Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P35237 (thrombin inhibitor)
 2,012 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The disturbance of microcirculation following cerebral ischemia leads to an enlargement of cerebral infarct volume. Endogenous thrombin may play a role in this disturbance of microcirculation following cerebral ischemia. Therefore, the inhibition of thrombin may improve neurodegeneration and the accumulation of cerebral edema following cerebral ischemia in gerbils. The effects of thrombin inhibitor (argatroban) on cerebral ischemia were investigated in comparison with thromboxane A2 synthase inhibitor (ozagrel) and cyclooxygenase inhibitor (aspirin) following bilateral common carotid artery occlusion and reperfusion (CCA:O/R) in male Mongolian gerbils. This study consisted of three experiments: (1) morbidity and survival ratio (n=40 for each), (2) histopathology (n=12 for each), and (3) mean arterial blood pressure, local cerebral blood flow (CBF), and cerebral specific gravity (n=8 for each). Argatroban treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex and hippocampus and cerebral edema in cortex compared with aspirin and saline, in concert with the fast recovery of local CBF without reactive hyperemia following bilateral CCA:O/R. Ozagrel treatment also improved those factors compared with saline, in concert with the fast recovery of local CBF with reactive hyperemia. Aspirin treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex. Thrombin inhibition with argatroban decreases neurodegeneration and cerebral edema following bilateral CCA:O/R in gerbils.
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PMID:Thrombin inhibition attenuates neurodegeneration and cerebral edema formation following transient forebrain ischemia. 1138 20

Dramatic activation of the coagulation cascade has been extensively documented for pulmonary fibrosis associated with acute and chronic lung injury. In addition to its role in hemostasis, thrombin exerts profibrotic effects via activation of the major thrombin receptor, protease-activated receptor-1. In this study, we examined the effect of the direct thrombin inhibitor, UK-156406 on fibroblast responses in vitro and on bleomycin-induced pulmonary fibrosis in rats. UK-156406 significantly inhibited thrombin-induced fibroblast proliferation, procollagen production, and connective tissue growth factor (CTGF) mRNA levels when used at equimolar concentration to the protease. Thrombin levels in bronchoalveolar lavage fluid and expression of thrombin and protease-activated receptor-1 in lung tissue were increased after intratracheal instillation of bleomycin. The characteristic doubling in lung collagen in bleomycin-treated animals (38.4 +/- 2.0 mg versus 17.1 +/- 1.4 mg, P < 0.01) was preceded by significant elevations in alpha1(I) procollagen and CTGF mRNA levels (3.0 +/- 0.4-fold and 6.3 +/- 0.4-fold respectively, (P < 0.01), and total inflammatory cell number. UK-156406, administered at an anticoagulant dose, attenuated lung collagen accumulation in response to bleomycin by 35 +/- 12% (P < 0.05), inhibited alpha1(I) procollagen and CTGF mRNA levels by 50% and 35%, respectively (P < 0.05), but had no effect on inflammatory cell recruitment. This is the first report showing that direct thrombin inhibition abrogates lung collagen accumulation in bleomycin-induced pulmonary fibrosis.
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PMID:Direct thrombin inhibition reduces lung collagen, accumulation, and connective tissue growth factor mRNA levels in bleomycin-induced pulmonary fibrosis. 1158 66

Thrombosis is an important pathophysiologic component of many cardiovascular diseases. Thrombin, a serine protease, plays a central role in thrombosis formation. Detection and imaging of thrombin activity may thus be of considerable biomedical interest. The goal of this study was to design, synthesize, and characterize a novel thrombin-activated near-infrared fluorescence (NIRF) probe. The probe consisted of a thrombin-cleavable peptide spacer (...D-Phe-Pip-Arg...; Pip=pipecolic acid) and contained a terminal fluorescence reporter which was quenched when conjugated to a biocompatible delivery vehicle. A control peptide spacer was synthesized that differed by one amino acid. Following thrombin addition, the probe was activated within minutes. The NIRF signal increased by a factor of 27-fold within 20 minutes, and was inhibited by hirudin, a specific thrombin inhibitor. NIRF optical imaging experiments confirmed rapid activation of the probe in both buffer and human blood. The control probe showed minimal activation in all experiments. In addition to potentially furthering our understanding of thrombin regulation in vivo, the thrombin-activated near-infrared probe may have broad clinical application to the diagnosis of arterial and venous thrombosis.
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PMID:A novel near-infrared fluorescence sensor for detection of thrombin activation in blood. 1192 99

Thrombin is a key enzyme in the blood coagulation system where it converts fibrinogen to fibrin. It participates in a variety of biological processes such as the induction of mitogenesis and of morphological changes, the production of cytokines and growth factors, and apoptosis. To clarify the role of thrombin in the proliferation of human malignant gliomas, we investigated its effect on the expression of vascular endothelial growth factor (VEGF) in vitro and determined its intrinsic expression in human glioma tissues. In 3 human glioma cell lines tested, U-87 MG, U-251 MG, and U-105 MG, thrombin induced the VEGF mRNA expression and protein in a dose- and time-dependent manner. The thrombin receptor expression was detectable by RT-PCR and immunoblot. The secretion of VEGF protein in glioma cells was stimulated by the thrombin receptor agonist peptide and the induction of VEGF was significantly blocked by the thrombin inhibitor hirudin, indicating that the up-regulation of VEGF was mediated by the thrombin/thrombin receptor pathway. Immunoblot analysis demonstrated that prothrombin, the precursor of thrombin, was distributed in all 10 glioma tissues examined. In situ hybridization and immunohistochemical analysis revealed the co-localization of prothrombin mRNA-positive and GFAP-positive cells in the glioma tissues. Although various factors may be involved in the up-regulation of VEGF, our results suggest that human gliomas per se express prothrombin, and that thrombin, converted from prothrombin in glioma tissues, substantially stimulates angiogenesis in an autocrine fashion.
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PMID:The role of thrombin in the neo-vascularization of malignant gliomas: an intrinsic modulator for the up-regulation of vascular endothelial growth factor. 1195 84

The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptide-like thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.
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PMID:Structure-based design of novel potent nonpeptide thrombin inhibitors. 1196 Apr 87

Heparin is a commonly used anticoagulant in patients with coronary artery disease but its use does not always result in low rates of ischaemic and bleeding events, so the search for new anticoagulants continues. Thrombin plays a key role in both thrombosis and haemostasis and direct thrombin inhibitors modelled on the hirudin molecule found in the saliva of the medicinal leech, Hirudo medicinalis, have recently been developed. To date, the only direct thrombin inhibitor shown to reduce both the ischaemic and the bleeding complications associated with percutaneous coronary intervention (PCI) is bivalirudin, which is approved for this indication in the US and New Zealand. This agent is currently being studied in patients undergoing PCI with or without glycoprotein IIb/IIIa inhibitors and stenting. Bivalirudin has been shown to significantly reduce the risk of reinfarction in patients with acute myocardial infarction (MI) treated with streptokinase, but its use for this indication is not approved in the US. It may also prove to be beneficial in patients with acute MI treated with other fibrinolytic regimens or with primary or facilitated PCI. Bivalirudin is suitable for use as an alternative to heparin in the majority of patients undergoing PCI and in patients receiving streptokinase for acute MI.
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PMID:Bivalirudin: an anticoagulant for acute coronary syndromes and coronary interventions. 1203 17

Hypoxia-inducible factor-1 (HIF-1), a transcription factor composed of HIF-1alpha and HIF-1beta protein subunits, has been implicated in cellular protection and cell death in cerebral ischemia. The extent to which HIF-1 plays a role in brain pathology during intracerebral hemorrhage (ICH) is unknown. This study determined whether HIF-1alpha is upregulated at different time points in a rat model of ICH and the role of thrombin and red blood cell lysis in upregulation. Recently, thrombin has been implicated as a nonhypoxic regulator of HIF-1alpha in cultured smooth-muscle cells. Male Sprague-Dawley rats received intracerebral infusions of saline, autologous whole blood, blood plus hirudin, thrombin, thrombin plus hirudin, or lysed erythrocytes. Rats were killed at different time points for Western blot analysis, immunohistochemistry, immunofluorescent double staining, and reverse transcription polymerase chain reaction measurements of HIF-1alpha. HIF-1alpha protein levels increased without changing HIF-1alpha messenger RNA levels after intracerebral infusions of blood, thrombin, and lysed erythrocytes. HIF-1alpha positive cells, which proved to be neurons, were found in the brain after ICH. Hirudin, a specific thrombin inhibitor, reduced HIF-1alpha upregulation in response to both thrombin and blood. This study demonstrates that perihematomal HIF-1alpha protein is upregulated after ICH. This phenomenon is an early response of brain parenchyma to the clot. Thrombin and erythrocyte lysate are involved in HIF-1alpha upregulation through reducing HIF-1alpha degradation.
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PMID:Hypoxia-inducible factor-1alpha accumulation in the brain after experimental intracerebral hemorrhage. 1204 67

Acute coronary syndromes encompass a spectrum of conditions, including myocardial infarction and unstable angina. These syndromes are related to the formation and disruption of atherosclerotic plaque. Rupture of plaque leads to thrombin generation, fibrin deposition, and platelet aggregation, ultimately resulting in restriction of blood flow and ischemia of cardiac tissue. Percutaneous coronary intervention (PCI), including angioplasty and coronary stent placement, has been developed to open occluded arteries. The frequency with which these procedures are performed speaks to their largely successful outcomes. However, the mechanical manipulations of PCI result in additional plaque rupture and damage to the vessel wall, exposing subendothelial components to blood and resulting in the initiation of the clotting cascade and in platelet activation. Left unchecked, these intertwined processes lead to formation of arterial thrombi at the site of endothelial damage, and potentially to abrupt vessel closure or embolization of thrombi into the distal microcirculation. Thrombin plays a central role in thrombus formation and platelet activation, and its inhibition significantly reduces thrombus-related sequelae. Current antithrombotic strategies during PCI are based on the traditional indirect thrombin inhibitor heparin. Heparin has several limitations in efficacy and safety, due in part to its indirect mechanism of action. Bivalirudin, a direct thrombin inhibitor, offers significant improvement over heparin in the clinical outcomes and risks associated with PCI.
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PMID:The role of thrombin inhibition during percutaneous coronary intervention. 1206 71

Chronic lung disease of prematurity (CLD) is a common consequence of neonatal respiratory distress syndrome (RDS) and is characterized by pulmonary fibrosis. Increased thrombin activity in the alveolar compartment is associated with pulmonary fibrosis in adults and animals, and contributes to bronchoalveolar lavage (BAL) fluid mitogenicity for fibroblasts. We hypothesized that BAL fluid from infants who develop CLD contains increased mitogenic activity for lung fibroblasts compared to BAL fluid from resolving RDS, and that increased thrombin levels contribute to this activity. Sequential BAL (postnatal days 2-14) was obtained from 37 premature infants who were ventilated for RDS. Twenty-six infants developed CLD, whereas 11 resolved. BAL fluid mitogenic activity was determined in a proliferation assay, using human fetal lung fibroblasts. The contribution of thrombin to mitogenic activity was determined using the thrombin inhibitor PPACK. Furthermore, thrombin levels in BAL fluid were measured using a specific substrate to detect thrombin activity and by measuring thrombin-antithrombin III complex (TATIII). BAL fluid mitogenic activity was comparable between CLD and RDS (CLD, 33% proliferation on day 2 to 41% on day 14; RDS, 21% on day 2 to 54% on day 7). Thrombin inactivation by PPACK completely inhibited mitogenic activity in BAL samples obtained on days 2 and 4 (CLD, P < 0.001 on days 2 and 4; RDS, P < 0.05 on day 4). From day 7 onwards, inhibition of thrombin only partly reduced (P < 0.05) CLD BAL fluid mitogenic activity, indicating that other mitogenic factors contribute as well. Surprisingly, thrombin activity and TATIII were decreased in BAL fluid from CLD compared with RDS patients on days 2 and 4. In conclusion, our study shows that BAL fluid from infants with and without CLD development is equally mitogenic for lung fibroblasts, and that thrombin is a major mitogen in these samples. This suggests that fibroproliferation may occur early in the lungs from infants with both CLD and RDS, and that thrombin contributes to this.
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PMID:Thrombin contributes to bronchoalveolar lavage fluid mitogenicity in lung disease of the premature infant. 1246 37

An imbalance between thrombin and antithrombin III contributed to vascular hyporeactivity in sepsis, which can be attributed to excess NO production by inducible nitric-oxide synthase (iNOS). In view of the importance of the thrombin-activated coagulation pathway and excess NO as the culminating factors in vascular hyporeactivity, this study investigated the effects of thrombin on the induction of iNOS and NO production in macrophages. Thrombin induced iNOS protein in the Raw264.7 cells, which was inhibited by a thrombin inhibitor, LB30057. Thrombin increased NF-kappaB DNA binding, whose band was supershifted with anti-p65 and anti-p50 antibodies. Thrombin elicited the phosphorylation and degradation of I-kappaBalpha prior to the nuclear translocation of p65. The NF-kappaB-mediated iNOS induction was stimulated by the overexpression of activated mutants of Galpha(12/13) (Galpha(12/13)QL). Protein kinase C depletion inhibited I-kappaBalpha degradation, NF-kappaB activation, and iNOS induction by thrombin or the iNOS induction by Galpha(12/13)QL. JNK, p38 kinase, and ERK were all activated by thrombin. JNK inhibition by the stable transfection with a dominant negative mutant of JNK1 (JNK1(-)) completely suppressed the NF-kappaB-mediated iNOS induction by thrombin. Conversely, the inhibition of p38 kinase enhanced the expression of iNOS. In addition, JNK and p38 kinase oppositely controlled the NF-kappaB-mediated iNOS induction by Galpha(12/13)QL. Hence, iNOS induction by thrombin was regulated by the opposed functions of JNK and p38 kinase downstream of Galpha(12/13). In the JNK1(-) cells, thrombin did not increase either the NF-kappaB binding activity or I-kappaBalpha degradation despite I-kappaBalpha phosphorylation. These results demonstrated that thrombin induces iNOS in macrophages via Galpha(12) and Galpha(13), which leads to NF-kappaB activation involving the protein kinase C-dependent phosphorylation of I-kappaBalpha and the JNK-dependent degradation of phosphorylated I-kappaBalpha.
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PMID:Thrombin induces nitric-oxide synthase via Galpha12/13-coupled protein kinase C-dependent I-kappaBalpha phosphorylation and JNK-mediated I-kappaBalpha degradation. 1260 53


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