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)

Inherited or "acquired" deficiency of alpha 1-antitrypsin (believed to be the cause of pulmonary emphysema) will probably be treated in the future by replacement with alpha 1-antitrypsin purified from human plasma or produced by recombinant DNA, which seems promising because it permits site-specific mutagenesis in the oxidizable active site of the normal human alpha 1-antitrypsin. The aim of this in-vitro study was to investigate the elastase inhibitory activity and the resistance to oxidizing agents of normal human alpha 1-antitrypsin, a recombinant yeast-produced variant (VAL 358) and a recombinant E. coli-produced variant (LEU 358). The inhibitors were exposed to chemical oxidants (NCS, H2O2, xanthine/xanthine oxidase, chloramine-T) and to PMA-activated neutrophils. The elastase inhibitory activity was assayed on porcine pancreatic elastase and neutrophil elastase. Normal alpha 1-antitrypsin and VAL 358 variant were good inhibitors of both elastases. LEU 358 variant was the best inhibitor for neutrophil elastase, but it poorly inhibited the porcine pancreatic elastase. Normal alpha 1-antitrypsin was affected by all oxidants; both variants were almost totally resistant to chemical oxidants and to activated neutrophils. We conclude that recombinant alpha 1-antitrypsin variants differ in their elastase inhibitory activity and offer increased resistance to oxidant agents.
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PMID:Alpha 1-antitrypsin variants produced by recombinant DNA: differences in elastase inhibitory activity and resistance to oxidant agents. 210 1

Human peripheral blood monocytes contain human leukocyte elastase (HLE) and cathepsin G (CG), serine proteinases originally described in azurophil granules of polymorphonuclear neutrophils (PMN). Immunoreactive HLE and CG of freshly harvested monocytes have been quantified in this study; to begin to elucidate potential roles for these enzymes in extracellular events, release in response to stimuli has been measured, along with proteolytic activity of monocytes toward surface-bound proteins. Our results indicate that whole-cell extracts of monocytes contain approximately 6% of the amount of HLE as do extracts of comparable numbers of PMN. In response to PMA in vitro, monocytes released 39 to 53% of their content of HLE and CG within 60 min, a fractional release greater than that of PMN. Furthermore, when phorbol-stimulated monocytes were adherent to a fibronectin-coated surface, extensive HLE-mediated proteolysis of the surface-bound protein was observed. Proteolysis by such cells in the presence of proteinase inhibitors was of considerable interest, since a subpopulation (15 to 20% of the total) expressed marked but localized proteolytic activity, possibly escaping inhibition through contact-mediated mechanisms. These data indicate that a subpopulation of freshly harvested monocytes is rich in HLE and CG (serine proteinases traditionally associated with PMN), can promptly release HLE and CG in response to stimuli, and can utilize HLE for extracellular proteolysis. Monocyte-derived serine proteinases may participate in extracellular events formerly associated with PMN-derived HLE and CG.
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PMID:Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity. 268 19

Homozygous inheritance of the null bellingham alpha 1-antitrypsin (alpha 1AT) gene is associated with early-onset emphysema, resulting from the lack of alpha 1AT to protect the lung from neutrophil elastase. Cloning and sequencing of the null bellingham gene demonstrated that the promoter region, coding exons, and all exon-intron junctions were normal except for a single base substitution in exon III, causing the normal lys217 (AAG) to become a stop codon (TAG). Evaluation of genomic DNA of family members by using oligonucleotides directed toward this region demonstrated that the index case had inherited this mutation in a homozygous fashion. Although the consequences to the individual (i.e., emphysema) are identical to those associated with the common homozygous Z mutation, the homozygous null bellingham form of alpha 1AT deficiency has a very different genetic basis.
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PMID:Emphysema associated with complete absence of alpha 1- antitrypsin in serum and the homozygous inheritance [corrected] of a stop codon in an alpha 1-antitrypsin-coding exon. 325 51

CD43, an anionic rod-like mucin molecule on white blood cells, is thought to provide a barrier that prevents interactions of other surface molecules and acts as negative regulator of cell function. As a correlate, CD43 is expected to be altered or down-regulated when blood cells are functionally activated. This study examines CD43 of blood neutrophils before and after treatment with known activating agents. Flow cytometry indicated that PMA and A23187, and to a much lesser extent, FMLP and IL-8, decrease neutrophil expression of CD43. Two separate mechanisms were identified for CD43 down-regulation. Both are proteolytic processes. PMA-induced down-regulation is a rapid process involving proteolysis at a minimum of two sites, one within the N-terminal distal region recognized by mAbs and the other at a membrane-proximal site. The PMA-induced protease, cd43' ase, is characterized by insensitivity to DFP, TLCK, leupeptin, pepstatin, and 1,10 phenanthroline (< 5 mM). PMA-induced CD43 down-regulation is extensive but never complete, terminating at approximately 10 min after down-regulating 65 to 85% of molecules, and thereby converting neutrophils from dense to sparse CD43 expression. The second CD43 down-regulation mechanism, although likely a regulated event in vivo, occurred slowly in this study in neutrophils incubated without additives; the process is not affected by PMA, involves the action of a DFP-sensitive protease, releases N-terminal mAb-reactive fragments of 52 kDa or 40 kDa and can be mimicked by exogenous neutrophil elastase. The complexity and apparent tight regulation described here for the two down-regulatory mechanisms are consistent with an important role for CD43 in preventing or dampening cell surface interactions of blood neutrophils.
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PMID:Two proteolytic pathways for down-regulation of the barrier molecule CD43 of human neutrophils. 751 53

Human neutrophil and its elastase play an important role in the pathogenesis of various lung diseases. We investigated the damaging effect of human neutrophils stimulated with PMA (phorbol myristate acetate 10ng/ml) or calcium ionophase A23187 (2ng/ml) on isolated perfused rat lungs. The study specimens consisted of 4 groups of animals. A control, B perfused with human neutrophils, C perfused with human neutrophils stimulated with PMA, and D perfused with human neutrophils stimulated with A23187. By using the ELISA method, we found that the level of human neutrophil elastase (HNE) in perfusate increased significantly at 30min (1.68 +/- 0.79ng/ml P < 0.05) and 60min (2.35 +/- 0.87 ng/ml P < 0.01) after PMA stimulating, but the HNE in the lung lavage fluid of the same group only slightly increased and the concentration of protein in lavage fluid did not change. After stimulating with A23187, the concentration of HNE in perfusate increased markedly at 30min (4.03 +/- 1.96ng/ml P < 0.01) and maintained at high level (P < 0.01). There was a significant increase of HNE level in lung lavage fluid (2.49 +/- 0.61ng/ml) from group D rat lungs, compared with group A, B or C, and the protein as well (1.61 +/- 0.58mg/ml P < 0.05). All the results indicate that the stimulated human neutrophils can release elastase in perfused rat lung. Neutrophil stimulated with A23187 can increase pulmonary permeability and injure the lung. We suggest that the lung damage, caused by human neutrophils, may be the effect of neutrophil elastase or the synergistic effect with some other substances derived from neutrophil.
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PMID:[The damaging effect of activated human neutrophils on isolated perfused rat lungs--the role of elastase]. 765 88

Secretory leukoprotease inhibitor (SLPI), a 12-kD nonglycosylated serine antiprotease, helps to protect the epithelial surface of the airways from the destructive capacity of neutrophil elastase. Based on the recognition that SLPI levels can increase in the presence of airway inflammation, we hypothesized that inflammatory stimuli should modulate the expression of the SLPI gene in airway epithelial cells. To evaluate this, the modulation of SLPI gene expression with various inflammatory stimuli was evaluated in the HS-24 human bronchial epithelial cell line. After preliminary studies showed that several inflammatory mediators enhanced SLPI messenger RNA (mRNA) levels, PMA was used as a model inflammatory stimulus. PMA significantly increased the level of 0.7-kb SLPI mRNA transcripts in HS-24 cells in a dose- and time-dependent fashion and increased the amount of SLPI protein in the culture supernatant. Nuclear run-on analyses showed that the SLPI gene transcription rate increased approximately twofold after PMA stimulation. Transfection studies using fusion genes composed of fragments of up to 1.2 kb of the 5' flanking sequence of the SLPI gene and a luciferase reporter gene demonstrated potent promoter activity in the 131-bp segment (-115 to +16 relative to the transcription start site), and all longer segments up to 1.2 kb, whereas smaller segments showed low promoter activity. An 18-bp element (-98 to -115), in a region with homology to PMA-responsive regions in the Moloney murine leukemia virus enhancer and the IL-8 gene, was shown to be of importance in the level of transcription of the SLPI gene. However, this element was not responsible for the upregulation of SLPI gene expression by PMA. Evaluation of HS-24 cells in the presence of actinomycin D demonstrated that SLPI mRNA transcripts were very stable and became more so in the presence of PMA. Thus, SLPI gene expression in airway epithelial cells can be upregulated by an inflammatory stimulus, and this modulation is regulated at both the transcriptional and posttranscriptional levels. These mechanisms of SLPI upregulation likely play a role in defending the epithelial surface in the local milieu of inflammatory lung diseases.
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PMID:Modulation of secretory leukoprotease inhibitor gene expression in human bronchial epithelial cells by phorbol ester. 791 12

Elevated levels of soluble intercellular adhesion molecule-1 have been shown predictive of post-injury multiple organ failure. We hypothesized that sICAM-1 augments distant organ injury via its affect on the PMN and; thus, have examined neutrophil elastase and superoxide production in response to sICAM-1. To obtain soluble ICAM-1, Chinese Hamster Ovarian (CHO) cells were transfected with human ICAM-1 (cDNA vector CD1.8), lysed and centrifuged at 150,000g for 1 hr; supernatant was passed over an ICAM-1 affinity gradient, eluted with 0.1 mM glycine x HCl, and concentrated using an Amicon Spin-X filter. PMNs were incubated for 1 hr with sICAM-1 at 37 degrees C. Quiescent and PMA-activated PMNs served as negative and positive controls respectively. Elastase activity was measured by the cleavage of methoxy-succinyl-alalyl-alalyl-prolyl-valyl-p-nitroanilide. Superoxide production was determined by superoxide dismutase inhibitive ferricytochrome C reduction over a 5-60 min incubation. PMN incubation with sICAM-1 provoked marked increase in elastase release 10.43 +/- 2.90 (10(-6) U/hr) compared to control 1.64 +/- 0.57, and was equivalent to PMA-activated PMN elastase release 11.60 +/- 1.50 (10(-6) U/hr). In contrast, sICAM-1 alone did not promote spontaneous PMN superoxide production beyond buffer treated PMNs (0.25 +/- 0.09 nmole/2.5 x 10(5) PMN/min). In sum, sICAM-1 stimulates PMN elastase release in vitro. Clinically, this may represent a mechanism by which sICAM-1 participates in the genesis of post-injury multiple organ failure.
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PMID:Soluble ICAM-1 (sICAM-1) provokes PMN elastase release. 866 Nov 63

Migration of inflammatory cells requires cell adhesion and their subsequent detachment from the extracellular matrix (ECM). Leukocyte activation and migration must be terminated to stop inflammation. Here, we report that IL-2 enhances human T cell adherence to laminin, collagen type IV, and fibronectin (FN). In contrast, neutrophil elastase, an enzyme activated during inflammation, degrades IL-2 to yield IL-2 fractions that inhibit IL-2-induced T cell adhesion to FN. The amino acid composition of two of these IL-2 fractions, which appear to block T cell adherence to FN, were analyzed, and three peptides were consequently synthesized. The three peptides IVL, RMLT, and EFLNRWIT, but not the corresponding inversely synthesized peptides, inhibited T cell adhesion to FN induced by a variety of activators: IL-2, IL-7, macrophage inflammatory protein (MIP)-1beta, and PMA, as well as anti-CD3 and anti-beta1 integrin-activating mAb. Moreover, these IL-2 peptides inhibited T cell chemotaxis via FN-coated membranes induced by IL-2 and MIP-1beta. Inhibition of T cell adherence and migration apparently involves abrogation of the rearrangement of the T cell actin cytoskeleton. Thus, the migrating immune cells, the cytokines, and the ECM can create a functional relationship in which both inflammation-inducing signals and inhibitory molecules of immune responses can coexist; the enzymatic products of IL-2 may serve as natural feedback inhibitors of inflammation.
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PMID:IL-2 induces T cell adherence to extracellular matrix: inhibition of adherence and migration by IL-2 peptides generated by leukocyte elastase. 972 45

Activated polymorphonuclear leukocytes (PMNs) release various types of proteases and express them on the cell surface. The proteases play important roles in PMN-mediated events. In the present study, flow cytometric analysis revealed that CD14 expression on human gingival fibroblasts (HGF) was markedly reduced by PMA-activated PMNs in a coculture system. We found that this reduction was caused by both secreted and cell surface proteases produced by activated PMNs. A protease responsible for the reduction was found to be human leukocyte elastase (HLE) secreted from the activated PMNs by use of various protease inhibitors, although HLE was only partially involved in CD14 reduction caused by cell-bound molecule(s) on fixed PMNs. Analysis with purified HLE revealed a time- and dose-dependent reduction of CD14 on HGF, and complete reduction was observed by 20 microg/ml HLE treatment for 30-60 min, but the other molecules such as CD26, CD59, CD157, and MHC class I on HGF were only slightly reduced. This reduction of CD14 resulted from direct proteolysis by HLE on the cell surface, because HLE reduced CD14 on fixed HGF and also on purified cell membranes. As a result of CD14 proteolysis, IL-8 production by HGF was suppressed when triggered by 10 ng/ml LPS, but not by IL-1alpha, indicating that HLE inhibited a CD14-dependent cell activation. These findings suggested that activated PMNs have a potential negative feedback mechanism for HGF function at the inflammatory site, particularly in periodontal tissues.
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PMID:Cleavage of CD14 on human gingival fibroblasts cocultured with activated neutrophils is mediated by human leukocyte elastase resulting in down-regulation of lipopolysaccharide-induced IL-8 production. 1106 40

In an infection, polymorphonuclear neutrophils (PMN) become activated and they produce oxidizing compounds and elastase in the extracellular medium. Alpha-1-proteinase inhibitor (alpha1PI), a protease inhibitor which is inactivated by oxidants, is the main endogenous inhibitor of elastase helping to limit excessive elastase activity. This study evaluates the ability of a plant extract, Cola nitida nuts, to protect alpha1PI from inactivation by oxidizing compounds as reactive oxygen species. On the one hand, we have evaluated the direct effect of cola nut extract on neutrophil elastase, and on the H(2)O(2) and myeloperoxidase (MPO)-H(2)O(2) system via cell-free systems. Results showed that cola nut extract scavenges H(2)O(2) and therefore protects alpha1PI from HOCl which is produced from the MPO-H(2)O(2) system. Experiments also showed that cola extract has the capacity to limit elastase activity. On the other hand, we have worked on cellular systems including isolated PMN with the aim to study the effect of cola extract on PMN metabolism. PMN were stimulated with PMA, calcium ionophore or fMLP. Each stimulant possesses its own stimulation pathway. According to the inhibitory concentration obtained at 50%, the results on cellular systems led to the conclusion that cola extract can reduce elastase liberation from PMN. It can then be concluded that cola nut extract can protect alpha1PI from inactivation, and has an effect both on elastase liberation and elastase activity. The cola nut extract effect is rather biased towards a reduction in elastase release, thus limiting the injurious effects caused by this enzyme.
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PMID:Effects of a caffeine-free Cola nitida nuts extract on elastase/alpha-1-proteinase inhibitor balance. 1452 46


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