Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective was to evaluate tumour necrosis factor (TNF) status in patients with systemic juvenile chronic arthritis (s-JCA). Plasma levels of TNF-alpha, and serum levels of soluble TNF receptor 1 and 2 (sTNFR1 and sTNFR2) were measured using specific immunoassays in 20 patients with s-JCA, 10 with polyarticular JCA and 15 with pauciarticular JCA, and in 20 controls comparable for age. In patients with active s-JCA, circulating levels of TNF-alpha, sTNFR1 and sTNFR2 were significantly (P < 0.001) higher than those of controls. The levels of sTNFR1 and sTNFR2, but not those of TNF-alpha, were associated with the persistence and severity of systemic symptoms and were significantly correlated with prolongation of partial thromboplastin time and decrease in prothrombin activity. In two patients evaluated during a s-JCA-associated macrophage activation syndrome, a marked increase in sTNFR1 and sTNFR2 was found. Our results suggest that in s-JCA, TNF is involved in systemic manifestations, in the subclinical coagulation abnormalities, and in the development of the macrophage activation syndrome.
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PMID:Soluble tumour necrosis factor receptor levels reflect coagulation abnormalities in systemic juvenile chronic arthritis. 918 61

Ribavirin, a synthetic guanosine analogue, possesses a broad spectrum of activity against DNA and RNA viruses. It has been previously shown to attenuate the course of fulminant hepatitis in mice produced by murine hepatitis virus strain 3. We therefore studied the effects of ribavirin on murine hepatitis virus strain 3 replication, macrophage production of proinflammatory mediators including TNF, IL-1, and the procoagulant activity (PCA), fgl2 prothrombinase; and Th1/Th2 cytokine production. Although ribavirin had inhibitory effects on viral replication (<1 log), even at high concentrations complete eradication of the virus was not seen. In contrast, at physiologic concentrations (up to 500 microg/ml), ribavirin markedly reduced viral-induced parameters of macrophage activation. With ribavirin treatment, the concentrations of PCA, TNF-alpha and IL-1beta all decreased to basal concentrations: PCA from 941 +/- 80 to 34 +/- 11 mU/10(6) cells; TNF-alpha from 10.73 +/- 2.15 to 2.74 +/- 0.93 ng/ml; and IL-1beta from 155.91 +/- 22.62 to 5.74 +/- 0.70 pg/ml. The inhibitory effects of ribavirin were at the level of gene transcription as evidenced by Northern analysis. Both in vitro and in vivo, ribavirin inhibited the production of IL-4 by Th2 cells, whereas it did not diminish the production of IFN-gamma in Th1 cells. In contrast, ribavirin had no inhibitory effect on TNF-alpha and IL-1beta production in LPS-stimulated macrophages. These results suggest that the beneficial effects of ribavirin are mediated by inhibition of induction of macrophage proinflammatory cytokines and Th2 cytokines while preserving Th1 cytokines.
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PMID:Ribavirin inhibits viral-induced macrophage production of TNF, IL-1, the procoagulant fgl2 prothrombinase and preserves Th1 cytokine production but inhibits Th2 cytokine response. 953 10

Spontaneous resorption in the CBA x DBA/2 model is attributed to NK cells, macrophages, and Th1-type cytokines. In vivo depletion of NK cells by anti-asialoGM1 Ab or macrophage depletion by silicon dioxide treatment reduced abortion rates, which could no longer be boosted by injecting TNF-alpha (which activates NK cells) or IFN-gamma (which activates macrophages). TNF-alpha + gamma-IFN coadministration aborted >80% of the embryos whether or not NK cells or macrophages had been depleted or estradiol + progesterone was injected to correct potential reduction in ovarian function by cytokines. The cytokines also aborted IRF1+/+ C57BL/6 but not IRF1-/- females pregnant by IRF1+/+ DBA/2. Both spontaneous and cytokine-boosted abortions in CBA x DBA/2 were blocked by Ab to fgl2 prothrombinase [corrected] expressed by cytokine-stimulated vascular endothelial cells and monocytes; in vivo Ab depletion of granulocytes also prevented TNF-alpha + IFN-gamma-induced abortions. Cytokine-triggered thrombotic/inflammatory processes in maternal uteroplacental blood vessels causes abortion.
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PMID:Cytokine-dependent abortion in CBA x DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase [correction of prothombinase]. 955 85

Proinflammatory effects induced by the serine protease factor Xa were investigated in HUVEC. Exposure of cells to factor Xa (5-80 nM) concentration dependently stimulated the production of IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) and the expression of E-selectin, ICAM-1, and VCAM-1, which was accompanied by polymorphonuclear leukocyte adhesion. The effects of factor Xa were blocked by antithrombin III, but not by the thrombin-specific inhibitor hirudin, suggesting that factor Xa elicits these responses directly and not via thrombin. IL-1alpha and TNF-alpha were not implicated, since neither the IL-1 receptor antagonist nor a TNF-neutralizing Ab could suppress the factor Xa responses. Active site-inhibited factor Xa and factor Xa depleted from gamma-carboxyglutamic acid residues were completely inactive. The effector cell protease receptor-1 (EPR-1) seems not to be involved since anti-EPR-1 Abs failed to inhibit cytokine production. Moreover, neither the factor X peptide Leu83-Leu88, representing the inter-epidermal growth factor sequence in factor Xa that mediates ligand binding to EPR-1, nor the peptide AG1, corresponding to the EPR-1 sequence Ser123-Pro137 implicated in factor Xa binding, inhibited the factor Xa-induced cytokine production. In conclusion, these findings indicate that factor Xa evokes a proinflammatory response in endothelial cells, which requires both its catalytic and gamma-carboxyglutamic acid-containing domain. The receptor system involved in these responses induced by factor Xa remains to be established.
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PMID:Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. 978 Feb 8

Recent studies have focused on a myriad of mechanisms by which inflammation can potentiate blood clotting. Inflammatory mediators like endotoxin and tissue necrosis factor (TNF)-alpha can cause the expression of tissue factor on monocytes and, possibly, endothelium, thereby initiating the coagulation cascade. Activation of the complement system can lead to exposure of membrane surfaces capable of amplifying the initial tissue factor stimulus by facilitating the assembly of the factor VIIIa-factor IXa and the factor Xa-factor Va complexes. Inflammatory mediators, particularly interleukin-6, can also increase the levels of fibrinogen, an acute-phase reactant. In addition, the inflammatory mediators can elevate the levels of plasminogen activator inhibitor, thus suppressing the fibrinolytic system. These studies alone, however, do not prove that inflammation can trigger clinically relevant thrombus formation in vivo. For instance, TNF-alpha has been studied in cancer patients as a potential cure for cancer, and even though these patients are hypercoaguable, thrombosis was not commonly observed as a side effect of the near-lethal doses of TNF-alpha that were administered. Based on primate studies, inflammatory mediators like TNF-alpha can promote clot deposition effectively only if there is reduced flow and inhibition of the natural anticoagulant pathways. The requirement for multiple simultaneous injurious events probably explains why inflammation alone is not observed as a major cause of thrombosis.
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PMID:Does inflammation contribute to thrombotic events? 1125 39

Microglia, the major immune effector cells in the CNS, become activated when the brain suffers injury. In this study, we observed that prothrombin, a zymogen of thrombin, induced NO release and mRNA expression of inducible NO synthase, IL-1beta, and TNF-alpha in rat brain microglia. The effect of prothrombin was independent of the protease activity of thrombin since hirudin, a specific inhibitor of thrombin, did not inhibit prothrombin-induced NO release. Furthermore, factor Xa enhanced the effect of prothrombin on microglial NO release. Kringle-2, a domain of prothrombin distinct from thrombin, mimicked the effect of prothrombin in inducing NO release and mRNA expression of inducible NO synthase, IL-1beta, and TNF-alpha. Prothrombin and kringle-2 both triggered the same intracellular signaling pathways. They both activated mitogen-activated protein kinases and NF-kappaB in a similar pattern. NO release stimulated by either was similarly reduced by inhibitors of the extracellular signal-regulated kinase pathway (PD98059), p38 (SB203580), NF-kappaB (N-acetylcysteine), protein kinase C (Go6976, bisindolylmaleimide, and Ro31-8220), and phospholipase C (D609 and U73122). These results suggest that prothrombin can activate microglia, and that, in addition to thrombin, kringle-2 is a domain of prothrombin independently capable of activating microglia.
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PMID:Prothrombin kringle-2 activates cultured rat brain microglia. 1202 83

We studied 33 women during normal uneventful pregnancies and with no history of previous adverse pregnancy events for markers of activated coagulation and thrombin activity including prothrombin fragment 1.2(PF1.2), thrombin- antithrombin (TAT), and soluble fibrin polymer (SFP). In addition, we measured potential thrombin generation through the addition of thromboplastin to patient plasma in the presence of a thrombin-specific chromogenic substrate determined serially over a period of time--Endogenous Thrombin Potential assay (ETP). This assay was performed with plasma treated and untreated with activated protein C (APC). The fibrinolytic system was assessed by measurement of thrombin activatable fibrinolysis inhibitor (TAFI). These findings were correlated with the levels of pro-inflammatory cytokines, interleukine-1 beta and tumor necrosis factor-alpha. Our data supports previous reports that indicate that resistance to activated protein C and coagulation activation markers are commonly increased in the later 2/3rds of pregnancy. There are no differences in thrombin generation potential, as determined by the ETP assay without the addition of APC, in the three trimesters. However, the thrombin reserve (TR), the ETP result without APC divided by the ETP result with the addition of APC, is increased above the reference range in the 2nd and 3rd trimesters. Patients with increased TR and resistance to APC had increased levels of TNF-alpha. Increased proinflammatory cytokines are reportedly associated with changes in the APC system with a decrease in the ability to generate APC. A sub-group of pregnancies with APC resistance had increased levels of TNF-alpha and may be important in the risk for adverse pregnancy outcomes.
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PMID:Circulating levels of inflammatory cytokines (IL-1 beta and TNF-alpha), resistance to activated protein C, thrombin and fibrin generation in uncomplicated pregnancies. 1465 39

Antithrombin (AT) reveals its antiinflammatory activity by promoting endothelial release of prostacyclin (PGI(2)) in vivo. Since neuroinflammation is critically involved in the development of ischemia/reperfusion (I/R)-induced spinal cord injury (SCI), it is possible that AT reduces the I/R-induced SCI by attenuating the inflammatory responses. We examined this possibility using rat model of I/R-induced SCI in the present study. AT significantly reduced the mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. Microinfarctions of the spinal cord seen after reperfusion were markedly reduced by AT. AT significantly enhanced the I/R-induced increases in spinal cord tissue levels of 6-keto-PGFIalpha, a stable metabolite of PGI2. AT significantly inhibited the I/R-induced increases in spinal cord tissue levels of TNF-alpha, rat interleukin-8 and myeloperoxidase. In contrast,Trp(49) -modified AT did not show any protective effects. Pretreatment with indomethacin significantly reversed the protective effects of AT. An inactive derivative of factor Xa, which selectively inhibits thrombin generation, has been shown to fail to reduce SCI. Taken together, these observations strongly suggested that AT might reduce I/R-induced SCI mainly by the antiinflammatory effect through promotion of endothelial production of PGI(2). These findings also suggested that AT might be a potential neuroprotective agent.
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PMID:Antithrombin reduces the ischemia/reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses. 1469 82

Thrombosis is a prominent feature of acute vascular rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF-alpha in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2(+/+) and fgl2(+/-) mice into Lewis rats developed AVR with intravascular thrombosis associated with induction of fgl2 in graft vascular ECs. In contrast, xenografts from fgl2(-/-) mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.
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PMID:Endothelial induction of fgl2 contributes to thrombosis during acute vascular xenograft rejection. 1510 Mar 14

This study was conducted to determine which isoform of cyclooxygenase (COX) is more significantly involved in the anti-thrombin (AT)-induced increase in prostaglandin production in the liver of rats, subjected to hepatic ischemia/reperfusion (I/R). Hepatic tissue levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin (PGI(2)), and PGE(2) were transiently increased 1 hour after reperfusion. Thereafter, hepatic PGE2 levels were gradually increased until 6 hours after reperfusion, while hepatic 6-keto-PGF(1alpha) levels were decreased to the pre-ischemia levels at 6 hours after reperfusion. AT significantly enhanced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, while it inhibited increases in hepatic PGE(2) levels seen 6 h after reperfusion. Neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp(49)-modified AT which lacks affinity for heparin, showed any effects on these changes. Pretreatment with indomethacin (IM), a non-selective inhibitor of COX, inhibited AT-induced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and PGE(2) seen 1 hour after reperfusion, whereas pretreatment with NS-398, a selective inhibitor of COX-2, did not. The increase in hepatic tissue blood flow and inhibition of hepatic inflammatory responses seen in animals given AT were reversed by pretreatment with IM, but were not affected by pretreatment with NS-398. Administration of ilo-prost, a stable analog of PGI(2), and PGE(2) produced effects similar to those induced by AT. Increases in hepatic tissue levels of PGE(2) 6 hours after reperfusion were inhibited by pretreatment with NS-398. Although AT did not affect COX-1 mRNA levels 1 hour after reperfusion, it inhibited the I/R-induced increases in hepatic tissue levels of both PGE(2) and COX-2 mRNA 6 hours after reperfusion. These observations strongly suggested that AT might reduce the I/R-induced liver injury by increasing the production of PGI2 and PGE2 through activation of COX-1. Furthermore, since TNF-alpha is capable of inducing COX-2, inhibition of TNF-alpha production by AT might inhibit COX-2-mediated PGE(2) production. These effects induced by AT might contribute to its anti-inflammatory activity.
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PMID:Antithrombin reduces ischemia/reperfusion-induced liver injury in rats by activation of cyclooxygenase-1. 1535 51


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