Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hemostatic system is severely disturbed during endotoxemia, leading to a hypercoagulable state. However, it remains uncertain to what extent hypercoagulability is the critical factor in determining the clinical course rather than just the consequence of a severe systemic inflammatory response. To answer this question, we evaluated the evolution of hemostatic and inflammatory markers, as well as histological features, in mice sensitive and resistant to two models of endotoxemia: lipopolysaccharide-injection and cecal ligation puncture. Genetic (knockout mice) and pharmacological (PJ34) blockade of the nuclear enzyme PARP-1 was used to achieve resistance to the endotoxemia. In both models, endotoxemia resulted in antithrombin deficiency, decreased platelets, and fibrin deposition in organs, which were similar in all groups of mice. By contrast, proinflammatory mediators, inflammatory cell infiltration (especially that mediated by mononuclear cells), and organ degeneration were more intense in sensitive animals. Further studies supported a negative role for the triggering of the coagulation cascade in the mortality associated with the endotoxic shock. Hirudin had a minor effect on cell infiltration and organ damage, despite causing a potent inhibition of fibrin deposition. On the other hand, a sublethal dose of lipopolysaccharide yielded significant fibrin deposition but weak activation of the inflammatory response. Our results suggest that activation of coagulation by endotoxemia is severe and independent of the inflammatory response. However, such activation may act with fibrin deposition to have a minor influence on survival in sepsis.
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PMID:Role of lipopolysaccharide and cecal ligation and puncture on blood coagulation and inflammation in sensitive and resistant mice models. 1579 89

In a rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC), we used urokinase (UK) in an attempt to clarify the role of fibrinolysis and to investigate changes in plasma endothelin levels. Two kinds of experiment were performed. The first one: experimental DIC was induced by sustained infusion of 30 mg/kg LPS for 4 h via the tail vein, and two doses of UK (2.0 or 10.0 IU/g/4.5 h) were administered to rats 30 min before infusion of LPS, after which UK infusion was continued for a further 4 h. The second one: experimental DIC was induced by sustained infusion of 1 mg/kg/10 min LPS for 10 min, and two doses of UK (2.0 or 10.0 IU/g/4 h) were administered to rats at 30 min after LPS infusion. The parameters described below were determined at 4 h in the first experiment, at 4 h and 8 h in the second one. The similar results were observed in both kinds of experiment. There were no significant differences in plasma thrombin-antithrombin complex, fibrinogen or platelet number among the three DIC groups, in both kinds of experiment. Plasma levels of D-dimer were significantly increased in the LPS + higher dose of UK group when compared with the LPS group. The increased plasma plasminogen activator inhibitor (PAI) activity seen in the LPS group was significantly suppressed in the groups receiving UK (especially higher dose of UK). In addition, the increased plasma levels of creatinine and alanine aminotransferase seen in the LPS group were significantly suppressed in the groups receiving UK (especially higher dose of UK). Plasma levels of endothelin, known to be a potent vasoconstrictive agent, were markedly elevated by LPS infusion, and were significantly suppressed in the groups receiving UK of both kinds of experiment, in a dose-dependent fashion compared with LPS group. Glomerular fibrin deposition was significantly suppressed in the groups receiving UK when compared with the LPS group. No manifestations of bleeding were observed in any of the groups. Enhanced fibrinolysis and depressed endothelin induced by UK thus appear to play an important role in preventing the development of organ failure in the LPS-induced DIC model.
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PMID:Beneficial effects of urokinase on lipopolysaccharide-induced disseminated intravascular coagulation in rats: focus on organ function and endothelin levels. 1584 19

We examined the role of nitric oxide (NO) produced by an inducible isoform of NO synthase (iNOS) using N[6]-(iminoethyl)-lysine (L-NIL), a selective iNOS inhibitor, in the rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) and investigated changes in organ function, plasma levels of NOX (metabolites of NO) and endothelin. We induced experimental DIC by the sustained infusion of 30 mg kg(-1) LPS for 4 h via the tail vein. We then investigated the effect of L-NIL (6 mg kg(-1), from - 0.5 to 4 h) on LPS-induced DIC. Blood was withdrawn at 4 and 8 h, and all four groups (LPS with or without L-NIL at 4 and 8 h) consisted of eight rats. Three of the animals in the 8-h LPS group died, and we examined blood samples from five rats in this group. None of the other rats died. The LPS-induced elevation of creatinine, alanine aminotransferase, glomerular fibrin deposition and plasminogen activator inhibitor was significantly suppressed by L-NIL coadministration, although L-NIL did not affect the platelet count, fibrinogen concentration or the level of thrombin-antithrombin complex. Moreover, plasma levels of the D-dimer that reflect the lysis of cross-linked fibrin were significantly increased by L-NIL coadministration in the LPS-induced DIC model. Plasma levels of NOX and endothelin were obviously increased by LPS infusion. However, both levels were significantly suppressed in the LPS + L-NIL group, when compared with the LPS group. Although mean arterial pressure (MAP) was significantly decreased between 2 and 8 h compared with the control in the LPS group, this depression was significantly attenuated in the LPS + L-NIL group. Our results suggest that NO induced by iNOS contributes to hypotension (depressed MAP), the progression of hepatic and renal dysfunction, microthrombus deposition and elevated endothelin levels in the rat model of LPS-induced DIC.
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PMID:Selective inducible nitric oxide synthase inhibition attenuates organ dysfunction and elevated endothelin levels in LPS-induced DIC model rats. 1586 3

Pneumonia is frequently associated with changes in coagulation and fibrinolysis in the bronchoalveolar space. To determine the effect of lipopolysaccharide (LPS) on the hemostatic balance in the human lung, six healthy subjects inhaled nebulized LPS or saline in a randomized cross-over study and bronchoalveolar lavage fluid was obtained six hours thereafter. LPS induced soluble tissue factor and thrombin-antithrombin complexes and inhibited plasminogen activator activity in BALF. Additionally plasminogen activator inhibitor type 1 production was upregulated after LPS inhalation. LPS also elicited local activation of neutrophils (release of elastase, myeloperoxidase and bactericidal/permeability increasing protein) and secretion of interleukin (IL)-6 and IL-8. Inhalation of LPS by healthy humans reproduces major features of the procoagulant response to inflammatory and infectious lung diseases and may be used as a novel model to evaluate pathogenetic mechanisms and new interventions.
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PMID:Activation of coagulation and inhibition of fibrinolysis in the lung after inhalation of lipopolysaccharide by healthy volunteers. 1596 85

Pericytes are known to regulate brain capillary endothelial functions. The purpose of this study was to define the hemostatic regulatory role of human brain pericytes. We used blood-brain barrier models consisting of human pericytes grown on transwell membrane inserts and cocultured with human brain microvascular endothelial cells (HBEC), or pericytes grown in direct contact with HBEC. When grown in cocultures in which pericytes were physically separated from endothelial cells, pericytes induced significant changes in endothelial tissue plasminogen activator (tPA) messenger ribonucleic acid (mRNA) and protein: tPA mRNA level was decreased in pericyte cocultures (52%+/-25% of monocultures, P < 0.05) and tPA protein level was decreased (66%+/-23% of monocultures, P < 0.05). Pericyte effects on endothelial fibrinolysis were enhanced when the two cell types were cocultured in direct contact, with tPA protein reduced in cocultures compared with monocultures (25%+/-15% of monocultures, P < 0.05). Endotoxin (lipopolysaccharide (LPS)), used as a standardized stimulus to define brain-specific inflammation-induced change, amplified pericyte-induced enhanced release of the tPA inhibitor plasminogen activator inhibitor-1 (PAI-1); the latter was released by endothelial cells first cocultured with pericytes and then incubated with LPS in the absence of pericytes. Pericytes (in contrast to endothelial cells and astrocytes) were found to be the principal in vitro source of the serpin protease nexin-1 (PN-1), known to have primarily antithrombin effects. These in vitro findings suggest that pericytes negatively regulate brain endothelial cell fibrinolysis, while pericyte expression of PN-1 may provide endogenous anticoagulant activity.
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PMID:Brain endothelial hemostasis regulation by pericytes. 1601 79

We hypothesized that infusion of recombinant human antithrombin without concomitant heparin would have dose-dependent anticoagulant properties and potentially decrease endotoxin (lipopolysaccharide [LPS])-induced cytokine production. This was a randomized, double-blind, placebo-controlled study in parallel groups enrolling 30 healthy male volunteers. The active treatment groups received infusions of recombinant human antithrombin to increase antithrombin levels to 200% and 500% before infusion of 2 ng/kg endotoxin (LPS). Infusion of antithrombin dose-dependently decreased coagulation (P < .01 by repeated-measures ANOVA): peak levels of prothrombin fragment (1.8 nmol/L [95% confidence interval (CI), 1.3-2.3 nmol/L] in the 500% antithrombin group and 4.4 nmol/L [95% CI, 2.7-6.2 nmol/L] in the placebo group at 4 hours), thrombin antithrombin complexes (12 microg/L [95% CI, 8-16 microg/L] in the 500% antithrombin group and 34 microg/L [95% CI, 20-48 microg/L] in the placebo group at 4 hours), and D-dimer (0.2 microg/L [95% CI, 0.1-0.2 microg/L] in the 500% antithrombin group and 0.5 microg/L [95% CI, 0.4-0.7 microg/L] in the placebo group). Recombinant human antithrombin decreased peak interleukin-6 levels by 40% (222 pg/mL [95% CI, 148-295 pg/mL] and 216 pg/mL [95% CI, 112-320 pg/mL] in the 500% and 200% antithrombin groups, respectively, versus 357 pg/mL [95% CI, 241-474 pg/mL] in the placebo group; P < .001 by ANOVA). Finally, infusion of recombinant human antithrombin rapidly and transiently decreased neutrophil counts (by 19% [95% CI, 8%-30%] in the 500% antithrombin group versus 6% [95% CI, 1%-10%] in the placebo group, P = .002 by Kruskal-Wallis ANOVA) and monocyte counts (by 30% [95% CI, 16%-44%] in the 500% antithrombin group and 18% [95% CI, 9%-28%] in the 200% antithrombin group versus 8% [95% CI, 5%-20%] in the placebo group, P = .04) before LPS challenge, indicating that recombinant human antithrombin directly interacts with these leukocyte subsets. In summary, recombinant human antithrombin dose-dependently inhibited tissue factor-triggered coagulation. Effects on leukocytes and inhibition of interleukin-6 release seem to represent specific pharmacodynamic properties of recombinant human antithrombin.
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PMID:Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia. 1641 39

We have developed a cell-based model of thrombin generation using activated monocytes as a source of tissue factor (TF) and platelets serving as a surface for thrombin generation. Monocytes are activated by lipopolysaccharide and express cell-bound TF. To these are added physiologic (plasma) concentrations of all the plasma procoagulants as well as TF pathway inhibitor, antithrombin, and C1-esterase inhibitor. Coagulation takes place in microtiter wells and is initiated by factor VIIa (FVIIa) and calcium. At time intervals, aliquots are removed, platelet activation is measured by the expression of P-selectin, and thrombin generation is measured by chromogenic assay. In addition, one can measure the activation of FIX, FX, FVIII, FV, and FXI. Initial results reveal that the FVIIa-TF interaction results in the activation of FX to FXa and FIX to FIXa. FXa stays in the vicinity of the TF-bearing cell and, in the presence of FVa, converts a small amount of prothrombin to thrombin on the surface of the TF cell. This small amount of thrombin is not sufficient to clot fibrinogen, but is sufficient to activate platelets and FVIII, FV, and FXI. Following platelet activation, FVIIIa, FVa, and FXa occupy sites on the activated platelet surface. FIXa, activated by TF-FVIIa, does not remain on the TF cell, but converts FX to FXa on the platelet surface. FXIa acts to boost FIXa generation on the activated platelet, increasing FXa and subsequent thrombin generation. We have also shown that activated protein C does not inactivate Va on the platelet surface but rather on endothelial cell surfaces.
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PMID:A cell-based model of thrombin generation. 1667 64

Although it has been well documented that vitamin D receptor (VDR) activation influences the expression of various genes involved in calcium homeostasis and cell differentiation, the physiological role of VDR action in hemostasis remains unclear. We studied thrombogenicity in normocalcemic VDR knock-out (KO) mice on a high calcium diet in comparison with that in wild-type mice and that in hypocalcemic VDRKO mice fed a regular diet. Platelet aggregation was significantly enhanced in normocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretion were reduced in hypocalcemic VDRKO mice but not in normocalcemic VDRKO mice. The gene expression of antithrombin in the liver and that of thrombomodulin in the aorta, liver and kidney were down-regulated in hypo- and normocalcemic VDRKO mice, whereas tissue factor gene expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that the vitamin D-VDR system plays a pivotal role in antithrombogenicity in vivo.
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PMID:[Vitamin D-vitamin D receptor system regulates antithrombogenicity in vivo]. 1681 78

The aim of the present study was to determine the effects of mechanical ventilation on alveolar fibrin turnover in lipopolysaccharide (LPS)-induced lung injury. In a randomised controlled trial, Sprague-Dawley rats (n = 61) were allocated to three ventilation groups after intratracheal LPS (Salmonella enteritidis) instillations. Group I animals were subjected to 16 cmH(2)O positive inspiratory pressure (PIP) and 5 cmH(2)O positive end-expiratory pressure (PEEP); group II animals to 26 cmH(2)O PIP and 5 cmH(2)O PEEP; and group III animals to 35 cmH(2)O PIP and 5 cmH(2)O PEEP. Control rats (not mechanically ventilated) received LPS. Healthy rats served as a reference group. Levels of thrombin-antithrombin complex (TATc), D-dimer, plasminogen activator inhibitor (PAI) activity and PAI-1 antigen in bronchoalveolar lavage fluid were measured. LPS-induced lung injury increased TATc, D-dimer and PAI activity and PAI-1 antigen levels versus healthy animals. High pressure-amplitude ventilation increased TATc concentrations. D-dimer concentrations were not significantly raised. Instead, PAI activity increased with the amplitude of the pressure, from 0.7 U.mL(-1) in group I to 3.4 U.mL(-1) in group II and 5.0 U.mL(-1) in group III. There was no change in PAI-1 antigen levels. In conclusion, mechanical ventilation creates an alveolar/pulmonary anti-fibrinolytic milieu in endotoxin-induced lung injury which, at least in part, might be due to an increase in plasminogen activator inhibitor activity.
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PMID:Mechanical ventilation affects alveolar fibrinolysis in LPS-induced lung injury. 1683 99

Plasma-derived human antithrombin (pAT) is used for the treatments of disseminated intravascular coagulation (DIC) and hereditary antithrombin deficiencies. We expressed recombinant human antithrombin (rAT) in Chinese hamster ovary (CHO) cells. The purified rAT is composed of 55% alpha-isoform and 45% beta-isoform. The structure of the N-linked oligosaccharides of rAT is the same biantennary complex type as previously found in pAT with less sialylated on the non-reducing ends. Most of the oligosaccharides of rAT are fucosylated at the reducing ends of N-acetylglucosamine, while those of pAT are not fucosylated. Despite of the difference in sialylation and fucosylation of the oligosaccharide units, rAT and pAT showed indistinguishable heparin cofactor and progressive activities, and they bound to thrombin in a one-to-one stoichiometric manner. In lipopolysaccharide (LPS)-induced and thromboplastin-induced DIC rat models, rAT reduced fibrinogen and platelet consumption to a similar extent with pAT. In LPS-induced DIC model, both ATs similarly restrained the increase of alanine aminotransferase and aspartate aminotransferase activities. Finally, pharmacokinetic analysis showed that both ATs had similar half-lives in the circulation of normal rats. Together, the present study demonstrated that rAT prepared in CHO cells has potential for a substitute of pAT in therapeutic use.
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PMID:Recombinant human antithrombin expressed in Chinese hamster ovary cells shows in vivo efficacy on rat DIC model similarly to plasma-derived antithrombin regardless of different N-glycosylation. 1684 3


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