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

The influence of granulocyte elastase-like proteinase (ELP) on platelet functions was investigated. ELP inhibited the platelet aggregations induced by a wide variety of agonists. The inhibition was marked in the case of receptor-mediated agonists such as thrombin, ristocetin, etc. It was moderate with the pervading agonist, arachidonic acid, and mild with the bypassing agonist, Ca2+ ionophore A23187. ELP inhibited the release of thromboxane A2 from platelets in the case of the platelet aggregation induced by thrombin. On the other hand, ELP did not inhibit the release of thromboxane A2 from platelets in the platelet aggregation induced by arachidonic acid or Ca2+ ionophore A23187. ELP suppressed the release of serotonin from platelets induced by thrombin, while it did not markedly suppress the release of serotonin induced by Ca2+ ionophore A23187. Treatment of platelets with ELP resulted in a slight increase of intraplatelet cAMP levels. These results suggest that ELP acts on receptors and inhibits platelet functions. As a results, ELP markedly inhibits the platelet functions such as aggregation or release of serotonin or thromboxane A2 stimulated by receptor-mediated agonists. ELP slightly elevates the cAMP level in the platelets, resulting in the mild inhibition of the platelet functions stimulated by the pervading agonist, arachidonic acid, or the bypassing agonist, Ca2+ ionophore A23187.
 ...
PMID:Influence of granulocyte elastase-like proteinase (ELP) on platelet functions. 301 Apr 92

During blood coagulation, polymorphonuclear leukocytes release elastase in amounts that can exceed 100 nmol/L. We therefore studied the interaction between human leukocyte elastase and human alpha-thrombin. Elastase cleaved the thrombin B chain (Ala 150-Asn 151) near the gamma-cleavage site, resulting in two fragments held together by noncovalent interactions. The NH2-terminal fragment (FI), mol wt approximately 18,000, was disulfide-linked to the thrombin A chain. The COOH-terminal fragment (FII), mol wt approximately 13,000, contained the active-site serine and formed a covalent bond with antithrombin III. Heparin accelerated proteolysis of alpha-thrombin by elastase. Proteolyzed alpha-thrombin (T theta) retained full amidolytic activity; however, the concentration of T theta causing 50% maximal platelet aggregation and adenosine triphosphate (ATP) release was 7.9 nmol/L (1.1 nmol/L for alpha-thrombin and 220 nmol/L for gamma-thrombin). Fibrinogen clotting activity of T theta and gamma-thrombin was 32% and 1% that of alpha-thrombin, respectively. Elastase released during the coagulation process may modulate thrombin activity. In addition, elastase-modified thrombin may be a useful probe of the structure and function of the gamma-cleavage region.
 ...
PMID:Human neutrophil elastase alters human alpha-thrombin function: limited proteolysis near the gamma-cleavage site results in decreased fibrinogen clotting and platelet-stimulatory activity. 310 65

Using immunochemical analysis with standard antisera, leukocyte thermostable alpha-glycoprotein (LT alpha G) was shown to be distinct from lactoferrin, lysozyme, and fibronectin. The determination of peroxidase and nonspecific elastase in immune precipitates of LT alpha G gave negative results. Affinity sorption of LT alpha G onto the pus protein component was revealed. Purified LT alpha G had amidolytic activity in response to a substrate for elastase (p-nitroanilide succinyl-trialanyl). The ability of LT alpha G to cause the hydrolysis of substrates for thrombin, kallikrein, plasmin was investigated. The identity of LT alpha G and granulocyte elastase is suggested.
 ...
PMID:[Thermostable leukocyte alpha-glycoprotein: immunochemical study and enzyme activity research]. 310 19

Strong activity of acid-stable trypsin inhibitor (ASTI) was confirmed in some clinical thrombin preparations. Thrombin preparations of human plasma origin had no detectable ASTI activity, whereas some preparations of bovine plasma origin revealed more than 5,000 U/vial (5,000 thrombin units), indicating a higher content of ASTI than of thrombin in terms of protein concentration. Contamination by other biologically active substances was also suggested by variations in amidolytic activity with several synthetic substrates (S-2238, S-2251, S-2444, S-2266 and Bz-L-Arg-pNA). On isoelectric focussing, the ASTI activities migrated in acidic positions with pI values of 3.9, 4.5, 5.0, 5.9 and 6.5, respectively. They were almost parallel to the thrombin Bz-L-Arg-pNA hydrolytic activity, and differed from that of the purified thrombin preparation (pI = 7.0). By gel filtration on Sephadex G-100, the molecular weights of the inhibitors as calculated using standard proteins were 140,000 (main), 70,000 and less than 10,000 (minor), respectively. An immunological difference between the main inhibitor (pI = 3.9, mol wt 140,000) and previously reported plasma ASTI was also confirmed with goat anti-UTI serum by the double immunodiffusion and ELISA methods. The inhibitor exerted a strong inhibitory effect not only on trypsin and chymotrypsin, but also on non-plasmic fibrinolysis with human leukocyte elastase, and to a lesser extent on the blood coagulation system (lengthening of APTT and PT). Clearly, when using thrombin preparations and analyzing the data obtained after their administration, the effects of this and other contaminant biologically active substances must be taken into account.
 ...
PMID:Strong activity of acid-stable trypsin inhibitor in bovine thrombin for clinical use. 314 Oct 90

The prognosis of septicaemia depends on the occurrence of complications such as shock and coagulation defects. The damage to haemostasis is usually explained by the action of the main coagulation and fibrinolysis enzymes, thrombin and plasmin. This paper presents data concerning the role of a third protease, granulocytic elastase. 82 patients who had been admitted to our hospital with suspected septicaemia were examined. Septicaemia was proven in 22 patients by the growth of microorganisms in blood cultures, and was clinically diagnosed in 9 patients. The plasma levels of neutrophil elastase-like protease complexed to a1antitrypsin (a1AT-ELP) were measured by zone immunoelectrophoresis assay (ZIA). The a1AT-ELP values were significantly increased in the 31 septic as compared to the 51 non-septic patients. In patients with complicated septicaemia, negative correlations of a1AT-ELP with factor XIII and the coagulation inhibitor antithrombin III were demonstrable. Among the patients with septic complications, the 3 who survived exhibited a dramatic decrease of a1AT-ELP, whereas in the other 16 patients who died the levels remained elevated. It might be of therapeutic significance that in 9 patients receiving fresh plasma and AT III-concentrate substitution for DIC the a1AT-ELP levels dropped, whereas they remained high in the other septicaemia patients. There were no correlations between a1AT-ELP and the a2antiplasmin-plasmin complexes (a2AP-P1), but strong correlations with signs of coagulation. The data suggest an interaction of coagulation and elastase release, probably involving the Hageman factor.
 ...
PMID:Participation and interactions of neutrophil elastase in haemostatic disorders of patients with severe infections. 329 74

Neutrophils activated with serum opsonized zymosan, soluble heat-aggregated IgG, and ionophore A23187 in the presence of calcium release a material capable of initially activating factor V. Subsequent inactivation of factor V was only observed with neutrophil releasate derived from IgG and ionophore. In this study we examine the nature of this neutrophil activity and investigate its role in the regulation of factor V/Va. From early in the fractionation it was apparent that the cells contained different enzymes capable of cleaving factor V. The most active of these was isolated and found to be an isomer of human neutrophil elastase. The purified protease caused a dose-dependent activation of isolated factor V to a maximum of threefold. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, single-chain factor V was cleaved to form intermediates of 100 and 91 kilodaltons (kD). Coagulant activity correlated with the formation of a 97-kD heavy and 77-kD light chain. On prolonged incubation the formed factor Va(e) was inactivated in association with proteolysis of the 97-kD band to smaller peptides and cleavage of the 77-kD light chain to a molecular weight of 75 kD, which is similar to thrombin-activated factor Va light chain. Neutrophil elastase also caused rapid inactivation of thrombin-activated factor V, factor Va(t). These observations suggest that elastase cleaves factor V at sites distinct from that by thrombin and therefore represents a novel factor V activation pattern. It is proposed that upon neutrophil activation elastase is secreted into the plasma milieu to initiate factor V activation. This serves to generate small amounts of thrombin that, in turn, by positive feedback fully activates factor V and thus amplifies the coagulation reaction.
 ...
PMID:The regulation of human factor V by a neutrophil protease. 330 63

Proteolytically modified forms of human antithrombin III have been prepared by reaction of native antithrombin with thrombin, human neutrophil elastase, or porcine pancreatic elastase. These forms have two chains disulfide linked and are of the same molecular weight as native antithrombin III. 1H NMR spectroscopy has been used to characterize these proteins and to compare them to one another and to native antithrombin III. The three modified proteins have very similar NMR spectra and histidine residues with identical pH titration parameters, and they undergo the same spectral changes upon binding heparin. They differ from native antithrombin III in all of these respects. In addition, the proteins are much more stable than native antithrombin III. The three modified proteins behave identically as a function of temperature; at 372 K, 44 K above the unfolding temperature for native antithrombin III, the proteins are still folded and possess approximately 70 unexchanged amide protons even after several hours. The unfolding of the heparin binding domain at low concentrations of deuteriated guanidine hydrochloride seen in native thrombin III is absent in the modified forms. It is concluded that the thrombin- and elastase-modified forms of antithrombin have identical structures when allowance is made for the slightly different sites of cleavage by the two types of elastase and by thrombin. This structure is very different from that of native antithrombin III.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Properties of thrombin- and elastase-modified human antithrombin III. 340 16

Human lumbar disc tissue when extracted with 4M GuHCl and subjected to dissociative CsCl density gradient ultracentrifugation yielded trypsin inhibitor activity in the low bouyant density fractions (rho less than or equal to 1.38 g/ml). Disc proteoglycans sedimented in the high bouyant density fractions (rho greater than or equal to 1.5 g/ml). Sephadex G75F gel filtration of the low bouyant density protein fractions afforded a major low molecular weight (Kav = 0.5) trypsin inhibitor pool which was further purified by trypsin affinity chromatography. This latter step facilitated separation of the trypsin inhibitors from neutral proteinase activity also present. The trypsin inhibitor fraction so isolated was shown to possess potent inhibitory activity against a range of human serine proteinases including leukocyte elastase and cathepsin G, urokinase, kallikrein, plasmin and thrombin. Significantly this serine proteinase inhibitor preparation effectively prevented degradation of proteoglycans by a neutral proteinase also isolated from the human intervertebral disc.
 ...
PMID:Low molecular weight serine proteinase inhibitors of the human intervertebral disc. 348 24

In normal plasma, the serine protease inhibitor alpha 1-antitrypsin (alpha 1-AT) plays little or no role in the control of plasma kallikrein or activated Factor XII fragment (Factor XIIf), this function being performed by Cl-inhibitor. Recently, an alpha 1-AT variant was described with a Met----Arg mutation at the reactive center P1 residue (position 358) which altered the specificity of inhibition from the Met- or Val-specific protease neutrophil elastase to thrombin, an Arg-specific protease. We have now examined the inhibition of plasma kallikrein and Factor XIIf, both Arg-specific enzymes, with recombinant alpha 1-AT(Met358----Arg) produced by an Escherichia coli strain carrying a mutated human alpha 1-AT gene. The engineered protein was a very efficient inhibitor of both enzymes. It was more effective than Cl-inhibitor by a factor of 4.1 for kallikrein and 11.5 for Factor XIIf. These results suggest that recombinant alpha 1-AT(Met358----Arg) has therapeutic potential for disease states where activation of the plasma kinin-forming system is observed, for example in hereditary angioedema or septic shock.
 ...
PMID:Recombinant alpha 1-antitrypsin Pittsburgh (Met 358----Arg) is a potent inhibitor of plasma kallikrein and activated factor XII fragment. 348 56

Seven active site variants of human alpha 1-antitrypsin (alpha 1AT) were produced in Escherichia coli following site-specific mutagenesis of the alpha 1AT complementary DNA. alpha 1AT (Ala358), alpha 1AT (Ile358) and alpha 1AT (Val358) were efficient inhibitors of both neutrophil and pancreatic elastases, but not of cathepsin G. alpha 1AT (Ala356, Val358) and alpha 1AT (Phe358) specifically inhibited pancreatic elastase and cathepsin G respectively. The most potent inhibitor of neutrophil elastase was alpha 1AT (Leu358), which also proved to be effective against cathepsin G. The alpha 1AT (Arg358) variant inactivated thrombin with kinetics similar to antithrombin III in the presence of heparin. Electrophoretic analysis showed that SDS-stable high mol. wt complexes were formed between the mutant inhibitors and the cognate proteases in each case. These data indicate that effective inhibition occurs when the alpha 1AT P1 residue (position 358) corresponds to the primary specificity of the target protease. Moreover, alteration of the P3 residue (position 356) can further modify the reactivity of the inhibitor. Two of the variants have therapeutic potential: alpha 1AT (Leu358) may be more useful than plasma alpha 1AT in the treatment of destructive lung disorders and alpha 1AT (Arg358) could be effective in the control of thrombosis.
 ...
PMID:Altered specificities of genetically engineered alpha 1 antitrypsin variants. 350 63


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>