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)

Total proteolytic activity (PA) is increased in the circulation of pediatric burn patients. The extent of the increase correlates with the percent total body surface area (TBSA) burned and is associated with increased susceptibility to fatal infection. To determine the source or sources of this PA, three factors were evaluated: (1) levels of proteinase inhibitors--antithrombin, alpha 2-antiplasmin, and alpha 1-proteinase inhibitor; (2) levels of proteinase--neutrophil elastase; and (3) activation of circulating proteolytic cascade systems as indicated by changes in levels of system components--plasminogen and prekallikrein. All assays measured functional levels of the proteins. Normal levels were determined in 25 consecutive well children who were seeing their pediatrician for checkups (14 boys, 11 girls, ranging in age from 10 months to 17 years). Twenty-five consecutive burn victims admitted to the Shriners Burns Institute, Cincinnati Unit (19 boys, six girls, aged 10 months to 17 years), with a mean full-thickness burn of 43.2% TBSA (range, 6%-87%) were studied in the first week postburn. Antithrombin, alpha 2-antiplasmin, plasminogen, and prekallikrein levels decreased (p < 0.001) postburn, whereas elastase increased (p < 0.001). We conclude that, in pediatric burn patients, decreased proteinase inhibitors, increased proteinase, and activation of circulating proteinase cascades all contribute to elevated total circulating PA postburn.
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PMID:Components of the increased circulating proteolytic activity in pediatric burn patients. 147 19

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

Antithrombin (AT) is a serpin capable of trapping thrombin (IIa) in a stable and covalent complex. Complex formation is prevented by leukocyte elastase (LE) cleavage near the AT reactive centre. We mutated the known LE cleavage sites of AT to explore the possibility of producing an LE-resistant AT molecule. Initially, six rabbit AT variants differing only at residue 390 (P4) were generated in a cell-free system, and gel-based assays were used to assess IIa-mediated complex formation and LE-mediated cleavage of the variants. Substitution of charged residues (Glu or Arg) reduced complex formation by 50-60%, while the Ser variant was incapable of inhibiting thrombin; LE reactivity was less affected. The least (Trp) and most (Ser) affected variants were expressed in COS-1 cells. Again, the Ser variant was incapable of detectably reducing the rate of thrombin-mediated amidolysis while the Trp variant inhibited thrombin at a slightly reduced rate (-28%). LE inactivated the Trp variant and the wild-type AT to a similar extent. Recreation of the Trp mutation in COS-derived human AT showed similar results. Since retention of LE-sensitivity could have arisen due to cleavage at Val389 (P5), we produced and characterized a human AT substitution mutant with Trp at both P4 and P5. This variant showed a slight reduction in thrombin inhibitory activity (-22%), but remained susceptible to LE inactivation. These results suggest either that LE cleaves at secondary sites if its primary cleavage sites are blocked, or that the substrate specificity of LE differs in polypeptides as compared to peptide substrates.
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PMID:Impact of mutations at the P4 and P5 positions on the reaction of antithrombin with thrombin and elastase. 936 70

Circulating endotoxin is elevated in sepsis and plays a role in endothelial dysfunction whereas antithrombin is decreased by virtue of its consumption during complex formation with clotting factors and by proteolytic degradation by granulocyte elastase. Dysfunction of endothelium results in enhanced leukocyte rolling and diapedesis into tissues leading to edema formation and injury. Antithrombin exerts beneficial effects on endothelial function in sepsis. A direct anti-inflammatory action of anti-thrombin in inflammatory cells is exerted via heparan sulfate proteoglycans. In this study, we investigated whether antithrombin affects endotoxin-induced adhesion of neutrophils to human endothelial cells in vitro and whether glycosaminoglycans are involved in its signaling. Adhesion of human neutrophils to monolayers of umbilical vein endothelial cells was tested under static conditions. Endothelial cells were pretreated with endotoxin, interleukin-1, heparinase-I, chondroitinase-ABC or anti-syndecan-4-antibody. Endotoxin and interleukin-1 increased neutrophil adherence to human umbilical vein endothelial cells which was inhibited by antithrombin. Concomitant incubation with pentasaccharide abolished this effect of antithrombin. Treatment of endothelial cells with heparinase or chondroitinase led to higher adhesion and prevented effects of antithrombin. With antibodies to syndecan-4, enhanced adhesion of neutrophils was observed. As studied by Western blotting, endotoxin-induced signaling was diminished by antithrombin and the effect was reversible by chondroitinase or heparinase. From our results, we can conclude that endotoxin-induced adhesion of leukocytes to endothelium can be reversed by ligation of syndecan-4 with antithrombin's heparin-binding site and interferences with stress response signaling events in endothelium.
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PMID:Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin. 1465 50