Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that fluid phase platelet-activating factor (PAF) can enhance or "prime" polymorphonuclear (PMN) responses to subsequent stimulation with agonists such as formyl-methionine-leucine-phenylalanine (FMLP). Since thrombin induces PAF production in endothelial cells, we tested whether this thrombin-provoked endothelial PAF primes responses of marginated PMNs. Monolayers of human umbilical vein endothelial cells were exposed to either thrombin (0.5-5.0 units/ml) or buffer for up to 5 min and then PMNs were layered on top of the endothelial cells. After a further 5 min incubation, the PMNs were stimulated with a suboptimal concentration of FMLP (10(-7) M), and their superoxide production, elastase release, adhesion to endothelium, and capacity to cause endothelial cell lysis and detachment were assessed. Thrombin pretreatment significantly enhanced each of these FMLP-stimulated neutrophil responses. The extent of this enhancement correlated with both the dose and duration of thrombin treatment of endothelial cells and also the duration of PMN incubation with thrombin-exposed endothelium. Evidence that the augmentation was due to endothelial-derived PAF was obtained as follows: (1) thrombin induced [3H]acetate incorporation into endothelial PAF (assayed in lipid extracts); (2) antithrombin III conjointly inhibited this [3H]acetate uptake and prevented the priming effect of thrombin-treated endothelium on PMN responses; and (3) the PAF receptor antagonist BN52021, when preincubated with PMNs, also effectively blocked the enhancement of PMN responses. We conclude that thrombin stimulation of endothelial cells initiates a sequence of events culminating in the production of PAF--a membrane phospholipid capable of priming marginated PMNs. We suggest that this coagulation-fostered endothelial/PMN interaction may underlie a paracrine response that may potentiate PMN-mediated endothelial injury during sepsis and other thrombin-generating disorders.
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PMID:Thrombin-treated endothelium primes neutrophil functions: inhibition by platelet-activating factor receptor antagonists. 254 22

This review presents the rationale for and main results of coagulation inhibitor substitution during experimental and human sepsis. Activation of the contact system induces activation of the classical complement pathway with generation of anaphylatoxins, of the kinins pathway and of fibrinolysis. Physiologic inhibition depends on the C1-inhibitor (C1-Inh.). Septic patients exhibit a relative deficiency of biologically active C1-Inh. Substitution with concentrations of C1-Inh has been safely performed and preliminary results are consistent with a possible beneficial effect on hypotension and vasopressor requirement in septic shock. The extrinsic pathway is the main initial coagulation process involved in sepsis-induced DIC. Endothelial and monocyte generation of tissue factor (TF) is activated by bacterial products and endotoxin. Activation of TF is counteracted by a specific tissue factor pathway inhibitor (TFPI). The potential for TFPI substitution to inhibit the activation of the coagulation cascade in sepsis requires further study. Thrombin generation is inhibited by antithrombin III (AT III) and the protein C-protein S system. During sepsis, AT III is consumed and degraded by elastase. Animal studies have shown that DIC and death were prevented by high doses of AT III concentrates. Although a significant reduction in the duration of biological symptoms of DIC has been reported in most human studies, the usefulness of AT III substitution in human sepsis is still debated. None of the studies was able to document a statistically significant reduction in mortality. Protein C is activated by thrombomodulin and, with its cofactor protein S, inhibits factors Va and VIIIa. The free level of protein S depends on the level of the C4b binding protein (C4bBP), an acute-phase complement regulatory protein. During sepsis, protein C activity is significantly reduced, either by acute consumption or by thrombomodulin down-regulation, and increased levels of plasma C4bBP inhibit protein S. Infusion of activated protein C and protein S substitution both protect animals from the lethal effects of bacteria. Combining these different coagulation inhibitors should be carefully studied before its use in septic patients is recommended.
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PMID:Coagulation inhibitor substitution during sepsis. 863 34

Thrombin cleaves single-chain urokinase-type plasminogen activator (scu-PA) into a two-chain form (tcu-PA/T), which is virtually inactive in plasminogen activator assays. Little is known about the physiological importance of tcu-PA/T. To examine the occurrence of tcu-PA/T in vivo, we developed a sensitive and specific bioimmunoassay (BIA) for the assessment of tcu-PA/T in human body fluids. In this BIA, urokinase antigen was immuno-immobilized in microtiter plates and treated with cathepsin C, a specific activator of tcu-PA/T, after which plasminogen activator activity was measured. The occurrence of tcu-PA/T was examined in the plasma of 27 healthy individuals and of 17 sepsis patients, and in the synovial fluid of 16 rheumatoid arthritis patients. In addition, the concentration of urokinase antigen and scu-PA were measured in all three groups. In the plasma of the healthy individuals no measurable amounts of tcu-PA/T could be found(< detection limit of 0.2 ng/ml). In the plasma of almost all sepsis patients tcu-PA/T could be detected (median value 0.4 ng/ml). The amount of tcu-PA/T was 12% of the amount of scu-PA and accounted for about 9% of urokinase antigen. In the synovial fluid of all rheumatoid arthritis patients tcu-PA/T could be measured (median value 5.4 ng/ml) at a concentration which was twofold higher than the concentration found for scu-PA. In this group tcu-PA/T contributed to about 47% of the urokinase antigen. From these data we conclude that inactivation of scu-PA by thrombin can take place in vivo under pathological conditions which involve the production of large amounts of thrombin. This way thrombin may regulate fibrinolysis and extracellular proteolysis. The BIA for tcu-PA/T can be of use for further research on the physiological role of tcu-PA/T.
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PMID:A sensitive bioimmunoassay for thrombin-cleaved two-chain urokinase-type plasminogen activator in human body fluids. 882 85

Thrombosis and disseminated intravascular coagulation (DIC) are common complications of infections. Abnormal activation of coagulation is due in part of expression of tissue factor on intravascular cells in response to cytokines, including interleukin-1 beta (IL1 beta ) and tumor necrosis factor (TNF). Both TNF and IL1 beta are thought to play significant roles in producing the pathologic manifestations of sepsis. Therefore, we examined the effects of thrombin on TNF and IL1 beta secretion of monocytes, and the ability of monocyte products to promote tissue factor expression by endothelial cells. Human monocytes were treated with thrombin or a thrombin receptor agonist peptide (SFLLRN), and/or bacterial lipopolysaccharide (LPS). The agonists were removed, and monocytes cultured 18 hours. The monocyte-conditioned supernatants were assayed for TNF and IL1 beta antigen, and for their ability to induce tissue factor expression on human umbilical vein endothelial cells and the Ea.hy endothelial cell line. Thrombin alone did not promote monocyte TNF or IL-1 beta secretion. However, thrombin enhanced LPS-induced TNF and IL1 secretion. Supernatants from monocytes exposed to LPS plus thrombin promoted greater tissue factor expression on endothelial cells than supernatants from those treated with LPS only. SFLLRN did not increase TNF secretion in response to LPS, but did enhance LPS-induced IL1 beta secretion and tissue factor-inducing activity. Neither SFLLRN nor active thrombin augmented the level of mRNA for TNF above that induced by LPS alone. However, both increased the LPS-induced level of IL1 beta message. Thus, thrombin enhanced LPS-induced TNF and IL1 beta secretion by monocytes. Unexpectedly, the effects on these two cytokines were mediated by different mechanisms. Enhancement of LPS-induced IL1 beta secretion was largely mediated via the tethered ligand type thrombin receptor and correlated with an increase in the steady state level of mRNA. By contrast, enhanced TNF required proteolytically active thrombin, but was not mediated by the tethered ligand receptor. These data demonstrate that physiologically relevant amounts of thrombin can synergize with endotoxin to stimulate monokine release. Thrombin could thereby play a role in the complex network of mediators involved in the pathophysiology of sepsis. We speculate that limiting thrombin activity during DIC could be a beneficial adjunct in the management of sepsis.
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PMID:Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms. 884 45

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
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PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77

We have previously shown that an anticoagulant could attenuate inflammation in animal models of sepsis with disseminated intravascular coagulation (DIC) and that coagulation activation of human whole blood ex vivo results in a proinflammatory cytokine response. The current studies were performed to better understand mechanisms for the blood cell cytokine response and extend the investigation of such a response to endothelial cells as likely contributors to a vascular inflammatory response. Utilizing cell separation techniques, it was determined that the whole blood IL-8 response to coagulation activation or thrombin, specifically, was mediated by CD14+ monocytes. Moreover, thrombin was observed to stimulate both IL-8 and IL-6 production in cultured mononuclear cells. Analyses of the effects of coagulation activation and thrombin were extended to cultured human endothelial cells, and a similar cytokine response was observed. Thrombin catalytic activity appeared essential, since hirudin reduced thrombin-stimulated proinflammatory cytokine production in cultured monocytes and endothelial cells and prothrombin only weakly mimicked the thrombin response. The endothelial cell IL-8 and IL-6 response to thrombin could be mimicked by the thrombin receptor agonist peptide (TRAP), implicating a functional role of the classic thrombin receptor. Altogether, the results facilitate a better understanding of potential proinflammatory vascular responses to coagulation activation.
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PMID:Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. 959 Feb 65

Because plasma levels of protein C (PC) or activated protein C (APC) are altered in certain diseases associated with vascular dysfunction, and APC has therapeutic potential in preventing microvascular coagulation in severe sepsis, potential vascular effects of PC and APC were compared to those of the vasoactive peptide, thrombin. Thrombin was a more potent relaxant agonist than contractile agonist in aorta. Unlike thrombin, cumulatively administered APC (10(-9)-10(-7) M) did not exert vascular effects in rat or rabbit aorta. Noncumulative challenge of PC (10(-7) M) and APC (8 x 10(-8) M) also did not contract rat or rabbit aortae, either with or without endothelium. Likewise, the same concentrations of PC and APC also did not relax norepinephrine-induced (10(-7) M) vascular tone in either rat or rabbit aortae. Thus, in contrast to thrombin, PC and APC failed to modulate vascular tone, suggesting that the therapeutic use of APC is unlikely to be accompanied by any direct effects on vascular motility.
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PMID:Unlike thrombin, protein C and activated protein C do not affect vascular tone. 1103 10

Thrombin is a multifunctional protein, with procoagulant, inflammatory and anticoagulant effects. Binding of thrombin to thrombomodulin results in activation of Protein C and initiation of the Activated Protein C anticoagulant pathway, a process that is augmented by the endothelial cell Protein C receptor (EPCR). Activated Protein C has demonstrated antithrombotic, anti-inflammatory, and profibrinolytic properties. Its antithrombotic activity is particularly important in the microcirculation, and Protein C deficiency is associated with microvascular thrombosis. Activated Protein C has also been shown to modulate inflammation. When the level of thrombomodulin or Protein C is reduced in sepsis there is a vicious cycle of coagulation and inflammation, with potentially lethal consequences. In vitro studies and animal models have shown that Activated Protein C blunts the inflammatory and coagulant response to sepsis through a variety of mechanisms.
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PMID:The normal role of Activated Protein C in maintaining homeostasis and its relevance to critical illness. 1137 86

Because activation of the coagulation cascade and the generation of thrombin coexist with sepsis and the release of tumor necrosis factor (TNF)-alpha, we determined the effects of TNF-alpha on the mechanism of thrombin-induced increase in endothelial permeability. We assessed Ca(2+) signaling in human umbilical vein endothelial cells. In human umbilical vein endothelial cells exposed to TNF-alpha for 2 h, thrombin produced a rise in the intracellular Ca(2+) concentration ([Ca(2+)](i)) lasting up to 10 min. In contrast, thrombin alone produced a rise in [Ca(2+)](i) lasting for 3 min, whereas TNF-alpha alone had no effect on [Ca(2+)](i.) Thrombin-induced inositol 1,4,5-trisphosphate generation was not different between control and TNF-alpha-exposed cells. In the absence of extracellular Ca(2+), thrombin produced similar increases in [Ca(2+)](i) in both control and TNF-alpha-exposed cells. In TNF-alpha-exposed cells, the thrombin-induced Ca(2+) influx after intracellular Ca(2+) store depletion was significantly greater and prolonged compared with control cells. Increased Ca(2+) entry was associated with an approximately fourfold increase in Src activity and was sensitive to the Src kinase inhibitor PP1. After TNF-alpha exposure, thrombin caused increased tyrosine phosphorylation of junctional proteins and actin stress fiber formation as well as augmented endothelial permeability. These results suggest that TNF-alpha stimulation of endothelial cells results in amplification of the thrombin-induced Ca(2+) influx by an Src-dependent mechanism, thereby promoting loss of endothelial barrier function.
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PMID:Synergistic effects of tumor necrosis factor-alpha and thrombin in increasing endothelial permeability. 1155

There are global coagulation tests and hemostatic molecular markers in the diagnosis of disseminated intravascular coagulation (DIC). In the global coagulation tests, the sensitivity of prothrombin time ratio and fibrinogen for the diagnosis of DIC is low, but their specificity is high. In platelet count and FDP, the sensitivity for the diagnosis of DIC is good, but the specificity is low. Fibrinogen may be unsuitable for the diagnosis of DIC, because it increases of the inflammatory reaction. It is possible to theoretically diagnose DIC by increased tissue factor production. It is currently considered that hemostatic molecular marker should be utilized to diagnose DIC. Thrombin-antithrombin complex and soluble fibrin are reflected to hypercoagulable state, thrombomodulin to vascular endothelial cell injuries, and plasminogen activator inhibitor-I to hypofibrinolytic state. In leukemia with DIC, hyperfibrinolysis and marked bleeding symptoms are often observed. In septicemia with DIC, hypofibrinolysis and severe organ failure often occur. Early diagnosis and treatment of DIC are important to improve the prognosis, and hemostatic molecular markers should be useful for that purpose.
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PMID:[Hemostatic abnormalities in DIC]. 1237 12


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