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)

Antineutrophil cytoplasmic antibodies (ANCA) have been described as sensitive and specific markers for active Wegener's granulomatosis (WG). ANCA in WG produce a characteristic cytoplasmic staining pattern of neutrophils (c-ANCA) and are directed against proteinase 3 (Pr3), a serine protease from the azurophilic granules. c-ANCA, more or less equivalent to anti-Pr3, occur in more than 90% of patients with extended WG, in 75% of patients with limited WG without renal involvement, and in some 40% to 50% of patients with vasculitic overlap syndromes suggestive of WG such as microscopic polyarteritis. The presence of c-ANCA is highly specific for those diseases (greater than 98%). Changes of levels of c-ANCA precede disease activity and may be used as guidelines for treatment. Antibodies producing a perinuclear staining of ethanol-fixed neutrophils (p-ANCA) occur in a wide range of diseases. They are directed against different cytoplasmic constituents of neutrophils. Among those, antibodies to myeloperoxidase are found in patients with idiopathic crescentic glomerulonephritis, the Churg-Strauss syndrome, polyarteritis nodosa with visceral involvement, and vasculitic overlap syndromes. Their specificity for this group of necrotizing vasculitides is high (94% to 99%), although they may occur in patients with hydralazine-induced glomerulonephritis, anti-glomerular basement membrane disease, and possibly in some patients with idiopathic systemic lupus erythematosus. Antibodies to leukocyte elastase are incidentally found in patients with vasculitic disorders, whereas lactoferrin antibodies are detected in patients with primary sclerosing cholangitis with or without ulcerative colitis and in rheumatoid arthritis. Their diagnostic significance awaits further studies. p-ANCA of undefined specificity may distinguish ulcerative colitis (sensitivity of 75%) from Crohn's disease (sensitivity of 20%). p-ANCA also occur in autoimmune liver diseases: in 75% of patients with chronic active hepatitis, in 60% to 85% of those with primary sclerosing cholangitis, and in about 30% of patients with primary biliary cirrhosis. Finally, p-ANCA are detected in chronic arthritides and in some 5% of healthy controls. Assessment of their diagnostic value has to await further characterization of the antigens involved, allowing the development of antigen-specific assays.
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PMID:Antineutrophil cytoplasmic antibodies: a still-growing class of autoantibodies in inflammatory disorders. 782 11

Recent studies have suggested that leukocyte elastase activity (EA) in tissue exudates is an indicator of inflammatory disease. We assayed gingival fluid (GF) EA with a selective peptide substrate and compared it to GF flow rate with regard to its ability to detect differences in the clinical status of existing inflammatory periodontal disease in 56 human subjects. Compared to healthy sites (Gingival Index = 0, 1 to 3 mm) and mild gingivitis sites (GI = 1, 2 to 5 mm), mean GF EA was significantly (P < 0.05) higher at periodontitis sites with deep probing depths (GI = 2, 6 to 9 mm depth), but not at periodontitis sites with intermediate probing depths (GI = 2, 4 to 5 mm). When expressed as specific EA (i.e., normalized to GF protein content), mean EA was also significantly higher at deep periodontitis sites compared to healthy sites and mild gingivitis sites. In addition, specific EA was significantly higher at periodontitis sites with intermediate probing depths than at healthy sites. As predicted by previous studies, these significant increases in specific EA were associated with significant increases in mean GF flow rate. In contrast to specific EA, however, mean GF flow rate was significantly higher at gingivitis sites than at healthy sites. A strong correlation was observed between GF flow rate and specific EA (rs = 0.737, P = 0.0006). Thus, GF flow rate and GF EA appear to be related indicators of inflammation, but GF flow rate may be more sensitive to early inflammatory changes leading to mild gingivitis.
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PMID:The relationship of gingival fluid leukocyte elastase activity to gingival fluid flow rate. 147 74

N-(2-chloromethylphenyl) 3,3-difluoroazetidin-2-one (AA 231-1), a specific suicide-type inhibitor of elastase which is known to suppress the lysis of chromogenic oligopeptides, elastin and elastic fibers, is effective also in preventing the degradation of the vascular basement membrane. The degradation of porcine glomerular basement membrane by purified human leukocyte elastase (HLE), was reduced in proportion of inhibitor dose (8.3 microM for 50% inhibition). It is noteworthy that there was no reduction of the inhibitory effect when the addition of AA 231-1 was delayed for 1 h after the addition of the enzyme to the substrate. In the guinea pig, reduction of the dermal microhemorrhage due to HLE was related to the dose of inhibitor and to its preincubation time with HLE before intradermal injection. The inflammatory hemorrhage associated with the Arthus skin reaction was moderately depressed by AA 231-1 in situ. A part of the vascular permeability induced by HLE also responded to the inhibitor. In spite of the tissular diffusion and the time-dependence parameters which restrict responsiveness of elastase to AA 231-1 in vivo this biochemical compound should be helpful in the study and possibly the cure of vascular injury related to elastase.
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PMID:Protection of vascular basement membrane and microcirculation from elastase-induced damage with a fluorinated beta-lactam derivative. 147 89

A series of tripeptides which contain alpha,alpha-difluorostatone residues at P1-P1' and span the S3-S1' subsites have been shown to be potent inhibitors of human leukocyte elastase (HLE). The tripeptides described contain the nonproteinogenic achiral residue N-(2,3-dihydro-1H-inden-2-yl)glycine at the P2-position. This redidue has previously been shown in the case of HLE to be a good bioisosteric replacement for L-proline. Of the peptides prepared, those which contain the alpha,alpha-difluoromethylene keton derivative of L-valine (difluorostatone) are the preferred residue at the P1-primary specificity position. Substitution at P1 by the corresponding alpha,alpha-difluoromethylene ketones of L-leucine and L-phenylalanine gives inactive compounds. Of the tripeptides described the most potent in vitro compound is ethyl N-[N-CBZ-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycyl]- 4(S)-amino-2,2-difluoro-3-oxo-5-methylhexanoate (17B) (IC50 = 0.635 microM). It is presumed that the inhibitor 17b interacts with the S3-S1' binding regions of HLE. Additionally extended binding inhibitors were prepared which interact with the S3-S3' binding subsites of HLE. In order to effect interaction with the S1'-S3' subsites of HLE, the leaving group side of cleaved peptides, spacers based upon Gly-Gly, and those linked via the N epsilon of L-lysine were utilized. One of the most potent extended compounds (P3-P3') in vitro is methyl N6-[4(S)-[[N-[N-CBZ-L-valyl-N- (2,3-dihydro-1H-inden-2-yl)glycyl]amino]-2,2-difluoro-3-oxo-5- methylhexanoyl]-2(S)-(acetylamino)-6-aminohexanoate (24b) (IC50 = 0.057 microM). The described in vitro active inhibitors were also evaluated in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 22c, 5 min prior to HLE challenge (10 micrograms, it.) effectively inhibited hemorrhage (94.6%) in a dose-dependent manner. The described alpha,alpha-difluoromethylene ketone inhibitors are assumed to act as transition-state analogs. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing effect of the alpha,alpha-difluoromethylene functionality.
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PMID:Inhibition of human leukocyte elastase by N-substituted peptides containing alpha,alpha-difluorostatone residues at P1. 147 81

Procollagenase M(r) 85,000 (SDS-PAGE) was purified from buffy coat to homogeneity and represents a stable single polypeptide chain forming the entire proenzyme. The procollagenase can be activated by various proteinases, e.g. trypsin, chymotrypsin, cathepsin G, kallikrein and stromelysin and by different mercurial compounds. Proteolytic conversion of the latent enzyme to the active form by chymotrypsin is accompanied by a molecular weight reduction to an apparent M(r) 64,000. This active enzyme lacks the first 79 N-terminal residues. Activation by trypsin leads to a latent intermediate of apparent M(r) 70,000, lacking 48 N-terminal residues. The active enzyme is therefore generated upon prolonged incubation with trypsin by further cleavage of 22 N-terminal residues. Another latent intermediate form with apparent M(r) 69,000 is generated from the proenzyme upon incubation with leukocyte elastase by N-terminal cleavage of 53 or 64 residues, respectively. However, latent collagenase cannot be activated by plasmin. Activation by different mercurial compounds finally results in the formation of active collagenase with apparent M(r) 64,000. In contrast to the proenzyme, active collagenase can autolyse to give active M(r) 57,000 and 45,000 intermediates and two M(r) 28,000 fragments. Purification of latent leukocyte gelatinase yields three final products with apparent M(r) 98,000, 125,000 and 220,000 (SDS-PAGE; non reduced). Upon reduction, only the M(r) 98,000 form can be detected. The latent gelatinase can be activated in a similar manner as collagenase. Proteolytic activation by trypsin leads after N-terminal cleavage to an active gelatinase with sequence homology to leukocyte collagenase.
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PMID:Latent collagenase and gelatinase from human neutrophils and their activation. 148 34

In order to unravel the serine proteinase inhibition mechanism by cyclic thiolic compounds, the X-ray crystal structure of bovine alpha-chymotrypsin inhibited by 3-[2-(2-thiophencarboxythio)]-propanoyl-4-thioazolidin carboxylic acid (YS3025) has been studied by means of difference Fourier techniques and refined at 2.8 A resolution (R-factor = 0.174). The thiophencarbonyl moiety of YS3025 is covalently linked, in the acyl-enzyme complex, to Ser195 OG atom of bovine alpha-chymotrypsin, and located at the entrance of the proteinase primary specificity subsite (S1). The present data confirm previous hypotheses raised on the inhibition mechanism of serine proteinases, based on solution studies of human leukocyte elastase in the presence of the YS3025 parent compound 2-[3-thiophencarboxythio]-N-[dihydro-2(3H)- thiophenone-3-il]-propionamide (MR889).
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PMID:Serine proteinase inhibition by the cyclic thiolic compound YS3025: a crystallographic study. 148 82

The leukocyte elastase inhibitory activity of AA 231-1, a suicide substrate, was investigated in the presence of elastin, a natural substrate of elastase, and its efficiency to reduce the degradation of basement membrane and haemorrhage induced by elastase was analysed. Elastin only moderately decreased the inhibitory efficiency of AA 231-1. The digestion by human leukocyte elastase (HLE) of glomerular basement membrane prepared from pig kidney was prevented in the presence of AA 231-1. Intradermal microvascular haemorrhage was also significantly inhibited by AA 231-1. These results suggest that AA 231-1 may be a valuable candidate as an anti-inflammatory agent.
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PMID:Prevention of some types of inflammatory damage using AA 231-1, a fluorinated beta-lactam. 149 Apr 31

The metabolism of big endothelin 1 (bET) and endothelin 1 (ET-1) by subcellular fractions from human polymorphonuclear leukocytes (PMNs) was investigated by bioassay and reversed-phase high-performance liquid chromatography. More than 80% of endothelin-converting activity was recovered from the cytosolic fraction, which in addition to ET-1 generated other peptides from bET. The processing of bET to all its metabolites including ET-1 was prevented by the serine protease inhibitor 3,4-dichloroisocoumarin (DCI; 50 microM) or the elastase inhibitor ONO-5046 (100 microM) but not by phenylmethylsulfonyl fluoride (PMSF; 143 microM), another serine protease inhibitor. Paradoxically, human leukocyte elastase, despite generating a bET fragmentation pattern similar to that of PMN cytosol, produced very little ET-1. However, subsequent treatment of the elastase-derived metabolites of bET with PMN cytosol in the presence of ONO-5046 dramatically increased the amount of ET-1 formed. The generation of ET-1 following this intervention was inhibited by DCI. The PMN membrane preparation degraded ET-1 to a major metabolite, similar to that produced from ET-1 by elastase, and several minor products, paralleled by a loss of its smooth muscle contracting activity. The degradation of ET-1 by PMN microsomes was prevented by DCI, PMSF, or ONO-5046. Our results suggest that an elastase-initiated serine protease cascade is responsible for the sequential conversion of bET to ET-1 by the PMN cytosol. Elastase also partly accounts for the ET-metabolizing properties of PMN microsomes.
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PMID:The two-step conversion of big endothelin 1 to endothelin 1 and degradation of endothelin 1 by subcellular fractions from human polymorphonuclear leukocytes. 149 79

The role of the antiproteases alpha 1-proteinase inhibitor (alpha 1PI) and mucus proteinase inhibitor (MPI) in human lung emphysema was investigated by measuring their amount and functional activity against trypsin, leukocyte elastase, and pancreatic elastase in the bronchoalveolar lavage fluid (BALF). In addition, leukocyte elastase was quantified in the lavage samples by measuring the concentration of the elastase-alpha 1PI-complex. The study population consisted of 38 patients (5 nonsmokers, 8 former smokers, 25 smokers) with acquired emphysema (i.e., emphysema which is not caused by alpha 1PI deficiency), and 44 individuals (16 nonsmokers, 8 former smokers, 20 smokers) without emphysema. No differences were found between patients with and without emphysema in the activities of alpha 1PI and MPI, or in the concentration of alpha 1PI. The concentration of MPI was significantly higher in the BALF of patients with emphysema than in that of patients without emphysema (p = 0.025). A significantly higher concentration of elastase-alpha 1PI complex was found in patients with emphysema than in those without emphysema (p = 0.041). This finding could reflect the higher proteinase burden to which patients with emphysema are exposed. The increase of MPI in lavage fluid of patients with emphysema seems to be the result of increased production in emphysematous lungs. However, it remains unclear why patients develop emphysema while showing an increased content of MPI.
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PMID:Alpha 1-proteinase inhibitor and mucus proteinase inhibitor in human lung emphysema. 152 Oct 41

We describe a method to measure human leukocyte elastase (HLE) inhibitory capacity and compared it with porcine pancreatic elastase (PPE) inhibitory capacity and with a turbidimetric method using a specific antibody to alpha-1 antitrypsin (AAT), all performed on a Cobas Bio centrifugal analyser. This assay used methoxysuccinyl-dialanine-proline-valine-p-nitroanilide as substrate in the presence of 0.01% Brij 35, an HLE enzyme activator. Samples containing commonly used anti-coagulants and serum could be used in the assay, except for those containing heparin which strongly inhibited HLE. This assay was used to determine the functional AAT concentrations in plasma from a number of normal volunteers and patient groups, and was compared to the immuno-turbidimetric AAT assay. No difference in the proportion of functional to immuno-turbidimetric AAT was noted between any of the groups studied except for the adult respiratory distress syndrome (ARDS), where this percentage was reduced (p less than 0.05). An increase in both immuno-turbidimetric and functional AAT was seen for children (both p less than 0.01), in emphysema (p less than 0.05 and p less than 0.01 respectively) and ARDS (both p less than 0.05) when compared to adult non-smokers. This assay was also used to determine the HLE inhibitory capacity of serum and bronchoalveolar lavage (BAL) fluid from normal volunteer smokers (n = 4) and non-smokers (n = 4), and in the serum and BAL fluid from patients with ARDS (n = 5). Serum AAT was 94% functional in non-smokers (91% with PPE functional assay) and 96% in smokers (97% with PPE assay).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A rapid procedure for the measurement of elastase inhibitory function of plasma and bronchoalveolar lavage fluid. 152 82


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