Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serpin antithrombin III (AT III), the most important natural inhibitor of thrombin activity, has been shown to exert marked anti-inflammatory properties and proven to be efficacious in experimental models of sepsis, septic shock, and disseminated intravascular coagulation. Moreover, clinical observations suggest a possible therapeutic role for AT III in septic disorders. The molecular mechanism, however, by which AT III attenuates inflammatory events is not yet entirely understood. We show here that AT III potently blocks the activation of nuclear factor kappaB (NF-kappaB), a transcription factor involved in immediate early gene activation during inflammation. AT III inhibited agonist-induced DNA binding of NF-kappaB in cultured human monocytes and endothelial cells in a dose-dependent manner, suggesting that AT III interferes with signal transduction leading to NF-kappaB activation. This idea was supported by demonstrating that AT III prevents the phosphorylation and proteolytic degradation of the inhibitor protein IkappaBalpha. In parallel to reducing NF-kappaB activity, AT III inhibited the expression of interleukin-6, tumor necrosis factor-alpha, and tissue factor, genes known to be under the control of NF-kappaB. The observation that chemically modified AT III that lacks heparin-binding capacity had no effect on NF-kappaB activation supports the current understanding that the inhibitory potency of AT III depends on the interaction of AT III with heparinlike cell surface glycosaminoglycans. This hypothesis was underscored by the finding that the AT III beta-isoform, known to have higher affinity for glycosaminoglycans, is more effective in preventing NF-kappaB transactivation than alpha-AT III. These data indicate that AT III can alter inflammatory processes via inhibition of NF-kappaB activation.
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PMID:Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells. 1201 Aug 2

Leukocyte-endothelial cell interaction and microvascular perfusion failure are characteristic deteriorations of the microcirculation in endotoxaemia and are known to play a crucial role in the development of septic multiple organ dysfunction. Recent studies have indicated that antithrombin III treatment is capable of significantly ameliorating these microcirculatory disorders. Endothelial cells have important anticoagulant systems, including the heparan sulfate-antithrombin system. Antithrombin III stimulates prostacyclin generation in endothelial cells by interacting with heparan sulfate of endothelial cells and inhibits cytokine and tissue factor production in endothelial cells and monocytes. Similar mechanisms may be involved in cellular actions of antithrombin III causing desensitization of chemoattractant receptors of leukocytes by activating the heparan sulfate proteoglycan, syndecan-4. Thus, antithrombin III might be among the useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because it inhibits not only coagulation but also downregulation of anticoagulant activities of endothelial cells and affects leukocyte activation.
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PMID:The anti-inflammatory actions of antithrombin--a review. 1216 69

Oncologic diseases frequently need a central venous catheterization to improve pharmacological administration safety and patient's comfort. We report a case of a woman affected by acute myelocytic leukemia with a bilateral stenosis of the innominate veins, likely of thrombotic nature, diagnosed during central venous catheterization. These events, as that occurred to our patient, are usually caused by hypercoagulability inducted by oncologic diseases, sepsis, antithrombin III deficiency, catheters materials and repeated catheterizations. Although the treatment, based on local thrombolysis, systemic heparinization, and surgery to repair venous obstruction, is effective, the prevention of such events is fundamental. It can be achieved with catheters of particular characteristics and appropriate management techniques. Finally it is underlined that in oncology patients, before catheterization, especially when the objective examination is negative, radiological methodologies and in particular ultrasonography are an important aid to establish the presence or absence of thrombosis in internal jugular, subclavian and innominate veins.
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PMID:[Bilateral stenosis of the innominate veins in oncological patient]. 1224 96

A systemic inflammation with the release of multiple cytokines plays an important role in the pathophysiology of sepsis. During the last years, several anti-inflammatory substances have been investigated with respect to their effects on mortality in patients with sepsis. However, only the antibody fragment of the TNFalpha binding antibody afelimomab and the recombinant human activated protein C (drotrecogin alpha [activated]) were capable of improving the outcome in controlled studies with large sample sizes. The possible administration of these substances should be restricted to patients who meet the inclusion criteria of these studies. In particular, the tight time window, which usually ends 24 h after the onset of sepsis, should be taken into consideration before starting an anti-inflammatory medication. In addition to the anti-inflammatory treatment, the control of the infectious focus and an aggressive hemodynamic stabilization must not be neglected. Ibuprofen, interleukin-1 receptor antagonists and soluble TNFalpha-receptors as well as high dosages of corticosteroids and antithrombin III do not have a place in the anti-inflammatory treatment of sepsis.
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PMID:[Anti-inflammatory treatment in sepsis]. 1291

Sepsis is associated with the activation of several inflammatory cascades, including the cytokine network and the coagulation system, but it can also be associated with an immunodepressed state. This can lead to a situation in which the septic patient becomes more susceptible to secondary infections. In animal experiments, inhibition of the cytokine cascade by administration of tumour necrosis factor alpha (TNF alpha)-receptors or anti-TNF alpha antibodies has led to reduced mortality, but this has not been confirmed in clinical trials. After the data were pooled, there was a statistically significant decrease in mortality of 3-5%. Treatment with endotoxin antibodies, corticosteroids in high doses, other anti-inflammatory agents and agents designed to eliminate immunodepression generally also did not produce a convincing decrease in mortality. Research on antithrombotic agents has yielded, along with disappointing results with antithrombin III and 'tissue factor pathway inhibitor', one study with a positive result. In septic patients with organ failure who were treated with activated protein C, a coagulation inhibitor, the mortality decreased from 30.8 to 24.7%.
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PMID:[Immunomodulating strategies in the treatment of sepsis]. 1253 64

An imbalance between thrombin and antithrombin III contributed to vascular hyporeactivity in sepsis, which can be attributed to excess NO production by inducible nitric-oxide synthase (iNOS). In view of the importance of the thrombin-activated coagulation pathway and excess NO as the culminating factors in vascular hyporeactivity, this study investigated the effects of thrombin on the induction of iNOS and NO production in macrophages. Thrombin induced iNOS protein in the Raw264.7 cells, which was inhibited by a thrombin inhibitor, LB30057. Thrombin increased NF-kappaB DNA binding, whose band was supershifted with anti-p65 and anti-p50 antibodies. Thrombin elicited the phosphorylation and degradation of I-kappaBalpha prior to the nuclear translocation of p65. The NF-kappaB-mediated iNOS induction was stimulated by the overexpression of activated mutants of Galpha(12/13) (Galpha(12/13)QL). Protein kinase C depletion inhibited I-kappaBalpha degradation, NF-kappaB activation, and iNOS induction by thrombin or the iNOS induction by Galpha(12/13)QL. JNK, p38 kinase, and ERK were all activated by thrombin. JNK inhibition by the stable transfection with a dominant negative mutant of JNK1 (JNK1(-)) completely suppressed the NF-kappaB-mediated iNOS induction by thrombin. Conversely, the inhibition of p38 kinase enhanced the expression of iNOS. In addition, JNK and p38 kinase oppositely controlled the NF-kappaB-mediated iNOS induction by Galpha(12/13)QL. Hence, iNOS induction by thrombin was regulated by the opposed functions of JNK and p38 kinase downstream of Galpha(12/13). In the JNK1(-) cells, thrombin did not increase either the NF-kappaB binding activity or I-kappaBalpha degradation despite I-kappaBalpha phosphorylation. These results demonstrated that thrombin induces iNOS in macrophages via Galpha(12) and Galpha(13), which leads to NF-kappaB activation involving the protein kinase C-dependent phosphorylation of I-kappaBalpha and the JNK-dependent degradation of phosphorylated I-kappaBalpha.
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PMID:Thrombin induces nitric-oxide synthase via Galpha12/13-coupled protein kinase C-dependent I-kappaBalpha phosphorylation and JNK-mediated I-kappaBalpha degradation. 1260 53

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic formation of microthrombi and fibrin deposition in the vasculature. Cancer is one of the leading cause of DIC, which often complicates bleeding tendency and organ dysfunction. Even though DIC therapy is expectant, it is still important, since the bleeding tendency limits the quality of patients' life remarkably. Heparin, low molecular weight heparin, danaparoid, protease inhibitors for coagulation factors and antithrombin III are the choices for DIC. However, since the selection of the drugs is different depending on the basal disease, it is important to understand the pathophysiology of the individual situation. In general, protease inhibitors is recommended for 'fibrinolysis dominant DIC' like DIC associated with leukemia and terminal stage solid cancer, in contrast, danaparoid and antithrombin III are the first choice for 'coagulation dominant DIC' like sepsis. Supplement of concentrated platelets and fresh frozen should be limited for the patients whose primary disease can be controlled.
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PMID:[Disseminated intravascular coagulation]. 1280 52

Although coagulation abnormalities may partly underlie the physiologic derangements of the sepsis syndrome, anticoagulant therapies have produced mixed results on survival in clinical studies. We hypothesized that a meta-analysis of clinical trials of anticoagulants in sepsis may provide insight as to the therapeutic utility of targeting the clotting cascade in this syndrome. We searched electronic databases and reviewed bibliographies of pertinent articles to identify controlled clinical studies in which anticoagulants had been administered as adjunctive therapy to patients with sepsis. After establishing statistical homogeneity, odds ratios (OR; with 95% confidence intervals [CI]) for effect of these agents on mortality and bleeding complications were determined using Mantel-Haenszel methodology. Potential for publication bias was assessed by the use of a statistical test of funnel plot asymmetry. Weighted linear regression was performed to examine the effect of control group mortality rate on treatment efficacy. We identified 11 studies that satisfied our inclusion criteria. Collectively, these studies enrolled 4690 patients (range of 29-2314) and examined three agents: antithrombin III (2659 patients), tissue factor pathway inhibitor (210 patients), and activated protein C (1821 patients). After establishing statistical homogeneity (P > 0.10, chi-square), we found that the OR (with 95% CI) for effect on mortality for these agents, relative to control treatment, was 0.8692 (0.7519-1.006). Weighted linear regression analysis was consistent with a control group mortality dependent effect for these agents (P = 0.02). Only five of the studies reported bleeding complications. Pooling the results of these five studies (4376 patients) resulted in an OR (with 95% CI) of 1.70 (1.40-2.07) relative to control treatment for bleeding risk. Anticoagulants as adjuvant therapy do not appear to improve outcome in sepsis and are associated with a significant risk of bleeding complications. To the extent that their treatment effect is dependent upon disease severity, the safety and efficacy of these agents may be enhanced by refinement in techniques of clinical stratification.
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PMID:A meta-analysis of controlled trials of anticoagulant therapies in patients with sepsis. 1462 85

Cerebral infarcts are an important cause of neonatal convulsions. We report the etiologic factors, and clinical and neuroradiologic findings of four full term neonates who presented with neonatal convulsions and had cerebral infarct. In our patients the risk factors for the cerebral infarct were perinatal asphyxia, sepsis, dehydration and catheter application. All had convulsions as the initial sign of infarct and had cranial imaging which revealed the definitive diagnosis. The patients underwent an extensive evaluation for hereditary causes of cerebral infarct that included anticoagulant factors (Proteins C and S, antithrombin III, antiphospholipid antibodies), factor V Leiden and prothrombin gene mutations, blood and urine amino acid and urine organic acid levels. The results were found to be within normal limits. In conclusion, neonatal convulsions can be the first sign of cerebral infarct. For this reason it seems preferable to include cranial imaging by computed tomography or magnetic resonance imaging (MRI) in the work-up of cases with unexplained neonatal convulsions.
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PMID:Cerebral infarcts in full term neonates. 1292 2

Inter-alpha inhibitor protein (IalphaIp) is an endogenous serine protease inhibitor in human plasma. Circulating IalphaIp levels were lower in 51 patients with severe sepsis than in healthy volunteers. Mean levels were 688+/-295 mg/L in patients with severe sepsis who survived (n=32), 486+/-193 mg/L in patients with sepsis who died (n=19), and 872+/-234 mg/L in control subjects (n=25). IalphaIp levels were lower in patients with shock versus those without (540+/-246 [n=33] vs. 746+/-290 [n=18] mg/L; P=.0102). IalphaIp levels were inversely correlated with 28-day mortality rates and Acute Physiology and Chronic Health Evaluation II scores and directly correlated with antithrombin III, protein C, and protein S levels. The administration of IalphaIp (30 mg/kg body weight intravenously) increased the 50% lethal dose in mice by 100-fold after an intravenous challenge of Escherichia coli. Thus, human IalphaIp may be a useful predictive marker and potential therapeutic agent in sepsis.
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PMID:Correlation between mortality and the levels of inter-alpha inhibitors in the plasma of patients with severe sepsis. 1296 25


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