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)

The human protease inhibitor genes alpha 1 antitrypsin (alpha 1-PI) and alpha 1-antichymotrypsin (alpha 1-ACT) are acute-phase proteins which are induced in response to inflammation. These inhibitors function to limit the activity of serine proteases in vivo. alpha 1-PI acts as an inhibitor of neutrophil elastase to protect the elastin fibers of the lung. Genetic deficiencies of alpha 1-PI result in development of chronic pulmonary emphysema. The physiologic role of alpha 1-ACT has not been clearly defined, but it also appears to function in the maintenance of protease-protease inhibitor equilibrium in the lung. Nucleic acid and protein sequence homologies detected between alpha 1-PI and alpha 1-ACT suggested an evolutionary relationship. Gene mapping experiments were performed to determine if these protease inhibitor genes reside at the same chromosomal locus in man. In situ hybridization data demonstrate that both alpha 1-PI and alpha 1-ACT map to the same region, q31-q32.3, on chromosome 14.
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PMID:Regional location of alpha 1-antichymotrypsin and alpha 1-antitrypsin genes on human chromosome 14. 348 24

The concentration of granulocyte elastase-alpha-1-protease inhibitor (E-AT) complex in plasma is enhanced in inflammatory processes, e.g. in septicaemia and rheumatoid arthritis, being an expression of granulocyte activation during inflammatory response. In the present study we measured E-AT and fibronectin in the plasma of 46 patients with various connective-tissue diseases in relation to the course of the disease. In about 50% of the cases, E-AT was found to be elevated to 2-3 times the normal concentrations, in relation to increasing serum content of C-reactive protein. In follow-ups over 2 years, an elevation of E-AT and a decreasing fibronectin in plasma was found in patients with activated disease. Without relation to other parameters used in connective-tissue diseases, fibronectin was found to be diminished below the normal range in 7 patients with systemic lupus erythematodes and 1 patient with overlapping syndrome. Our results indicate that the concentration of E-AT and fibronectin in plasma may be helpful parameters for judging the activity of connective-tissue diseases.
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PMID:Concentration of fibronectin and granulocyte elastase in plasma of patients with systemic connective-tissue diseases. 349 2

Nitrogen dioxide is one form of an oxidizing free radical that is sufficiently stable to exist in relatively high concentrations in ambient air and cigarette smoke. We examined the effect of NO2 exposure on the functional activity against pancreatic elastase of alpha-1-protease inhibitor (alpha 1PI) in bronchoalveolar lavage (BAL) fluid of nonsmoking subjects. Ten nonsmokers (mean age, 25 +/- 2 SE yr) were exposed to NO2 (3 or 4 ppm) for 3 h with intermittent exercise. Seven nonsmokers (mean age, 24 +/- 2 SE yr) underwent a similar protocol but were exposed to NO2-free air and served as control subjects. Bronchoalveolar lavage was performed 3.5 to 4 h after the end of exposure. Exposure to NO2 caused a 45% decrease in functional activity of alpha 1PI in BAL. There was no significant difference in immunoreactive alpha 1PI between the groups whether expressed as micrograms per 100 ml of recovered fluid or per milligram of albumin. This inactivation of alpha 1PI was not associated with any neutrophil migration into the air spaces of the lung. The "elastaselike" activity of BAL using synthetic elastinlike chromophore substrate succinyl-trialanine-nitroanilide showed no significant difference between the NO2-exposed group (221 +/- 39 SE ng/dl BAL) and the control group (196 +/- 61 SE ng/dl BAL). Assay for human leukocyte elastase (HLE) in concentrated BAL using the synthetic substrate Methoxysuc-Ala3-Pro-Val-aminomethylcoumarin did not detect any HLE activity in the BAL. These results showed that nonsmoking subjects exposed to relatively low concentrations of NO2 for a short time have a significant inactivation of alpha 1PI in the lower respiratory tract fluid than did nonsmoking control subjects.
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PMID:Acute effect of nitrogen dioxide exposure on the functional activity of alpha-1-protease inhibitor in bronchoalveolar lavage fluid of normal subjects. 349 15

Alpha-1-protease inhibitor (alpha-1-PI) is the major regulator of extracellular leukocyte elastase activity and can be rendered impotent against elastase by oxidation of a critical methionine, residue 358. Alpha-1-PI was isolated from rat plasma by affinity chromatography on Sepharose-bound anhydrochymotrypsin, DEAE-cellulose anion-exchange, and Sephadex G-150 gel filtration. The product was radiolabeled using non-oxidative conditions with Bolton-Hunter reagent, and an aliquot subsequently oxidized with N-chlorosuccinimide. Turnover studies in rats indicated that both native and oxidized alpha-1-PI had half-lives of 170 min. Using partially purified human neutrophil methionine sulfoxide-peptide reductase (Met(O)PR), it was demonstrated that oxidized product could be converted back "in vitro" to an active inhibitor of elastase. To assess whether oxidized alpha-1-PI underwent reduction "in vivo," methionine-oxidized rat inhibitor was injected into the rats, aliquots of plasma samples were withdrawan and passed through a Sepharose-bound anhydrochymotrypsin affinity resin, and bound functional alpha-1-PI was eluted with 0.1 M chymostatin. Radioactive counting of bound and unbound fractions indicated that reduction does not occur in vivo and suggested that, at least under homeostatic conditions, the Met(O)PR is confined to intracellular sites where it does not have access to the circulating protein.
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PMID:Studies on the turnover of methionine oxidized alpha-1-protease inhibitor in rats. 349 3

The current working hypothesis concerning the pathogenesis of human pulmonary emphysema proposes that neutrophils migrate through the alveolar interstitium and degranulate, releasing proteolytic enzymes into the interstitium. These enzymes, in particular elastase, can bind to and degrade interstitial elastin. This report describes an immunohistochemical, ultrastructural technique that utilizes polyclonal antibodies to localize neutrophil elastase in human lungs. Using both the immunoperoxidase and the immunogold methods on thin, embedded sections of surgically resected human emphysematous lung tissue, elastase was localized in neutrophils in the lung interstitium and extracellularly in association with interstitial elastic fibers in human lungs that showed local emphysema of varying severity. Quantitative morphometric data were obtained from the lungs of eight patients undergoing lobectomy for removal of pulmonary carcinomas. Patients had preoperative forced expiratory volume (FEV1)% levels ranging from 55 to 77. There was a correlation between a quantitative measure of the local distribution of neutrophil elastase in contact with alveolar interstitial elastin and the local presence of emphysematous change as determined by mean linear intercept of the various histologic sections. These data support the validity of the "protease-protease inhibitor balance hypothesis" as an explanation of the pathogenesis of human pulmonary emphysema.
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PMID:Immunolocalization of elastase in human emphysematous lungs. 352 10

The fibrils of all systemic forms of amyloid (primary, AL; secondary, AA; and hereditary, AF) that had been isolated by the water extraction procedure demonstrated elastolytic enzyme activity when examined in a specific assay using tritiated elastin. The source of this fibril-bound enzyme activity was consistent with human neutrophil elastase (HNE), since it was readily extracted by high salt solutions and inhibited by an elastase-specific chloromethyl ketone inhibitor, human alpha-1-protease inhibitor or by an antibody specific for HNE. The presence of an elastase on the amyloid fibril may suggest physiologic mechanisms of amyloid precursor protein degradation.
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PMID:The association of an elastase with amyloid fibrils. 363 18

The peptide boronic acid, MeOSuc-Ala-Ala-Pro-boroVal-pinacol (AAPbV), is an effective inhibitor of both pancreatic and leukocyte elastase. Initial work showed that AAPbV diminishes the effect of emphysema induced by pancreatic elastase. This initial work has been expanded to show that AAPbV provides a high degree of protection against elastase-induced increases in lung volume and mean linear intercept when given intratracheally at 200 mg/kg either 15 min before, simultaneous with, or 15 min after instilling elastase. Intraperitoneal administration, although less effective, is dose dependent and dependent on the time of treatment. We conclude that a reversible protease inhibitor can be used to prevent aberrant proteolysis in vivo.
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PMID:Effects of dosage and timing of administration of a peptide boronic acid inhibitor on lung mechanics and morphometrics in elastase-induced emphysema in hamsters. 363 80

Addition of glucose oxidase (GO) increased H2O2 concentrations and decreased antielastolytic activities of beta-D-glucose containing perfusates of isolated rat lungs. Pretreatment with GO also caused acute edematous injury (increased lung weight gains, increased recovery of Ficoll in lung lavages, and increased pulmonary arterial pressures) in isolated lungs perfused with purified human neutrophil elastase (NE). Acute edematous injury in isolated lungs pretreated with GO and then NE exceeded levels found in lungs following addition of GO or NE alone or NE before GO. Simultaneous addition of catalase (an H2O2 scavenger) or methoxy-succinyl-L-alanyl-L-alanyl-prolyl-L-valine-chloromethyl ketone (an NE inhibitor, but not aminotriazole-inactivated catalase, N-tosyl-L-phenyl-alanine chloromethyl ketone (a chymotrypsin inhibitor) or N-alpha-p-tosyl-L-lysine chloromethyl ketone (a trypsin inhibitor), prevented acute edematous injury in isolated lungs perfused with both GO and NE. This observation indicated that injury was dependent on both H2O2 and NE, especially since the relative inactivating specificities of the inhibitors for H2O2 or NE, respectively, were confirmed under similar conditions in vitro. The synergistic nature of the interaction between H2O2 and NE-mediated injury was further clarified when GO- and NE-induced lung injury was prevented by addition of an oxidant-resistant NE inhibitor (Eglin-C), but not an oxidant-sensitive NE inhibitor (human alpha 1-protease inhibitor, alpha 1PI). Moreover, treatment with H2O2 also decreased the ability of alpha 1PI but not Eglin-C to decrease NE activity in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:O2 metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs. 364 11

Alpha-1-antitrypsin (alpha 1AT) is the major protease inhibitor in human serum, and plays an important role protecting tissues from potentially harmful enzymes released during inflammatory reactions. Proteolytic enzymes such as leukocyte elastase are usually released and inactivated locally at the site of inflammation, so there has been much recent interest in measuring local alpha 1AT concentrations in biologic fluids. In this study, we developed a modified double antibody sandwich enzyme-linked immunosorbent assay (ELISA) and used it to measure alpha 1AT concentrations in several biologic fluids. The assay was sensitive to as little as 20 ng/ml of alpha 1AT. Serum concentrations measured by the ELISA correlated well with levels determined by radial immunodiffusion (RID) and the ELISA was far more sensitive than RID. In synovial fluid, higher concentrations determined by the ELISA compared with RID probably reflect interference of diffusion of alpha 1AT in the RID gel by hyaluronic acid and protease-inhibitor complexes. Synovial fluid did not interfere with the detection of added alpha 1AT by ELISA, but it did reduce the amount detected by RID by about 30% in 2 fluids. In saliva, alpha 1AT concentrations of less than 1 microgram/ml were easily quantified. Bronchoalveolar lavage fluids have been extensively studied because of the important role of alpha 1AT in pulmonary inflammatory processes. We found concentrations of 1-3 micrograms/ml in most samples with our assay. These levels were comparable to those previously reported with assays that required up to 50-fold concentration of the fluid. Neither saliva nor bronchoalveolar fluid significantly interfered with detection by ELISA of added alpha 1AT. This modified double antibody sandwich ELISA may have broad applications for studies of the role of alpha 1AT in health and disease.
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PMID:A modified double antibody sandwich enzyme-linked immunosorbent assay for measurement of alpha-1-antitrypsin in biologic fluids. 387 16

The effect of leukocyte-derived oxidants on the elastase-inhibitory capacity of alpha 1-protease inhibitor was examined in an in vitro system using cells and purified proteins from human sources. The exposure of alpha 1-protease inhibitor to the myeloperoxidase-hydrogen peroxide-halide system resulted in a nearly complete loss of its ability to bind and inactivate purified human neutrophil elastase. A similar loss of binding to and inactivation of human neutrophil elastase was observed on exposure of alpha 1-protease inhibitor to human neutrophils in the presence of a halide and the neutrophil-activating agent, phorbol myristate acetate. This loss of elastase binding activity was abrogated by the addition of azide or catalase but not superoxide dismutase or heated catalase. The data suggest oxidative inactivation of alpha 1-protease inhibitor by secreted myeloperoxidase and hydrogen peroxide. Thus, the reported effects of leukocyte oxidants, especially the myeloperoxidase system, on alpha 1-protease inhibitor have been confirmed using the most pathophysiologically relevant protease, human neutrophil elastase, as the test enzyme. The role of the neutrophil in the pathogenesis of emphysema may, therefore, include the secretion of both elastase and oxidants that impair antielastase defenses.
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PMID:Human neutrophil elastase does not bind to alpha 1-protease inhibitor that has been exposed to activated human neutrophils. 631 Oct 62


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