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)

To determine in vivo effects of interleukin (IL)-12 on host inflammatory mediator systems, 4 healthy chimpanzees received recombinant human IL-12 (1 microg/kg) by intravenous injection. IL-12 induced increases in plasma concentrations of IL-15, IL-18, and interferon-gamma (IFN-gamma), plus a marked antiinflammatory cytokine response (IL-10, soluble tumor necrosis factor [TNF] receptors, IL-1 receptor antagonist) and secretion of alpha-chemokines (IL-8, IFN-gamma-inducible protein 10) and beta-chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1beta). In addition, IL-12 elicited neutrophilic leukocytosis, neutrophil degranulation (elastase-alpha1-antitrypsin complexes), coagulation activation (F1 + 2 prothrombin fragment, thrombin-antithrombin III complexes), and fibrinolytic activation (tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes). IL-12-induced activation of multiple host mediator systems was found only after 8-24 h, remained detectable until the end of the 48-h observation period, and occurred in the absence of detectable TNF and IL-1beta. These data may contribute to understanding the role of IL-12 in the pathogenesis of sepsis syndrome and the toxicity found after repeated injections of IL-12.
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PMID:Interleukin-12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees. 995 71

Interleukin-8, a member of the chemokine family of cytokines, is a potent neutrophil chemoattractant in many non-rodent species. In this study, recombinant bovine interleukin-8 (rbIL-8) was expressed in bacteria as a glutathione-S-transferase fusion protein. The fusion protein was purified by glutathione-Sepharose affinity chromatography and recombinant rbIL-8 was eluted by cleaving with thrombin. The purified rbIL-8 molecule was approximately 8 kDa and was confirmed as authentic IL-8 by Western analysis. Recombinant bovine IL-8 induced specific dose-dependent in vitro chemotaxis of neutrophils at doses as low as 1.0 ng/ml, and this activity was inhibited by pre-treatment of rbIL-8 with a monoclonal antibody to ovine IL-8. Neutrophils exposed to rbIL-8 developed pseudopodia and became elongated as determined by microscopic analysis and flow cytometry. Injection of 3.3 ng to 3.3 microg of rbIL-8 into the skin of a normal calf induced dose-dependent recruitment of neutrophils but not eosinophils. Intravascular margination of neutrophils was obvious at the injection sites from 15 to 60 min after administration of rbIL-8, and extravascular neutrophil numbers increased steadily from 1 to 18 h after injection. Neutrophils with morphologic features of apoptosis were detected in these lesions at 18 and 30 h after injection, and this correlated with reduction in the number of dermal neutrophils. These results confirm unequivocally that bovine IL-8 functions as a neutrophil, but not an eosinophil, chemoattractant in vitro and in vivo.
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PMID:Production and functional characterization of recombinant bovine interleukin-8 as a specific neutrophil activator and chemoattractant. 1020 1

Blood coagulation and inflammation pathways are linked in many aspects. A number of serum factors involved in coagulation cascades affect directly or indirectly inflammatory responses, whereas proinflammatory cytokines influence blood coagulation pathways. In this work we demonstrated that thrombin is an effective stimulus in inducing interleukin (IL)-8 expression in human monocytic cell line U937. IL-8 induction was found at the mRNA and protein levels. The effect of thrombin on IL-8 production was mimicked by thrombin receptor-activating peptide indicating that thrombin effect was mediated by the specific receptor for thrombin. Moreover, thrombin-induced IL-8 production by U937 cells was differentially regulated by interferon (IFN)-gamma and prostaglandin (PG)E2. While IFN-gamma enhanced thrombin-induced IL-8 production, PGE2 acted as a negative regulator. Taken together, thrombin may play an important role in communication between blood coagulation and inflammation by inducing IL-8 production by monocytes and this role for thrombin may be further regulated by lymphokines and lipid mediators.
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PMID:Thrombin-induced interleukin-8 production and its regulation by interferon-gamma and prostaglandin E2 in human monocytic U937 cells. 1036 30

A new disintegrin, an RGD-containing peptide of 6 kDa called jarastatin, was purified from Bothrops jararaca venom. It is a potent inhibitor of platelet aggregation induced by ADP, collagen, and thrombin. The effect of jarastatin on neutrophil migration in vivo and in vitro and on the actin cytoskeleton dynamics of these cells was investigated. Incubation in vitro with jarastatin significantly inhibited, in a concentration-dependent manner, the chemotaxis of human neutrophils toward fMLP, IL-8, and jarastatin itself. Despite this inhibitory effect, jarastatin induced neutrophil chemotaxis. A significant increase of F-actin content was observed in jarastatin-treated neutrophils. Furthermore, as demonstrated by confocal microscopy after FITC-phalloidin labeling, these cells accumulated F-actin at the plasmalemma, a distribution similar to that observed in fMLP-stimulated cells. Pretreatment of mice with jarastatin inhibited neutrophil migration into peritoneal cavities induced by carrageenan injection. The results suggest that binding of jarastatin to neutrophil integrins promotes cellular activation and triggers a dynamic alteration of the actin filament system and that this is one of the first event in integrin-mediated signaling.
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PMID:Effects of jarastatin, a novel snake venom disintegrin, on neutrophil migration and actin cytoskeleton dynamics. 1047 23

We have demonstrated recently that therapeutic moderate hypothermia of 32-33 degrees C, induced by surface cooling under the administration of narcotics, sedatives and muscle relaxant, suppresses cytokine production after traumatic brain injury. We present here the first documented case report of augmented cytokine production in two accidental hypothermia patients, unconscious 84- (acute immersion) and 87- (non-immersion) year-old women, whose rectal temperatures were below 28 degrees C. The victims were artificially ventilated after sedation with midazolam and buprenorphine in accordance with our protocol. Rewarming at the rate of approximately 1 degrees C/h was done by blowing forced-air with appropriate fluid resuscitation. Plasma interleukin(IL)-6 and/or IL-8 levels were measured using ELISA in the patients. In both patients, plasma IL-6 levels on admission were already elevated and the cytokine levels further increased during and after the rewarming period. In the patient with the poorer prognosis, the plasma IL-8 level on admission was not elevated remarkably but after rewarming the level rose significantly. Augmented IL-6 production in accidental hypothermia was sustained for 6 days in the patient with the poorer prognosis but not in the subject with good recovery, who was treated with anti-thrombin III in the early phase. Since the mechanisms for developing accidental hypothermia were different, simple comparisons between the two cases should be limited. But, these findings may suggest a need for testing a hypothesis whether cytokine modulation could be a therapeutic approach worthy of consideration. The results presented here also suggest that in hypothermia, changes in cytokine release may vary depending on procedures such as the anesthetic drugs used, the duration of the therapy, or the rate of rewarming from hypothermia.
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PMID:Activated cytokine production in patients with accidental hypothermia. 1050 12

Acute and chronic interstitial lung diseases are accompanied by evidence of inflammation and vascular injury. Thrombin activity in bronchoalveolar lavage fluid from such conditions is often increased, as well as interleukin (IL)-8. We observed that conditioned medium from lung fibroblasts exposed to thrombin has chemotactic activity for polymorphonuclear cells, and that this activity can be abolished by antibody to IL-8. We report that thrombin stimulates expression of IL-8 in human lung fibroblasts on both the messenger RNA and protein levels in a time- and dose-dependent manner. Stimulation of IL-8 expression by thrombin is inhibited by specific thrombin inhibitors. Synthetic thrombin receptor agonist peptide-14 mimics thrombin's stimulation of IL-8 expression in a dose-dependent manner consistent with the idea that upregulation of IL-8 by thrombin in human lung fibroblasts requires cleavage of proteolytically activated receptor-I. We demonstrate further that thrombin-induced IL-8 synthesis is regulated by protein kinase (PK) C. PKC-gamma may be involved in the upregulation of lung fibroblast IL-8 by thrombin because stimulation of lung fibroblasts with thrombin caused significant upregulation of PKC-gamma and because PKC-gamma antisense oligonucleotides inhibited the accumulation of PKC-gamma protein and IL-8 protein. Our data suggest that the PKC-gamma isoform increase observed after thrombin stimulation is required for thrombin-induced IL-8 formation by human lung fibroblasts.
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PMID:Thrombin upregulates interleukin-8 in lung fibroblasts via cleavage of proteolytically activated receptor-I and protein kinase C-gamma activation. 1065 45

The influence of the endothelial protein C receptor (EPCR) on the host response to Escherichia coli was studied. Animals were treated with 4 separate protocols for survival studies and analysis of physiologic and biochemical parameters: (1) monoclonal antibody (mAb) that blocks protein C/activated protein C binding to EPCR plus sublethal numbers of E coli (SLEC) (n = 4); (2) mAb to EPCR that does not block binding plus SLEC (n = 3); (3) SLEC alone (n = 4); and (4) blocking mAB alone (n = 1). Those animals receiving blocking mAb to EPCR plus sublethal E coli died 7 to 54 hours after challenge, whereas all animals treated with the other protocols were permanent survivors. Histopathologic studies of tissues from animals receiving blocking mAb plus SLEC removed at postmortem were compared with those animals receiving SLEC alone killed at T+24 hours. The animals receiving the blocking mAb exhibited consumption of fibrinogen, microvascular thrombosis with hemorrhage of both the adrenal and renal cortex, and an intense influx of neutrophils into the adrenal, renal, and hepatic microvasculature, whereas the tissues from animals receiving only sublethal E coli exhibited none of these abnormal histopathologic changes. Compared with the control animals, the animals receiving the blocking mAb exhibited significantly elevated serum glutamic pyruvic transaminase, anion gap, thrombin-antithrombin complex, IL-6, IL-8, and soluble thrombomodulin. The levels of circulating activated protein C varied too widely to allow a clear determination of whether the extent of protein C activation was altered in vivo by blocking protein C binding to EPCR. We conclude that protein C/activated protein C binding to EPCR contributes to the negative regulation of the coagulopathic and inflammatory response to E coli and that EPCR provides an additional critical step in the host defense against E coli. (Blood. 2000;95:1680-1686)
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PMID:The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. 1068 24

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.
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PMID:Endothelial function and hemostasis. 1079 71

Biocompatibility of a new type of heparin-coated cardiopulmonary bypass equipment, the Bioline, was evaluated in coronary artery bypass surgery cases. The heparin-coated (H) group (n = 15; Quadrox Bioline oxygenator/reservior and Carmeda BioMedicus BP-80 centrifugal pump) was compared with the nonheparin-coated (N) group (n = 12; uncoated, otherwise similar oxygenator, centrifugal pump, tubing, and filter set). Both groups used full systemic heparinization. The peak values of neutrophil elastase, C3a, IL-6, and IL-8 at 2 h after cardiopulmonary bypass (CPB), and C3a levels at the end of CPB and at 2 h after CPB were significantly reduced in the H group compared with those of the N group. However, no statistically significant intergroup differences were observed in thrombin-antithrombin complex, D-dimer, beta-thromboglobulin, or platelet factor-4. No significant differences were observed in hemostasis time, postoperative 12 h blood loss, required amount of blood transfusion, or intubation time. In conclusion, the Bioline demonstrated partially improved biocompatibility, in terms of leukocyte and complement activation, and proinflammatory cytokine production. However, it did not improve platelet activation, coagulation, or fibrinolysis cascade under full systemic heparinization. As a result, the clinical beneficial impact seemed to be the minimum.
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PMID:Biocompatibility of heparin-coated extracorporeal bypass circuits: new heparin bonded bioline system. 1097 Dec 48

In recent studies, we have demonstrated that fibrin is present in association with tumor cells in oral squamous cell carcinoma (OSCC) in vivo. We hypothesized that this fibrin can directly induce the expression of known angiogenic factors from oral tumor cells. Since IL-8 is known to be the major inducer of angiogenesis caused by these cells, we examined the ability of fibrin to stimulate IL-8 expression from OSCC cells in vitro. A physiologically relevant concentration of fibrin was found to cause a dose and time-dependent stimulation of IL-8 expression from oral and pharyngeal tumor cells but not from a non-tumorigenic oral cell line. Fibrinogen, thrombin and collagen were all unable to induce significant IL-8 expression, establishing the specificity of fibrin in causing this response. Gel filtration chromatography confirmed the molecular identity of the IL-8 antigen detected in the ELISA system used. These results suggest that fibrin may promote angiogenesis in oral tumors in vivo by directly upregulating the expression of IL-8 from tumor cells.
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PMID:Fibrin induces IL-8 expression from human oral squamous cell carcinoma cells. 1128 77


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