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:3.4.21.37 (neutrophil elastase)
4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antileukoprotease is known to be an antiproteolytic compound of mucous secretions in humans. While searching for peptide-like inhibitors of neutrophil-derived serine proteases in horny layers of human skin, we isolated a potent inhibitor of human leukocyte elastase (EC 3.4.21.37) and cathepsin G (EC 3.4.21.20) from psoriatic scales. This inhibitor showed inhibitory constants for human leukocyte elastase of approximately 0.5-2 x 10(-10) M and for cathepsin G of 2-4 x 10(-9) N. The N-terminal amino acid sequence of the purified peptide matched the sequence of antileukoprotease and both peptides showed the same M(r) on SDS-PAGE. Therefore, antileukoprotease may not only regulate serine protease activities in mucous secretions, but also in skin.
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PMID:Antileukoprotease in psoriatic scales. 837 Sep 66

Proteolytic inactivation of serine protease inhibitors (serpins) by neutrophil elastase (HNE) is presumed to contribute to the deregulation of plasma cascade systems in septic shock. Here, we report a supplementary approach to construct serpins, in our case C1 inhibitor, that are resistant to catalytic inactivation by HNE. Instead of shifting the specificity of alpha 1-antitrypsin towards the proteases of the contact activation and complement systems, we attempted to obtain a C1 inhibitor species which resists proteolytic inactivation by HNE. 12 recombinant C1 inhibitor variants were produced with mainly conservative substitutions at the cleavage sites for HNE, 440-Ile and/or 442-Val. Three variants significantly resisted proteolytic inactivation, both by purified HNE, as well as by activated neutrophils. The increase in functional half-life in the presence of FMLP-stimulated cells was found to be 18-fold for the 440-Leu/442-Ala variant. Inhibitory function of these variants was relatively unimpaired, as examined by the formation of stable complexes with C1s, beta-Factor XIIa, kallikrein, and plasmin, and as determined by kinetic analysis. The calculated association rate constants (k(on)) were reduced twofold at most for C1s, and appeared unaffected for beta-Factor XIIa. The effect on the k(on) with kallikrein was more pronounced, ranging from a significant ninefold reduction to an unmodified rate. The results show that the reactive centre loop of C1 inhibitor can be modified towards decreased sensitivity for nontarget proteases without loss of specificity for target proteases. We conclude that this approach extends the possibilities of applying recombinant serpin variants for therapeutic use in inflammatory diseases.
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PMID:Recombinant C1 inhibitor P5/P3 variants display resistance to catalytic inactivation by stimulated neutrophils. 845 33

Human leukocyte elastase, a neutrophil-derived serine protease, is present in psoriatic lesions in an enzymatically active form. Our purpose was to assess the significance of human leukocyte elastase determinations in estimating the inflammatory activity of psoriatic lesions. A standardized method was used to analyse lesional elastase activity. Elastase activities were correlated with erythema, induration and hyperkeratosis of psoriatic lesions in 54 patients. Lesional elastase activities were also determined during treatment with salt-water bathing and UVB irradiation. Lesional elastase activity correlated with skin induration and was inversely correlated with hyperkeratosis of the lesions. Psoriatic lesions with high elastase activity responded well to therapy, whereas lesions with low elastase activity appeared to be comparatively resistant. This study shows that by quantitative determination lesional elastase activities it is possible to distinguish predominantly inflammatory from predominantly hyperproliferative psoriasis. The latter shows delayed responsiveness to topical therapy with salt-water bathing plus UVB irradiation.
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PMID:Lesional elastase activity in psoriasis. Diagnostic and prognostic significance. 853 25

Alpha 1-proteinase inhibitor (alpha 1-Pi) is the main physiological inhibitor of neutrophil elastase, a serine protease that has been implicated in tissue degradation at inflammatory sites. We report here on an immunocytochemical study of various eukaryotic cells in order to show their content of alpha 1-Pi. The proteinase inhibitor is present in undifferentiated and differentiated HL-60 and U937 cells, in myeloblasts and neutrophils, and also in tissues such as liver, kidney, colon and eye where local inflammatory processes can take place. Labelling of HL-60, U937, neutrophils and HepG2 cells with [35S] methionine followed by immunoprecipitation of cell homogenates with an anti-alpha 1-Pi antibody revealed that these cells can synthesize alpha 1-Pi de novo, and secrete large amounts of the newly synthesized molecule into the medium. In contrast, neutrophil elastase is only present in white blood cells of myeloid and monocytic lineage but not in other tissues investigated which contain alpha 1-Pi. The results demonstrate the possibility of ubiquitous local synthesis of alpha 1-Pi ready to inhibit the elastase which is imported into the affected tissues during inflammatory processes by circulating cells of the haematopoietic system.
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PMID:Differences in distribution and synthesis of the functional opponents alpha 1-proteinase inhibitor and neutrophil elastase in eukaryotic cells. 854 50

Previous studies have demonstrated that neutrophils possess an active serine protease(s) which may be involved in the process of chemotaxis but the precise identity of this enzyme(s) remains to be determined. In this study fourteen different protease inhibitors were tested over a wide concentration range for their ability to inhibit unstimulated neutrophil movement and chemotaxis to C5a, fMLP and IL-8. Pretreatment of neutrophils with aspartyl or metallo-protease inhibitors had no effect on either chemotaxis or random cell movement. The thiol protease inhibitors E-64 and cystatin, as well as the thiol/serine inhibitors antipain and leupeptin, diminished only C5a-induced chemotaxis. Pretreatment of neutrophils with the serine protease inhibitors PMSF or 3,4-DCI significantly reduced chemotaxis to C5a, fMLP and IL-8. The inhibitor of trypsin-like serine proteases, TLCK, and the neutrophil elastase inhibitor MeO-Suc-AAPV-CMK had no inhibitory effect on cell movement. However, two different inhibitors of chymotrypsin-like serine proteases, TPCK and chymostatin, significantly inhibited movement to any chemoattractant. These results suggest that an active chymotrypsin-like serine protease is essential for neutrophils to respond to chemotactic stimuli.
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PMID:Inhibition of neutrophil chemotaxis by protease inhibitors. Differential effect of inhibitors of serine and thiol proteases. 854 71

In a previous report, we described the molecular cloning, expression, and partial characterization of a second human tissue factor pathway inhibitor (TFPI), which we designated as TFPI-2 [Sprecher, C. A., et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 3353-3357]. Recombinant TFPI-2 inhibited the amidolytic activity of trypsin as well as that of factor VIIa in complex with tissue factor. TFPI-2 recently has been shown to be identical to placental protein 5 (PP5), a glycoprotein originally isolated from placenta that exhibits serine protease inhibitory activity. In the present study, we have examined TFPI-2/PP5 for its ability to inhibit a number of serine proteases involved in blood coagulation and fibrinolysis, inasmuch as TFPI-2/PP5 prolonged the coagulation time of human plasma induced by either tissue factor or contact activation in a dose-dependent manner. In addition to its ability to inhibit the amidolytic and proteolytic activities of the factor VIIa-tissue factor complex, TFPI-2/PP5 strongly inhibited the amidolytic activities of human factor XIa, human plasma kallikrein, and human plasmin with Ki values of 15, 25, and 3 nM, respectively. TFPI-2/PP5 was also a weak inhibitor of the activation of factor X by a complex of human factor IXa and poly(lysine) with an apparent Ki of 410 nM. Heparin markedly enhanced the ability of TFPI-2/PP5 to inhibit factor VIIa-tissue factor both in the solution phase and on cell surfaces. In addition, heparin augmented the inhibition of human factor Xa amidolytic activity at relatively high levels (10-100 nM) of TFPI-2/PP5. No significant inhibition of glandular kallikrein, urinary plasminogen activator, tissue plasminogen activator, human activated protein C, human factor Xa, human thrombin, or leukocyte elastase was observed when these proteases were incubated with TFPI-2 in the absence of heparin.
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PMID:Inhibitory properties of a novel human Kunitz-type protease inhibitor homologous to tissue factor pathway inhibitor. 855 84

We investigated the effect of activated protein C (APC) on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats to investigate the possible usefulness of APC as a treatment for adult respiratory distress syndrome. Intravenously administered LPS (5 mg/kg) significantly increased pulmonary vascular permeability. APC prevented the LPS-induced increase in pulmonary vascular permeability observed at 6 hours. Heparin plus antithrombin III (ATIII) and active site-blocked factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, inhibited LPS-induced coagulopathy but did not prevent LPS-induced pulmonary vascular injury. LPS-induced pulmonary vascular injury was significantly attenuated in rats with nitrogen mustard-induced leukocytopenia and in rats treated with ONO-5046, a potent granulocyte elastase inhibitor. Administration of LPS also increased pulmonary accumulation of leukocytes, as evaluated by measurement of myeloperoxidase activity in the lungs. APC significantly reduced LPS-induced increases in pulmonary accumulation of leukocytes at 1 hour. Neither ATIII plus heparin nor DEGR-Xa inhibited leukocyte accumulation. Active site-blocked APC (DIP-APC) prevented neither the LPS-induced pulmonary accumulation of leukocytes nor the LPS-induced increase in pulmonary vascular permeability. These results suggest that the mechanism of APC inhibition of LPS-induced pulmonary vascular injury was independent of its anticoagulant activity and was related to its ability to inhibit accumulation of leukocytes. In addition, these findings suggest that the serine protease activity of APC may be essential to its inhibitory effect on LPS-induced pulmonary accumulation of leukocytes and subsequent pulmonary vascular injury.
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PMID:Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. 855 86

Met-ase-1 is a 30 000 Mr serine protease (granzyme) that was first isolated in the cytolytic granules of rat CD3(-) large granular lymphocytes. We screened a mouse genomic library with rat Met-ase-1 cDNA, and obtained bacteriophage clones that contained the mouse Met-ase-1 gene. The mouse Met-ase-1 gene comprises five exons spanning approximately 5.2 kilobases (kb) and exhibits a similar structural organization to its rat homologue and a family of neutrophil elastase-like serine proteases. Mouse Met-ase-1 mRNA was only detected in total cellular and poly A mRNA of mouse CD3(-) GM1(+) large granular lymphocytes derived from splenocytes stimulated with IL-2 and the mouse NK1.1(+) cell line 4 - 16. Spleen T-cell populations generated by Concanavalin A stimulation and a number of mouse pre-NK and T cell lines did not express mouse Met-ase-1 mRNA. The 5' flanking region of the mouse Met-ase-1 gene also shares considerable regions of identity with the 5' flanking region of the rat Met-ase-1 gene. A 3.3 kb segment of 5' sequence flanking the mouse Met-ase-1 gene was inserted upstream of the chloramphenicol acetyltransferase reporter gene and this construct transiently transfected into a variety of mouse and rat large granular lymphocyte leukemia and T-cell lines. The transcriptional activity of the mouse Met-ase-1 5' flanking region was significant in the RNK-16 large granular lymphocyte leukemia, strongest in the 4 - 16 mouse NK1.1(+) cell line, and weak in several mouse pre-NK cell lines. Reverse transcriptase polymerase chain reaction of mouse large granular lymphocyte mRNA was used to derive the full-length coding sequence for mouse Met-ase-1. The predicted hexapropeptide of mouse Met-ase-1 (Asn-6 to Gln-1), was deleted by polymerase chain reaction mutagenesis to enable expression of active mouse Met-ase-1 in mammalian COS-7 cells. Northern blot analysis and protease assays of transfected COS cell lysates against a panel of thiobenzyl ester substrates formally demonstrated that the mouse Met-ase-1 gene encodes a serine proteinase that hydrolyzes substrates containing a long narrow hydrophobic amino acids like methionine, norleucine, and leucine in the P1.
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PMID:Cloning and expression of the recombinant mouse natural killer cell granzyme Met-ase-1. 878 Nov 19

Human neutrophil elastase is a 29 kDa, 220-residue single chain glycoprotein which functions as a powerful serine protease. Because NE is capable of destroying a broad range of substrates including cross-linked elastin and the major forms of collagen as well as the cell walls of gram-negative bacilli, it possesses the two-edged sword property that is required for normal tissue turnover and host defense, yet potentially harmful in its ability to destroy normal tissues simultaneously. In this regard, NE plays a central role in the pathogenesis of pulmonary emphysema by destroying the alveolar walls of the lung in the conditions that antiproteases in the lung such as alpha 1-antitrypsin (alpha 1-AT) are inactivated-e.g., cigarette smoking, or alpha 1-AT deficiency caused by mutations of the alpha 1-AT gene-resulting in excess burden of NE in the lung. The gene encoding the NE protein has 5 exons and is located at chromosome 19p13.3. Expression of the NE gene is tightly controlled mainly at the transcriptional level, and limited to the early stage of myeloid cell differentiation in bone marrow cells, mostly in promyelocytes. The knowledge on the modulation of lineage- and differentiation-specific NE gene expression could offer the possible therapeutic strategy to the diseases such as pulmonary emphysema.
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PMID:[Structure and expression of the human neutrophil elastase gene--regulatory mechanism and its relevance to the respiratory diseases]. 883 87

Trifluoroacetylpeptide anilides are powerful reversible inhibitors of human neutrophil elastase (HNE), a serine protease implicated in the pathogenesis of pulmonary emphysema. The in vitro effectiveness of three inhibitors, CF3CO-Phe-Ala-NH-p-C6H4-CF3 (1), CF3CO-Val-Ala-NH-p-C6H4-CF3 (2) and CF3CO-Lys-Ala-NH-p-C6H4-CH(CH3)2 (3) was analyzed. The protection of lung tissue sections of rats from the degradation induced by HNE has been evaluated quantitatively by automated image analysis. Inhibitor 1 (22 microM), 2 (50 microM) or 3 (35 and 70 microM) significantly reduced the HNE-induced degradation of the elastin network by 75, 42, 54 and 44%, respectively. Inhibitor 3 was tested intratracheally on an experimental model of pulmonary emphysema. Rats that received the elastase inhibitor 1 h before instillation of HNE were significantly protected by 40% from experimental emphysema. Reduced protections were observed with the treatment by the inhibitor 1 or 4 h after challenge with the enzyme.
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PMID:Protection of rat lung from elastase-induced elastic fiber degradation in vitro and from emphysema in vivo by a trifluoroacetylpeptide anilide inhibitor. 888 99


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