD) have been well studied, and provide important insights into the underlying diseases. A defect in the ability to form microparticles leads to the severe bleeding disorder of Scott syndrome, which in turn provides a revealing insight into the physiology of coagulation. In addition the complex role of microparticles in vascular and cardiovascular diseases is an area of immense interest, that promises to yield important advances into diagnosis and therapy.
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PMID:Circulating microparticles: pathophysiology and clinical implications. 1711 1

Red blood cells (RBCs) that have been stored prior to transfusion show increased adherence to vascular endothelium in vitro, which suggests a potential for stored blood transfusion to impede blood flow in some patients. Transfusion is often required in patients with sepsis or inflammation; however, whether activation of endothelium affects stored RBC-endothelial cell (EC) interactions is unknown. We investigated whether storage time and leukocyte content of RBC products influences the adhesion of RBCs to activated ECs. RBCs from nonleukocyte-reduced (S-RBCs), buffy-coat-poor (BCP-RBCs), and leukocyte-filtered (LF-RBCs) products and cultured EC layers were pretreated with endotoxin, tumor necrosis factor-alpha (TNF-alpha), or medium alone prior to perfusion of the RBCs across the EC layer in a continuous flow microchamber. After a single day of RBC storage, the number of adherent RBCs was increased in the endotoxin and TNF-alpha pretreated groups compared to the unactivated-control group. These differences were statistically significant for S-RBCs and LF-RBC products (P < 0.05). In contrast, there was no significant difference in RBC adherence to activated and unactivated endothelium at other time-points of RBC product storage. The strength of adhesion of stored RBCs from S-RBC products to activated ECs was not altered following treatment; however, endotoxin significantly increased the adhesive strength of LF-RBCs to endothelium. These results demonstrate that while fresh RBCs show increased adhesion to activated endothelium, storage of RBCs did not promote increased adhesion to activated endothelium. However, inflammatory conditions promote stronger adhesion of stored RBCs to ECs, which may contribute to impaired tissue perfusion in some transfusion recipients.
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PMID:Variable adhesion of different red blood cell products to activated vascular endothelium under flow conditions. 1713 24

This review describes the laboratory evidence and microvascular mechanisms responsible for the beneficial effects of statins in sepsis. During sepsis, changes occur within the microcirculation including alterations in arteriolar tone influencing blood pressure, adaptations to endothelial cell integrity causing leakage of proteins and macromolecules, and adhesion and migration of leucocytes through the vascular endothelium. Statins are widely used as cholesterol-lowering agents, but appear to have anti-inflammatory actions during sepsis. We have discussed the effects of statins on specific pathological processed within the microcirculation and focused on the role of nitric oxide (NO). The main mechanism by which statins appear to be an effective treatment for sepsis is increased expression of endothelial nitric oxide synthase (eNOS), in conjunction with down-regulation of inducible nitric oxide synthase. Combined, this results in an increase in physiological concentrations of NO, thus restoring endothelial function. Laboratory studies have therefore suggested that enhancement of eNOS activity during sepsis may lead to restoration of microvascular tone, maintenance of microvascular integrity, and inhibition of cell adhesion molecules. However, other mechanisms independent of lipid-lowering effects, including antioxidant activity and alterations in the development of vascular atherosclerosis, may also contribute to the beneficial effects of statins. We have also addressed the influence on the effects of statins of lipid solubility and pre- and pro-phylactic administration.
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PMID:Beneficial effects of statins on the microcirculation during sepsis: the role of nitric oxide. 1725 Dec 10

A central event of systemic inflammation and septic organ injury is infiltration of tissues with polymorphonuclear neutrophils, likely modulated by the integrity of the extracellular matrix underlying the vascular endothelium. In the present study, the effect of matrix-modifying endoglycosidase (heparanase) on endotoxin (LPS)-induced inflammatory lung injury was investigated in rats. Animals were treated with heparanase or LPS or pretreated with heparanase before LPS injection, and acute lung injury was verified histologically and characterized by analysis of bronchoalveolar lavage fluids. Pretreatment with heparanase attenuated the mortality of animals and preserved the histological structure of the lungs. Furthermore, polymorphonuclear neutrophil accumulation and activation, analyzed by myeloperoxidase release and reactive oxygen species production associated with lung injury, were significantly reduced upon heparanase pretreatment. In addition, heparanase pretreatment elevated the IL-10 levels in the pulmonary compartment. Moreover, results from in vitro experiments have identified monocyte-derived IL-10 as an important mediator used by heparanase to suppress inflammatory reactions. The protective effect of heparanase may indicate a novel therapeutic strategy for sepsis.
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PMID:Heparanase pretreatment attenuates endotoxin-induced acute lung injury in rats. 1751 48

Antithrombin is a glycoprotein critical to the regulation of coagulation. Its primary action is the inhibition of the activated coagulation factors IIa (thrombin) and Xa. In addition there is growing evidence to suggest that antithrombin also plays a role in the inhibition of inflammation within the environment of the vascular endothelium. Reduced plasma antithrombin may result from congenital deficiency or arise secondarily from a range of disorders such as liver dysfunction, premature infancy and sepsis, or as a result of interventions such as major surgery or cardiopulmonary bypass. Congenital antithrombin deficiency is the most clinically important of the inherited thrombophilias resulting in thrombosis in the majority of those affected. The challenge in managing these patients is preventing potentially life-threatening thrombosis, while minimising the equally significant risk of haemorrhage associated with long-term anticoagulation. This is achieved in the first instance by identifying high-risk episodes such as surgery, immobility and pregnancy for which prophylactic anticoagulation can be used in the short term. Prophylaxis for such periods is best provided by the use of low molecular weight heparin (LMWH) with substitution by or addition of antithrombin concentrate in particularly high-risk circumstances. In the case of pregnancy, antithrombin concentrate is often used around the time of birth when LMWH may increase the risk of post-partum haemorrhage. As patients with congenital antithrombin deficiency get older so their thrombotic risk gradually increases and for many patients long-term anticoagulation becomes unavoidable because of recurrent episodes of venous thromboembolism. There has been much interest in the role of antithrombin deficiency in the setting of sepsis and the critically ill patient where there is a clear correlation between severity of illness and degree of antithrombin reduction. It is not clear yet, however, to what extent the depletion of antithrombin affects the clinical condition of such patients. A number of trials have investigated the use of antithrombin as a treatment in the intensive care setting with the overall conclusion being that there is some benefit to its use but only if large supra-physiological doses are used. It has also become clear that the concurrent use of any form of heparin removes whatever benefit may be derived from antithrombin treatment in this setting. Until recently, antithrombin replacement was only available as a pooled plasma-derived product, which despite effective viral inactivation still carries an uncertain risk of transfusion transmitted infection. A recombinant antithrombin product now under investigation, and recently licensed in Europe, may provide a useful alternative treatment option.
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PMID:Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. 1760 Mar 91

Dysfunction of the vascular endothelium (ET) causes an increase in serum ET-1 concentration, as observed in septic patients. It was assumed that in this patient population the ET-1 level correlates with the degree of sepsis severity, including the level of organ dysfunction and, in particular, the level of circulatory dysfunction. The aim of the present study was to assess the relationship between levels of ET-1 and levels of N-terminal brain natriuretic propeptide (NT-proBNP), procalcitonin (PCT), and C-reactive protein (CRP), as well as the Sepsis-related Organ Failure Assessment (SOFA) score in septic patients. PCT and CRP were used to estimate the level of sepsis severity; the SOFA score was used to estimate multiorgan dysfunction; and NT-proBNP was used as a marker of cardiac dysfunction. Twenty patients with sepsis and severe sepsis were included in the study. Blood serum ET-1, NT-proBNP, PCT, and CRP concentrations were determined at specific time intervals, and the SOFA score was calculated. Mean ET-1, NT-proBNP, PCT, and CRP concentrations were 8.39 pg/ml +/- 6.39 pg/mL, 140.80 pg/mL +/- 84.65 pg/mL, 22.32 ng/mL +/- 97.41 ng/mL, and 128.51 mg/L +/- 79.05 mg/L, respectively. Correlation between ET-1 levels and levels of NT-proBNP, PCT, and CRP was .3879 (P < .001), .358 (P < .001), and .225 (P = .011), respectively. Mean SOFA score was 6.31 pts +/- 3.75 pts. Correlation between the ET-1 levels and SOFA score was .470 (P < .001). Six patients (30%) died during the observation period of 28 days. ET-1 levels correlate with levels of NT-proBNP, PCT, and CRP, as well as the SOFA score in septic patients.
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PMID:Plasma endothelin-1 levels in septic patients. 1772 67

The mechanism of pseudoaneurysm formation caused by prolonged sepsis is thought to be related to the vascular endothelium being directly invaded and broken by bacteria. Moreover, matrix metalloproteinases (MMPs) which are up-regulated by chronic inflammation have been reported to be implicated in the pathogenesis of aneurysm development through increased proteolysis of extracellular matrix proteins. An effective treatment for infected pseudoaneurysm remains unsettled. Surgery is generally performed, however, because the patients in most of these cases are in very poor physical condition, the operation is associated with high morbidity and mortality. A more successful alternative is endovascular treatment. Recent reports indicate low morbidity and mortality rates with this treatment. If the patient in this case had been in better condition, we could have selected endovascular stent-grafting for her treatment.
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PMID:Abdominal aortic pseudoaneurysm caused by prolonged methicillin-resistant Staphylococcus aureus sepsis. 1796 61

Angiopoietin (angpt) 1 and angpt-2 are circulating proteins first ascribed opposing roles in embryonic angiogenesis. Both bind the tyrosine kinase with immunoglobulin-like loop and epidermal growth factor homology domains (Tie) 2 receptor on endothelial cells, but angpt-1 is a Tie-2 agonist, whereas angpt-2 antagonizes Tie-2 signaling. In the developed vasculature, angpt-1 protects against vascular leak, whereas angpt-2 promotes increased vascular permeability. Because alterations in vascular permeability are common in septic shock, we obtained plasma from critically ill children within 24 h of diagnosis of the systemic inflammatory response syndrome (SIRS, n = 20), sepsis (n = 20), or septic shock (n = 61), as well as 15 healthy controls. Plasma levels of angpt-1 and angpt-2 were measured via a commercially available enzyme-linked immunosorbent assay. Plasma angpt-2 levels were significantly elevated in children with septic shock when compared with healthy children, as well as critically ill children with either SIRS or sepsis, and circulating angpt-2 levels seemed to correlate with disease severity and outcome. In addition, plasma angpt-1 levels were significantly decreased in critically ill children with septic shock compared with critically ill children with either SIRS or sepsis. Given the contrasting effects of angpt-2 and angpt-1 on the vascular endothelium, these two factors may play an important role in the pathophysiology of septic shock in children, and further studies are warranted.
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PMID:Admission angiopoietin levels in children with septic shock. 1809 80

Septic shock remains the leading cause of death in intensive care units in North America. Recent evidence implicates matrix metalloproteinases (MMP) in the pathogenesis of sepsis. MMP activity is upregulated in blood vessels exposed to bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines and contributes to vascular hyporeactivity to vasoconstrictors. The exact mechanism of MMP-mediated vascular hyporeactivity is unknown. We investigated the contribution of the endothelium in the MMP response to LPS-mediated vascular hyporeactivity in vitro. Tone induced by phenylephrine in isolated rat aortic rings with either intact or denuded endothelium was measured in the presence of LPS for 6 h. These rings were incubated with the nitric oxide (NO) synthase inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), to determine whether NO synthase was involved in the response, or the MMP inhibitors, doxycycline or GM6001. MMP activity was measured after 6 h. LPS caused a greater reduction of phenylephrine-induced tone in endothelium-intact rings versus endothelium-denuded rings, indicating both endothelium-independent and -dependent mechanisms for LPS-induced vascular hyporeactivity. l-NAME abolished the response to LPS in both endothelium-intact and endothelium-denuded rings. MMP inhibitors prevented the LPS-induced loss of tone in endothelium-intact but not endothelium-denuded rings. LPS caused significantly greater MMP-2 activity in endothelium-intact aortae which was attenuated by doxycycline. MMP-2 activity in endothelium-denuded aortae was unchanged by LPS. The vascular endothelium contributes to MMP-mediated vascular dysfunction induced by LPS. The protective effect of MMP inhibition is endothelium-dependent and is a novel mechanism by which MMPs contribute to vascular dysfunction.
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PMID:Endothelial dependence of matrix metalloproteinase-mediated vascular hyporeactivity caused by lipopolysaccharide. 1824 97


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