Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombomodulin (TM), a membrane-bound receptor for thrombin on the endothelial cell surface, contributes to the regulation of the coagulation system. TM is known to exist in human plasma and urine as soluble forms. We purified soluble TM from human urine (MR-33) and investigated the anticoagulant effects of MR-33 in vitro and in vivo. In human plasma, MR-33 inhibited not only the procoagulant activity of thrombin, but also the thrombin generation via accelerating the thrombin-catalyzed protein C activation. In rat disseminated intravascular coagulation (DIC) models, intravenous infusion of MR-33 improved the hematological abnormalities without excessive prolongation of APTT and bleeding time. Benefit (dose required for 50% inhibition of fibrinogen decrease: ED50) to risk (minimum dose required for significant prolongation of bleeding time) ratio was 1:27 for MR-33. Furthermore, the anticoagulant activities of MR-33 was independent of AT III activity, and MR-33 was effective on heparin-resistant DIC models with low AT III level in rats. Intravenous injection of MR-33 prevented the endotoxin-induced increases in TAT, TNF-alpha and IL-6 level and pulmonary vascular permeability in mice. These results indicate that MR-33 may be a clinically useful antithrombotic agent with reduced risk for hemorrhage, and this drug also has anti-inflammatory effects. Clinical trials of MR-33 for the treatment of DIC are now in progress in Japan.
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PMID:[Thrombomodulin]. 1121 78

In April 1996, a 77-year-old man initially presented with fever, rash and polyarthralgia, and was diagnosed as having low titer cold agglutinin disease with acute hemolytic anemia. The patient's condition and laboratory findings improved after administration of corticosteroid (prednisolone 60 mg). In June 1996, however, he developed acute cholecystitis and died due to sepsis, disseminated intravascular coagulation and multiple organ failure. During the course, the levels of inflammatory cytokines such as TNF-alpha and IL-6 were correlated with the pathology, and the disease was diagnosed as systemic inflammatory response syndrome (SIRS). Autopsy revealed necrotizing cholecystitis, erythrophagocytosis in the liver, and cytomegalovirus infection in the lung and gall bladder. This was considered to be a rare case of low titer cold agglutinin disease complicated by SIRS.
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PMID:[Systemic inflammatory response syndrome triggered by necrotizing cholecystitis after treatment of underlying low titer cold agglutinin disease]. 1123 30

The influence of social disruption stress (SDR) on the susceptibility to endotoxic shock was investigated. SDR was found to increase the mortality of mice when they were challenged with the bacterial endotoxin lipopolysaccharide (LPS). Histological examination of SDR animals after LPS injection revealed widespread disseminated intravascular coagulation in the brain and lung, extensive meningitis in the brain, severe hemorrhage in the lung, necrosis in the liver, and lymphoid hyperplasia in the spleen, indicating inflammatory organ damage. In situ hybridization histochemical analysis showed that the expression of the glucocorticoid receptor mRNA was down-regulated in the brain and spleen of SDR animals while the ratio of expression of AVP/CRH-the two adrenocorticotropic hormone secretagogue, increased. After LPS injection, the expression of pro-inflammatory cytokines, IL-1beta and TNF-alpha, was found significantly higher in the lung, liver, spleen, and brain of the SDR mice as compared with the LPS-injected home cage control animals. Taken together, these results show that SDR stress increases the susceptibility to endotoxic shock and suggest that the development of glucocorticoid resistance and increased production of pro-inflammatory cytokines are the mechanisms for this behavior-induced susceptibility to endotoxic shock.
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PMID:Social stress increases the susceptibility to endotoxic shock. 1128 52

FR167653 inhibits the production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, powerful inducers of CXC chemokines IL-8 and growth related oncogene (GRO)-alpha. The production of IL-8 and GRO-alpha was investigated and the effects of FR167653 were examined in a rabbit model of endotoxin shock. Male New Zealand rabbits were given endotoxin at a dose sufficient to induce DIC. Three groups of rabbits received FR167653 at different doses. TNF-alpha, IL-1beta, IL-8, and GRO-alpha levels were measured, several pathologic features were evaluated, and the results were compared with those obtained in control rabbits, which received only endotoxin. Endotoxin increased serum levels of IL-8 and GRO-alpha, which were associated with hypotension, renal dysfunction, and mortality, peaking at 4 h. FR167653 improved mortality, an event that was associated with decreased levels of not only TNF-alpha and IL-1beta but also IL-8 and GRO-alpha. TNF-alpha peaked at 2 h, at a time point before IL-8 and GRO-alpha reached their peak, and the TNF-alpha level was tightly correlated with that of IL-8 and GRO-alpha. Altogether, these data suggest the possible involvement of IL-8 and GRO-alpha in endotoxin shock, and FR167653 may foster a beneficial outcome in part by modulating the chemokines level by inhibiting TNF-alpha and IL-1beta.
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PMID:Interleukin (IL)-8 and growth related oncogene-alpha in severe endotoxemia and the effects of a tumor necrosis factor-alpha/IL-1beta inhibitor on these chemokines. 1256 97

The specter of bioterrorism employing genetically engineered Rickettsia resistant to all antibiotics should reawaken the world's desire to elucidate the pathogenesis of typhus and spotted fever rickettsioses in a search for mechanisms vulnerable to interdiction. The pathogenetic sequence includes rickettsial entry into the dermis, hematogenous dissemination to vascular endothelial cells (most critically in brain and lungs), increased vascular permeability, edema, and immunity mediated by NK cells, IFN-gamma, TNF-alpha, RANTES, antibodies, and cytotoxic T lymphocytes. Silverman has demonstrated the role of reactive oxygen species (ROS) produced by R. rickettsii-infected endothelial cells in peroxidative damage to cell membranes in vitro, and Heinzen has described actin-based rickettsial intracellular mobility and intercellular spread. At this point the availability of sequences of rickettsial genomes and excellent animal models of rickettsioses have yielded insufficient progress towards the identification of rickettsial virulence factors and knowledge of the importance of injury mediated by ROS, phospholipase A(2), protease(s) or other mechanisms in vivo. Attention to the rickettsiosis-associated procoagulant state led to determination that hemostatic mechanisms largely prevent major hemorrhage without disseminated intravascular coagulation or thrombosis-mediated ischemia. Particularly lacking is knowledge of early events in vivo at the portal of entry in skin (or lung), of the effects of the inoculum medium (arthropod saliva or feces), mediators produced by infected endothelium under conditions of flow and of the contributions in vivo of immune effectors to pathology, of the role of apoptosis in rickettsial infection, and of the endothelial cell alterations that account for increased vascular permeability. The host cell receptor for the Rickettsia ligand and the mechanism of rickettsial escape from the phagosome need to be elucidated.
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PMID:Pathogenic mechanisms of diseases caused by Rickettsia. 1286 May 94

Bacillus anthracis lethal toxin (LT) is the major virulence factor of anthrax and reproduces most of the laboratory manifestations of the disease in animals. We studied LT toxicity in BALB/cJ and C57BL/6J mice. BALB/cJ mice became terminally ill earlier and with higher frequency than C57BL/6J mice. Timed histopathological analysis identified bone marrow, spleen, and liver as major affected organs in both mouse strains. LT induced extensive hypoxia. Crisis was due to extensive liver necrosis accompanied by pleural edema. There was no evidence of disseminated intravascular coagulation or renal dysfunction. Instead, analyses revealed hepatic dysfunction, hypoalbuminemia, and vascular/oxygenation insufficiency. Of 50 cytokines analyzed, BALB/cJ mice showed rapid but transitory increases in specific factors including KC, MCP-1/JE, IL-6, MIP-2, G-CSF, GM-CSF, eotaxin, FasL, and IL-1beta. No changes in TNF-alpha occurred. The C57BL/6J mice did not mount a similar cytokine response. These factors were not induced in vitro by LT treatment of toxin-sensitive macrophages. The evidence presented shows that LT kills mice through a TNF-alpha-independent, FasL-independent, noninflammatory mechanism that involves hypoxic tissue injury but does not require macrophage sensitivity to toxin.
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PMID:Bacillus anthracis lethal toxin induces TNF-alpha-independent hypoxia-mediated toxicity in mice. 1295 14

This paper presents the results of the clinical trial with the use of hr TNF-alpha (human recombinant tumor necrosis factor-alpha) in 16 advanced gastrointestinal cancer patients. Hr TNF-alpha was administered intravenously in a short, 30-min infusion. According to authors' previous experiences with daily dose escalation (modified Fibonacci scheme), a daily dose of 150 microg/m2 was established as safe, and was well tolerated by the patients. The treatment consisted of 5-day cycles, repeated six times, every 14 days. Special attention was paid regarding the possible side-effect and safety of hr TNF-alpha administration in men, as many acute and chronic haematological toxicities have been reported. After careful analysis of TNF-alpha side-effects, we did not find any acute haematological complications (e.g. thrombosis, DIC, embolism) in any of the patients. Haemoglobin values and erythrocyte and leucocyte counts gradually decreased during each cycle, with the tendency for spontaneous renewal after the treatment had been completed. No cases of thrombocytopenia and severe neuropenia were observed.
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PMID:Tumor necrosis factor in advanced gastrointestinal neoplasms. A clinical trial with a focus on haematological effects. 1465 Dec 25

Our retrospective analysis of 105 patients with alcoholic liver injury confirmed that patients with severe alcoholic hepatitis (SAH) showed severe hyperbilirubinemia, reduced hepatic biosynthetic capacity, and marked acute inflammatory reactions, and developed multiple organ failure (MOF). Multivariate analysis using the Cox proportional hazards model showed serum C-reactive protein and DIC as significant independent prognostic factors among SAH, LC+AH, and AH groups. Improved assay showed an increase of plasma endotoxin with the progression of alcoholic liver injury. In most survivors, plasma Et levels decreased in the recovery phase. Serum interleukin (IL)-6 and IL-8 levels in the acute phase were high in patients with AH and LC+AH, especially in non-survivors and in patients with SAH. In the recovery phase, these cytokine levels in survivors tended to decrease, but in non-survivors, IL-6 remained high, and IL-8 further increased. Serum levels of HDL and albumin, which are protective against endotoxicity by inhibiting endotoxin uptake and TNF production by macrophages, were decreased with the progression of alcoholic liver injury. Animal experiments supported that the increase in endotoxin-binding capacity of HDL and albumin may serve as a protective mechanism against endotoxin in chronic ethanol-loaded rats and that an addition of high-dose ethanol to these rats may lead to impaired binding and inactivation of endotoxin. Lipopolysaccharide-binding protein (LBP) which enhances endotoxin uptake and TNF production by macrophages, was generally increased in patients with alcoholic liver injury. This imbalance among endotoxin binding proteins in the blood may induce overproduction of cytokines by macrophages in patients with severe alcoholic liver injury. Our animal experiments further revealed that an additional administration of a high-dose ethanol to chronic alcohol-fed rats led to decrease of endotoxin clearance, increased extrahepatic accumulation of endotoxin and elevation of plasma TNF. The splenic macrophages and pulmonary alveolar macrophages are demonstrated to be important for endotoxin uptake, and excessive production of TNF in rats given large amounts of alcohol. An in vitro culture experiment in the presence of rat LBP suggested a role of these macrophages in excessive production of TNF-alpha. When the functions of various macrophages were compared in rats given alcohol, maximum TNF-alpha secretion was noted in alveolar macrophages, In conclusion, endotoxemia and its effects on extrahepatic macrophages may play key roles in the progression of severe alcoholic liver injury and MOF.
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PMID:Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure. 1634 5

We investigated the role played by cytokines in the mortality of patients with Crimean-Congo hemorrhagic fever (CCHF). Serum levels of several cytokines were measured in 3 patients with fatal CCHF and in 27 patients with nonfatal CCHF. Levels of interleukin (IL)-6 (P< or = .001) and tumor necrosis factor (TNF)-alpha (P = .004) were significantly higher in patients with fatal CCHF than in patients with nonfatal CCHF, whereas levels of IL-10 were not significantly different between the 2 groups (P = .937). Disseminated intravascular coagulation (DIC) scores were also higher in the patients with fatal CCHF (P = .023). Levels of IL-6 and TNF-alpha were positively correlated with DIC scores, whereas levels of IL-10 were negatively correlated with DIC scores. In conclusion, these findings demonstrate that proinflammatory cytokines play a major role in the mortality of patients with CCHF.
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PMID:Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever. 1651 55

This review describes the role of oxidative stress caused by endotoxin challenge in sepsis or septic shock symptoms. We observed that endotoxin injection resulted in lipid peroxide formation and membrane damage (near 60-150 kDa) in the livers of experimental animals, causing decreased levels of scavengers or quenchers of free radicals. The administration of alpha-tocopherol completely prevented injury to the liver plasma membrane caused by endotoxin, and suggested that lipid peroxidation by free radicals might occur in a tissue ischemic state, probably by disseminated intravascular coagulation (DIC), in endotoxemia. In mice, depression of Ca(2+)-ATPase activity in the liver plasma membrane may contribute to the membrane damage caused by endotoxin, and the increase of [Ca(2+)](i) in the liver cytoplasm may partially explain the oxidative stress that occurs in endotoxemia. It seems that endotoxin-induced free radical formation is regulated by Ca(2+) mobilization. Moreover, we have suggested that the oxidative stress caused by endotoxin may be due, at least in part, to the changes in endogenous zinc or selenium regulation during endotoxemia. Interestingly, the extent of TNF-alpha-induced oxidative stress may be the result of a synergism between TNF-alpha and gut-derived endotoxin. It is likely that bacterial or endotoxin translocation plays a significant role in TNF-alpha-induced septic shock. On the other hand, although nitric oxide (NO) has been implicated in the pathogenesis of vascular hyporesponsiveness and hypotension in septic shock in our experimental model, it is unlikely that NO plays a significant role in liver injury caused by free radical generation in endotoxemia.
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PMID:Oxidative stress and septic shock: metabolic aspects of oxygen-derived free radicals generated in the liver during endotoxemia. 1683 Dec 3


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