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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In using autologous muscles for cardiac assistance, it is crucial to reduce ischemia-reperfusion injury in the surgically traumatized skeletal muscle. In adult sheep, we developed a simple model of surgically designed 2 latissimus dorsi muscle leaflets by modifying the vascular supply to these leaflets. Three pockets with graded injury were established, and muscle morphology and vascular remodeling were monitored in 3 experimental groups: muscle leaflets without any treatment (Group 1, n = 6) that served as controls; muscle leaflets integrated with a fibrin interlayer (Group 2, n = 6); and leaflets integrated with fibrin and entrapped pyrrolostatin (Group 3, n = 6). We applied the fibrinogen and thrombin solutions, which polymerize to form a three-dimensional meshwork joining the tissues, creating a provisional matrix for angiogenesis, and acting as a delivery depot for agents aimed at minimizing ischemia-reperfusion lesion formation. After 2 months, the muscle leaflets biointegrated with the fibrin interface showed none of the signs of necrosis or ischemia-reperfusion lesions seen in the controls. Although no angiogenic factors were incorporated, the fibrin interlayer rapidly (<2 weeks) became a densely vascularized tissue replete with a voluminous capillary network. In contrast, controls showed poor bonding between the tissues, muscle fiber deterioration, and a compromised vascular network. Muscle structure was best preserved and angiogenesis was greatest when pyrrolostatin, a free radical scavenger, was added to the fibrin meshwork to reduce damage caused by overproduction of free radicals. This newly designed model will be useful to study many current approaches in cardiovascular biology, from pharmaceuticals to gene therapy, which might prove advantageous in muscle-designed cardiac assistance.
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PMID:Biodesign of a skeletal muscle flap as a model for cardiac assistance. 1071 67

This study was performed to determine whether human urinary soluble thrombomodulin plays a role in liver ischemia-reperfusion injury. Liver ischemia was induced in two groups of dogs. Group 1 was exposed to 60 min ischemia, and group 2 was exposed to 60 min ischemia after preischemic administration of human urinary soluble thrombomodulin. In group 1, the thrombin-antithrombin complex and hyaluronic acid were significantly elevated after ischemia, compared with the preischemic values. While liver issue blood flow and the plasmin-alpha(2)-plasmin inhibitor complex significantly decreased, AST, ALT and m-AST dramatically increased after reperfusion. In group 2, the increase in the thrombin-antithrombin complex and hyaluronic acid was significantly suppressed, and AST, ALT and liver tissue blood flow significantly improved, compared with group 1. Histologically, in group 2, the hepatic tissue structure, including endothelial cells, was relatively intact. These findings suggest that administration of thrombomodulin inhibits endothelial cell injury and coagulopathy and offers protection from liver ischemia-reperfusion injury.
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PMID:Protective effect of human urinary thrombomodulin on ischemia- reperfusion injury in the canine liver. 1081 Feb 13

Our previous studies have shown that prior intracerebral infusion of a low dose of thrombin (thrombin preconditioning; TPC) reduces the brain edema that follows a subsequent intracerebral infusion of a high dose of thrombin or an intracerebral hemorrhage. In vitro studies have also demonstrated that low concentrations of thrombin protect neurons and astrocytes from hypoglycemia and oxidative stress-induced damage. This study, therefore, examines the hypothesis that TPC would offer protection from ischemic brain damage in vivo. This was a blinded design study. The rat brain was preconditioned with 1 U thrombin by direct infusion into the left caudate nucleus. Seven days after thrombin pretreatment, permanent middle cerebral artery occlusion (MCAO) was induced. Twenty-four hours post-ischemia, neurological deficit was evaluated and infarction volume, brain water and ion contents were measured. Compared to saline-treated rats, thrombin pretreatment significantly attenuated brain infarction in cortex (90+/-33 vs. 273+/-22 mm(3); P<0.05) and basal ganglia (56+/-17 vs. 119+/-12 mm(3); P<0.05) that followed 24 h of permanent MCAO. TPC also reduced the brain edema in cortex and basal ganglia by 50 and 53% (P<0.05). Neurological deficit was improved in thrombin pretreatment group (P<0.05). These effects of TPC were, in part, prevented by co-injection of hirudin, a thrombin inhibitor, indicating that the protection was indeed thrombin mediated. Cerebral TPC significantly reduces ischemic brain damage, perhaps by activation of the thrombin receptor. This finding provides a new mechanism by which to study ischemic tolerance.
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PMID:The effects of thrombin preconditioning on focal cerebral ischemia in rats. 1083 11

Microglia, brain resident macrophages, become activated in brains injured due to trauma, ischemia, or neurodegenerative diseases. In this study, we found that thrombin treatment of microglia induced NO release/inducible nitric-oxide synthase expression, a prominent marker of activation. The effect of thrombin on NO release increased dose-dependently within the range of 5-20 units/ml. In immunoblot analyses, inducible nitric-oxide synthase expression was detected within 9 h after thrombin treatment. This effect of thrombin was significantly reduced by protein kinase C inhibitors, such as Go6976, bisindolylmaleimide, and Ro31-8220. Within 15 min, thrombin activated three subtypes of mitogen-activated protein kinases: extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase/stress-activated protein kinase. Inhibition of the extracellular signal-regulated kinase pathway and p38 reduced the NO release of thrombin-treated microglia. Thrombin also activated nuclear factor kappaB (NF-kappaB) within 5 min, and N-acetyl cysteine, an inhibitor of NF-kappaB, reduced NO release. However, thrombin receptor agonist peptide (an agonist of protease activated receptor-1 (PAR-1)), could not mimic the effect of thrombin, and cathepsin G, a PAR-1 inhibitor, did not reduce the effect of thrombin. These results suggest that thrombin can activate microglia via protein kinase C, mitogen-activated protein kinases, and NF-kappaB but that this occurs independently of PAR-1.
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PMID:Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-kappa B. 1089 7

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in a marked cardiac contractile dysfunction. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, suppresses superoxide production from PMNs. Therefore, we hypothesized that wortmannin could attenuate PMN-induced cardiac dysfunction by suppression of superoxide production from PMNs. We examined the effects of wortmannin in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. Wortmannin at 10, 20, or 40 nM given to hearts during the first 5 min of reperfusion, significantly improved left ventricular developed pressure (P < .01), and the maximal rate of development of left ventricular developed pressure (P < .01) compared with ischemic/reperfused hearts perfused with PMNs in the absence of wortmannin. In addition, wortmannin significantly reduced PMN infiltration into the myocardium by 50 to 75% (P < .001). Superoxide radical release also was significantly reduced in N-formylmethionyl-leucylphenylalanine-stimulated PMNs pretreated with 10 or 40 nM wortmannin by 70 and 95%, respectively (P < .001 versus untreated PMNs). Rat PMN adherence to rat superior mesenteric artery endothelium exposed to 2 U/ml thrombin was significantly attenuated by 10 to 40 nM wortmannin compared with untreated vessels (P < .001). These results provide evidence that wortmannin can significantly attenuate PMN-induced cardiac contractile dysfunction in the ischemic/reperfused rat heart via attenuation of PMN infiltration into the myocardium and suppression of superoxide release by PMNs.
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PMID:Wortmannin, a potent antineutrophil agent, exerts cardioprotective effects in myocardial ischemia/reperfusion. 1099 58

Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac dysfunction. C-peptide, a cleavage product of proinsulin to insulin processing, induces nitric oxide (NO)-mediated vasodilation. NO is reported to attenuate cardiac dysfunction caused by PMNs after ischemia-reperfusion (I/R). Therefore, we hypothesized that C-peptide could attenuate PMN-induced cardiac dysfunction. We examined the effects of C-peptide in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. C-peptide (70 nmol/kg iv) given 4 or 24 h before I/R significantly improved coronary flow (P < 0.05), left ventricular developed pressure (LVDP) (P < 0.01), and the maximal rate of development of LVDP (+dP/dt(max)) compared with I/R hearts obtained from rats given 0.9% NaCl (P < 0.01). N(G)-nitro-L-arginine methyl ester (L-NAME) (50 micromol/l) blocked these cardioprotective effects. In addition, C-peptide significantly reduced cardiac PMN infiltration from 183 +/- 24 PMNs/mm(2) in untreated hearts to 44 +/- 10 and 58 +/- 25 PMNs/mm(2) in hearts from 4- and 24-h C-peptide-treated rats, respectively. Rat PMN adherence to rat superior mesenteric artery exposed to 2 U/ml thrombin was significantly reduced in rats given C-peptide compared with rats given 0.9% NaCl (P < 0.001). Moreover, C-peptide enhanced basal NO release from rat aortic segments. These results provide evidence that C-peptide can significantly attenuate PMN-induced cardiac contractile dysfunction in the isolated perfused rat heart subjected to I/R at least in part via enhanced NO release.
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PMID:C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion. 1100 29

In recent investigations, we could demonstrate that thrombocytes are able to contribute to ischemia- and reperfusion-induced injury of the heart. The aim of the current study was to investigate whether reactive oxygen species are responsible for induction of myocardial dysfunction under these conditions. Isolated, perfused, and pressure-volume work-performing guinea pig hearts were exposed to a 30-min low-flow ischemia (1 ml/min) and were reperfused (5 ml/min). Washed, homologous blood platelets were administered as a 1-min bolus (20,000 per microliter of perfusion buffer), either during the 15th minute of ischemia or in the first or fifth minute of reperfusion in the presence of thrombin (0.3 U/ml perfusion buffer)). The radical scavengers superoxide dismutase (SOD; 10 U/ml perfusate) and catalase (30 U/ml perfusate) were added during ischemia or in the first or fifth minute of reperfusion, respectively. Intracoronary platelet retention (in percentage of platelets applied) and recovery of EHW (postischemic EHW in percentage of preischemic EHW) were quantified. Ischemic and reperfused hearts with time-matched application of platelets but without administration of SOD or catalase served as controls. Interestingly, both administration of SOD during ischemia and in reperfusion significantly improved recovery of EHW (88.4 +/- 2%, 82. 6 +/- 1%, and 90 +/- 3%, respectively) as compared with the case of controls (56.2 +/- 3%, 42 +/- 2%, and 75 +/- 2%, respectively). Platelet retention, however, was not significantly influenced by administration of SOD during ischemia or reperfusion (26 +/- 2%, 31 +/- 2%, and 26 +/- 2%) compared with controls (30.5 +/- 3%, 33 +/- 2%, and 22 +/- 3%, respectively). Coadministration of catalase, on the other hand, exhibited some cardioprotective potential only in the first minute of reperfusion (recovery, 61% +/- 4%) as compared with the case of control (42 +/- 2%). We conclude that thrombocytes under conditions of ischemia and reperfusion are able to induce a myocardial dysfunction mediated by reactive oxygen species. Superoxide seems to play a major role in this respect.
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PMID:A thrombocyte-induced myocardial dysfunction in the ischemic and reperfused guinea pig heart is mediated by reactive oxygen species. 1111 14

The pathophysiologic role of thrombin in the development of lung injury after the normothermic cardiopulumonary bypass (CPB) was studied in the rabbit model. A control group (group D) was subjected to the pericardiotomy without institution of CPB. Group A rabbits (n = 6) underwent left heart bypass (80 ml/kg/min) for 60 minutes without occlusion of the systemic or pulmonary artery and a succeeding reduced flow (20-30 ml/kg/min) for another 30 minutes, group B rabbits (n = 6) underwent complete CPB (80 ml/kg/min) for 60 minutes in the working mode with occlusion of the pulmonary arterial trunk and a succeeding reduced flow without occlusion of the pulmonary artery for another 30 minutes, group C rabbits (n = 6) underwent the same CPB technique as group B in conjunction with continuous intravenous infusion of argatroban (60 micrograms/kg/min), the specific thrombin inhibitor. In this group, infusion of argatroban was initiated 60 minutes prior to institution of CPB and terminated at the end of the experiment. We sacrificed rabbits four hours after the experiment began, and assessed not only morphometrically thrombus formation, leukocytic infiltration and luminal narrowing of small-sized pulmonary arteries but also immunohistochemically the expression of tissue factor (TF) and IL-1 beta, and physico-functionally respiratory index (RI) and pulmonary vascular resistance (PVR). Rabbits in group A showed multiple occurrence of lung thrombi, luminal narrowing of small arteries, and mild infiltration of macrophages and neutrophils positive for TF, and, in addition, their RI and PVR became mildly worse. In group B, all these morphological and physico-functional parameters became much worse than those observed in group A rabbits (p < .01). In contrast, argatroban treatment could significantly improve these parameters (p < .01). The expression of TF and IL-1 beta, however, was not significantly different in group A, B and C. These findings indicate that thrombin function intimately participates in the development of pulmonary ischemia-reperfusion injury during CPB. In addition, the anti-thrombin treatment would be an effective therapeutical tool for the prevention of not only activation of extrinsic coagulation pathway but also its sequential inflammatory and circulatory disturbance in ischemia-reperfusion injury of lung during CPB.
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PMID:[Specific inhibition of thrombin activity during cardiopulmonary bypass reduces ischemia-reperfusion injury of the lung]. 1124 85

Polymorphonuclear granulocytes (PMNs) are known to contribute to reperfusion injury of the heart. However, whether PMNs compromise myocardial function of hearts exposed to a low-flow ischemia has not been determined. Moreover, not much is known about deleterious effects of PMNs at different times during ischemia and reperfusion. Isolated, working guinea pig hearts were subjected to 30 min of low-flow ischemia and reperfusion. Homologous PMNs were applied as 1-min boluses in the presence of thrombin during either ischemia or the first or fifth minute of reperfusion, and postischemic recovery of external heart work (REHW) and intracoronary PMN retention (PMNR) were quantified. In further experiments, the radical scavenger superoxide dismutase (SOD) was added. Compared with controls without PMNs (REHW, 92.4%), application of PMNs led to a significant loss of myocardial function, which was detected at all three examination times. Moreover, intracoronary PMNR increased significantly in comparison with that of controls with hearts not exposed to ischemia or reperfusion. On the other hand, addition of SOD significantly increased REHW. Intracoronary PMNR was not significantly changed by coapplication of SOD. We conclude that thrombin-stimulated PMNs applied at different times during ischemia and reperfusion significantly impaired cardiac function in hearts exposed to a low-flow ischemia.
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PMID:Polymorphonuclear granulocytes induce myocardial dysfunction during ischemia and in later reperfusion of hearts exposed to low-flow ischemia. 1135 80

Normal endothelial cells express several membrane components with anticoagulant properties, which include: 1) tissue factor pathway inhibitors (TFPI), i.e. surface molecules able to accelerate the action of antithrombin (AT) on coagulation proteases; 2) thrombomodulin (TM), a thrombin binding surface protein able to inhibit thrombin activity; the complex TM-thrombin, also, activates protein C (PC); 3) endothelium derived factors such as nitric oxide and prostacyclin, which have antiadhesive properties and activate plasminogen. Exposure to inflammatory and/or septic stimuli can rapidly lead to a procoagulant response, activated by bacterial endotoxins, and to a decrease of endothelial anticoagulant membrane components. Activation of coagulation concomitant to impaired fibrinolysis is associated with fibrin deposition, tissue ischemia and necrosis. This review presents the results of different strategies aimed at reducing organ dysfunction and mortality in septic shock by modulating coagulation activity. In various animal models and in phase II clinical studies, the treatment with TFPI, AT and activated PC reduced organ dysfunction and mortality. Two phase III trials showed no efficacy of AT and a reduction of the relative risk of death with activated PC. In animal studies, supplementation with l-arginine and administration of perindopril were able to prevent septic shock-associated endothelial injury. A marked reduction of endothelial injury and improved survival of treated animals were also seen with antiglycoprotein IIb/IIIa which attenuated the role of monocytes in the disseminated intravascular coagulation process.
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PMID:Microthrombosis in sepsis. 1137 28


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