Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigated the reaction of heparin cofactor II (HCII) with stimulated polymorphonuclear leukocytes (PMN). We have expanded upon previous studies showing that HCII can be degraded by stimulated PMN (Sie, P., Dupouy, D., Dol, F., and Boneu, B., Thromb. Res. 47, 657-664, 1987), and that chemotactic activity is produced when HCII is partially proteolyzed with purified leukocyte elastase or cathepsin G (Hoffman, M., Pratt, C.W., Brown, R.L., and Church, F.C., Blood, 73, 1682-1695, 1989). We found that HCII was proteolyzed by stimulated PMN, generating peptides with chemotactic activity. Both proteolysis and generation of chemotactic activity were inhibited by a specific leukocyte elastase inhibitor and by more general proteinase inhibitors. Leukocyte elastase activity was lost upon addition of either inhibitor. Heparin and dermatan sulfate altered the pattern of proteolysis. Our results suggest that HCII may be involved not only in functions related to thrombin inhibition but also in regulating acute inflammation.
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PMID:Production of chemotactic peptides by neutrophil degradation of heparin cofactor II. 230 Sep 26

We investigated the interaction of the human plasma proteinase inhibitor heparin cofactor II (HC) with human neutrophil elastase and cathepsin G in order to examine 1) proteinase inhibition by HC, 2) inactivation of HC, and 3) the effect of glycosaminoglycans on inhibition and inactivation. We found that HC inhibited cathepsin G, but not elastase, with a rate constant of 6.0 x 10(6) M-1 min-1. Inhibition was stable, with a dissociation rate constant of 1.0 x 10(-3) min-1. Heparin and dermatan sulfate diminished inhibition slightly. Both neutrophil elastase and cathepsin G at catalytic concentrations destroyed the thrombin inhibition activity of HC. Inactivation was accompanied by a dramatic increase in heat stability, as occurs with other serine proteinase inhibitors. Proteolysis of HC (Mr 66,000) produced a species (Mr 58,000) that retained thrombin inhibition activity, and an inactive species of Mr 48,000. Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC. Since cathepsin G is inhibited by HC and also inactivates HC, we conclude that cathepsin G participates in both reactions simultaneously so that small amounts of cathepsin G can inactivate a molar excess of HC. High concentrations of heparin and dermatan sulfate accelerated inactivation of HC by neutrophil proteinases, with heparin having a greater effect. Heparin and dermatan sulfate appeared to alter the pattern, and not just the rate, of proteolysis of HC. We conclude that while HC is an effective inhibitor of cathepsin G, it can be proteolyzed by neutrophil proteinases to generate first an active inhibitor and then an inactive molecule. This two-step mechanism might be important in the generation of chemotactic activity from the amino-terminal region of HC.
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PMID:Interaction of heparin cofactor II with neutrophil elastase and cathepsin G. 231 47

125I-labeled heparin cofactor II (HCII) was mixed with plasma and coagulation was initiated by addition of CaCl2, phospholipids, and kaolin or tissue factor. In the presence of 67 micrograms/ml of dermatan sulfate, radioactivity was detected in a band which corresponded to the thrombin-HCII complex (Mr = 96,000) upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. No other complexes were observed. The thrombin-HCII complex was undetectable when 5 units/ml of heparin was present or when prothrombin-deficient plasma was used. In experiments with purified proteases, HCII did not significantly inhibit coagulation factors VIIa, IXa, Xa, XIa, XIIa, kallikrein, activated protein C, plasmin, urokinase, tissue plasminogen activator, leukocyte elastase, the gamma-subunit of nerve growth factor, and the epidermal growth factor-binding protein. HCII inhibited leukocyte cathepsin G slowly, with a rate constant of 8 X 10(4) M-1 min-1 in the presence of dermatan sulfate. These results indicate that the protease specificity of HCII is more restricted than that of other plasma protease inhibitors and suggest that the anticoagulant effect of dermatan sulfate is due solely to inhibition of thrombin by HCII.
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PMID:The protease specificity of heparin cofactor II. Inhibition of thrombin generated during coagulation. 383 15

The present paper describes chemical and functional properties of protease nexin, a serine protease inhibitor released from cultured human fibroblasts. It is shown that protease nexin is actually synthesized by fibroblasts and represents about 1% of their secreted protein. Analysis of the amino acid composition of purified protease nexin indicates that it is evolutionarily related to antithrombin III and heparin cofactor II. Protease nexin contains approximately 6% carbohydrate, with 2.3% amino sugar, 1.1% neutral sugar, and 3.0% sialic acid. The Mr calculated from equilibrium sedimentation analysis is 43,000. Protease nexin is a broad specificity inhibitor of trypsin-like serine proteases. It reacts rapidly with trypsin (kassoc = 4.2 +/- 0.4 X 10(6) M-1 s-1), thrombin (kassoc = 6.0 +/- 1.3 X 10(5) M-1 s-1), urokinase (kassoc = 1.5 +/- 0.1 X 10(5) M-1 s-1), and plasmin (kassoc = 1.3 +/- 0.1 X 10(5) M-1 s-1), and slowly inhibits Factor Xa and the gamma subunit of nerve growth factor but does not inhibit chymotrypsin-like proteases or leukocyte elastase. In the presence of heparin, protease nexin inhibits thrombin at a nearly diffusion-controlled rate. Two heparin affinity classes of protease nexin can be detected. The present characterization pertains to the fraction of protease nexin having the higher affinity for heparin. The low affinity material, which is the minor fraction, is lost during purification.
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PMID:Protease nexin. Properties and a modified purification procedure. 399 57

Protein C inhibitor (PCI), antithrombin, and heparin cofactor II are members of the serine proteinase inhibitor (serpin) superfamily that inhibit proteinases at rates which increase in the presence of the glycosaminoglycan heparin. These studies were undertaken to understand how PCI activity is modulated by various substances that are found in or interact with the vascular endothelium/basement membrane. The effects of antithrombin-heparin, thrombomodulin, vitronectin and leukocyte elastase on PCI-thrombin and PCI-activated protein C (APC) interactions were investigated. Antithrombin, which does not inhibit APC but which does bind to heparin/heparan sulphate with higher affinity than PCI, caused only a small decrease in the inhibition rate of PCI-APC in the presence of unfractionated heparin. Thrombomodulin, a chondroitin sulphate-containing proteoglycan, accelerated PCI inhibition of thrombin and APC. PCI-thrombin in the presence or absence of heparin bound plastic absorbed vitronectin, but neither PCI alone nor PCI-APC bound. Vitronectin also decreased the inhibition rate of PCI-thrombin and PCI-APC in the presence of low concentrations of heparin. Leukocyte elastase proteolytically inactivated PCI in a reaction that was accelerated by heparin. Overall, these results indicate that PCI activity is modulated by these endothelial cell/basement membrane-based substances in similar ways as other heparin-binding serpins, especially antithrombin.
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PMID:Modulation of protein C inhibitor activity. 753 47

Several samples of oversulfated chondroitin and dermatan were obtained by chemical sulfation and by SAX-HPLC enrichment. The starting products and oversulfated products were tested as potential inhibitors of human leukocyte elastase, an enzyme hypothesized to be involved in the etiology of diseases such as emphysema, atherosclerosis, and rheumatoid arthritis. Chemical oversulfation (SO3H/COOH 1.6-3.2), preferentially occurring at C-6 of galactosamine residues, was found generally to increase the inhibitory power on elastase. Chemically oversulfated galactosaminoglycans thus have potential as therapeutic agents, considering that they produce non-significant effects on the hemocoagulative system. Two naturally oversulfated dermatans sulfate (SO3H/COOH ca. 1.2), mainly oversulfated at C-2 of iduronic acid residues, showed comparatively higher anticoagulant activity (in the HC-II mediated thrombin inhibition test).
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PMID:Inhibition of human leukocyte elastase by chemically and naturally oversulfated galactosaminoglycans. 854 7

Pulmonary injury may result from the use of cardiopulmonary bypass (CPB). We investigated changes in the haemostatic system in the pulmonary vein during CPB compared with blood that circulated through the bypass circuit. Paired samples were taken from the pulmonary vein and central venous pressure (CVP) line during the peri-operative period from ten patients. Plasma levels of factor VII (P < 0.001), prekallikrein (P < 0.05), antithrombin III (P < 0.001) and heparin cofactor II (P < 0.005) were decreased in the pulmonary vein after 20 min of bypass compared with pre-operative levels. In the pulmonary vein there was a significant increase in neutrophil expressed CD11b (P < 0.001), neutrophil elastase: alpha 1-antitrypsin complexes (P < 0.001), endothelin-1(P < 0.001) and thrombin-antithrombin complexes (P < 0.001) by the end of bypass compared with pre-operative levels. There was no significant change in monocyte expressed CD11b, factor XII or C1-esterase inhibitor in the pulmonary vein for the study period. None of these variables were significantly different in the pulmonary vein compared with CVP line. In the pulmonary vein plasma levels of activated factor VII decreased following heparin administration (P < 0.001) in the majority of patients which was coincidental to an increase (P < 0.001) in tissue factor pathway inhibitor (TFPI). This increase in TFPI was significantly higher in the pulmonary vein compared with CVP line (P < 0.05) There was a decrease in neutrophil count by 20 min on CPB in both the pulmonary vein and CVP line (P < 0.001) and this did not return to pre-operative levels in the pulmonary vein. Soluble thrombomodulin levels decreased by 20 min on CPB in the CVP line (P < 0.05) but tended to increase in the pulmonary vein, although this was not statistically significant. In conclusion we found evidence of thrombin generation and possible endothelial damage together with increased neutrophil activation and adhesion molecule expression in the pulmonary vein during CPB which may play an important role in the development of post-CPB pulmonary injury.
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PMID:Haemostatic changes in the pulmonary blood during cardiopulmonary bypass. 887 68

Very-low-density lipoprotein receptor (VLDLR) and alpha2-macroglobulin receptor/low-density-lipoprotein-receptor-related protein (alpha2MR/LRP) are multifunctional endocytosis receptors of the low-density lipoprotein receptor family. Both have been shown to mediate endocytosis and degradation of complex between plasminogen activators and type-1 plasminogen-activator inhibitor (PAI-1) by cultured cells. We have now studied the specificity of binding and endocytosis by VLDLR and alpha2MR/LRP among a variety of serine proteinase/serpin complexes, including various combinations of the serine proteinases urokinase-type and tissue-type plasminogen activators, plasmin, thrombin, human leukocyte elastase, cathepsin G, and plasma kallikrein with the serpins PAI-1, horse leukocyte elastase inhibitor, protein C inhibitor, C1-inhibitor, alpha2-antiplasmin, alpha1-proteinase inhibitor, alpha1-antichymotrypsin, protease nexin-1, heparin cofactor II, and antithrombin III. Binding was estimated with radiolabelled ligands in ligand blotting analysis and microtiter well assays. Endocytosis was estimated by measuring receptor-associated protein (RAP)-sensitive degradation of radiolabelled complexes by Chinese hamster ovary cells transfected with VLDLR cDNA and by COS-1 cells, which have a high endogenous expression of alpha2MR/LRP. We found that the receptors bind with high affinity to some, but not all, combinations of plasminogen activators and thrombin with PAI-1, protease nexin-1, protein C inhibitor, and antithrombin III, while complexes of many serine proteinases with their primary inhibitor, i.e. plasmin/alpha2-antiplasmin complex, do not bind, or bind with a very low affinity. Both the serine proteinase and the serpin moieties contribute to the binding specificity. The binding specificities of VLDLR and alpha2MR/LRP are overlapping, but not identical. The results suggest that VLDLR and alpha2MR/LRP have different biological functions by having different binding specificities as well as by being expressed by different cell types.
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PMID:Specificity of serine proteinase/serpin complex binding to very-low-density lipoprotein receptor and alpha2-macroglobulin receptor/low-density-lipoprotein-receptor-related protein. 934 78

The adherence of activated neutrophils to endothelial cells during ischemia/reperfusion injury is mediated by inside-out signal transduction. Subsequently, outside-in signal transduction occurs following ligation of adhesion molecules with their ligands triggering respiratory bursts of neutrophils. In addition, neutrophil elastase enhances CC- and CXC-chemokine production by monocytes and macrophages. MCP-1, a CC-chemokine, enhances tissue factor production by macrophages and increases ICAM-1 expression on endothelial cells. Chemotaxis and respiratory bursts of neutrophils are augmented by CXC-chemokines. Furthermore, neutrophil elastase inactivates anticoagulants including antithrombin III, heparin cofactor II, and thrombomodulin, suggesting that neutrophil elastase aggravates microcirculatory disturbance after ischemia/reperfusion. Thus neutrophil elastase modulates the interation of neutrophils and endothelial cells during ischemia/reperfusion injury. Taken together with these observations, a therapeutic regimen with antibodies against adhesion molecules in combination with neutrophil elastase inhibitor and anticoagulants may attenuate ischemia/reperfusion injury.
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PMID:[Interaction between neutrophils and endothelial cells following ischemia/reperfusion]. 1041 50

The rate of thrombin inhibition by heparin cofactor II (HCII) is facilitated by heparin or dermatan sulfate in vitro. The distributions of these glycosaminoglycans (GAGs) in vivo are not the same; heparin-like substance is rich on the surface of endothelial cells and dermatan sulfate is relatively dominant in the extravascular region. When inflammation takes place, at least two other possible existent forms of HCII, the complexed form with thrombin and the cleaved form by leukocyte elastase, are assumed to be present at relatively high concentrations in a local circumstance. We examined the interactions of HCII with the two forms of HCII on thrombin inhibition in the presence of the GAGs. By HCII in complex with thrombin or cleaved by leukocyte elastase, the affinity of HCII moiety for heparin increases and that for dermatan sulfate decreases. The two forms possibly occur at relatively high concentrations in a local pathological situation, although the heparin cofactor activity for thrombin inhibition by HCII decreases and dermatan sulfate determines the cofactor activity. These results indicate efficient thrombin inhibitory activity of HCII in the extravascular region.
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PMID:Thrombin inhibition by HCII in the presence of elastase-cleaved HCII and thrombin-HCII complex. 1115 May 88


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