UMLS:C0034067 - FACTA Search

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Query: UMLS:C0034067 (emphysema)
11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteinase-3 (PR-3) is a neutral serine proteinase present in the azurophil granules of human polymorphonuclear leukocytes. It degrades a variety of extracellular matrix proteins including elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters. It is identical to the target autoantigen (c-ANCA) associated with Wegener's granulomatosis and to myeloblastin, a serine proteinase first identified in HL-60 leukemia cells. In this study, the gene encoding PR-3 was cloned and sequenced. The gene spans approximately 6.5 kilobase pairs and consists of five exons and four introns. The genomic organization of PR-3 is similar to that of the other serine proteinases expressed in hemopoietic cells. Each residue of the catalytic triad of PR-3 is located on a separate exon, and the positions of the residues within the exons are similar to those in human leukocyte elastase and cathepsin G. The phase and placement of the introns in the PR-3 gene are also similar to those in human leukocyte elastase and cathepsin G. The 400-base pair (bp) 5'-flanking sequence of the PR-3 gene contains a TATA box at position 379. There is no CAAT box promoter element. The 3'-untranslated region is 200 bp, extending from a TGA stop codon to the site of polyadenylation 10 bp after the canonical AATAAA signal. Amplification of PR-3 from a human/hamster hybrid cell line localizes the gene to human chromosome 19. Evidence from Northern analysis suggests that PR-3 expression is primarily confined to the promyelocytic/myelocytic stage of bone marrow development.
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PMID:Structure, chromosomal assignment, and expression of the gene for proteinase-3. The Wegener's granulomatosis autoantigen. 140 Apr 30

A peptidyl carbamate, p-nitrophenyl N-(succinyl-L-alanyl-L-alanyl-L-prolyl-methyl)-N-isopropylcarbamate++ + (PCI) was tested for its ability to inhibit the elastolytic activity of human neutrophil elastase (HNE) and to prevent HNE-induced emphysema and secretory cell metaplasia in the hamster. In vitro, 50% of the elastolytic activity of 10 micrograms of HNE was inhibited by 0.9 micrograms of PCI, a molar ratio of PCI to HNE of 4.5. Bronchoalveolar lavage of hamsters receiving PCI intratracheally showed a rapid decrease in HNE inhibitory activity (4 min for 50% decrease), suggesting rapid clearance, binding, or inactivation of the PCI. Instillation of 300 micrograms of HNE combined with 100, 500, or 3,000 micrograms PCI, a 16-, 83-, and 503-fold molar excess of PCI, respectively (molar ratios of 17, 84, and 504), suppressed HNE-induced lung hemorrhage, but it did not moderate HNE-induced emphysema despite the large molar excess of inhibitor. When PCI was covalently bound to a linear hydrophilic polymer of alpha,beta-poly[N(2-hydroxyethyl)-D,L-aspartamide], producing a polymer-bound carbamate inhibitor (PPCI) of HNE, the time for a 50% decrease of PPCI functional activity from the hamster lung lavage was 421 min. Instillation of 100 micrograms of PPCI 1 h before instillation of 300 micrograms HNE resulted in significant amelioration of emphysema; 900 micrograms of PPCI was required to obtain amelioration of bronchial secretory cell metaplasia. The larger dose of PPCI also provided significant amelioration of emphysema when the interval between PPCI and HNE administration was 8 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Covalently linking a peptidyl carbamate elastase inhibitor to a hydrophilic polymer increases its effectiveness in preventing emphysema and secretory cell metaplasia in the hamster. 148 40

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

There is indirect evidence that unopposed human neutrophil elastase (HNE) is responsible for emphysema in patients with alpha 1-proteinase inhibitor (Pi) deficiency. To directly explore this possibility, we developed an assay for fibrinopeptide A alpha 1-21 and its degradation products and used it to measure HNE activity in 128 subjects of known Pi phenotype. The mean elastase-specific fibrinopeptide (ESF) level in 49 deficient PiZ individuals is significantly higher than that in 56 PiMZ heterozygotes (4.5 and 1.5 nM, respectively; P less than 0.01), while the mean ESF value in heterozygotes is significantly elevated over that in 23 normal PiM subjects (1.5 and 0.6 nM, respectively; P less than 0.01), consistent with increased HNE activity in those deficient in the major regulator of the enzyme. These results are not due to differences in smoking history because after correction for pack-years of smoking, ESF values in PiZ subjects are fourfold higher than those in PiMZ individuals (P = 0.005), while the ESF levels in heterozygotes are threefold higher than those in PiM subjects (P = 0.02). In addition, this analysis suggests that cigarette smoking and alpha 1-proteinase inhibitor deficiency have additive effects on ESF levels thereby explaining why PiZ and some PiMZ individuals are at especially high risk for the development of lung disease if they smoke. Finally, the observation that ESF levels in nonsmoking PiZ subjects are inversely related to the percent of predicted forced expiratory volume in 1 s (FEV 1%) provides direct support for the concept that unregulated HNE activity causes alveolar septal destruction in patients with alpha 1-proteinase inhibitor deficiency.
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PMID:Plasma levels of elastase-specific fibrinopeptides correlate with proteinase inhibitor phenotype. Evidence for increased elastase activity in subjects with homozygous and heterozygous deficiency of alpha 1-proteinase inhibitor. 154 71

A series of tripeptides possessing trifluoromethyl or aryl ketone residues at P1 were prepared and evaluated both in vitro and in vivo as potential inhibitors of human leukocyte elastase (HLE). Tripeptides containing non naturally occurring N-substituted glycine residues at the P2-position have been demonstrated to be potent in vitro inhibitors of HLE, with IC50 values in the submicromolar range. Sterically demanding substituents on the P2-nitrogen have no detrimental effect on in vitro potency. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing trifluoromethyl functionality. Deletion of the amino acid at the P3-subsite region affords inactive compounds. Valine is the preferred residue at the P1-position, whereas the corresponding glycine, alanine, alpha,alpha-dimethylglycine, or phenylalanine analogues are all inactive. The compounds described herein all confer a high degree of in vitro specificity when tested against representative cysteine, aspartyl, metallo, and other serine proteases. One of the most potent in vitro inhibitors is (3RS)-N-[4-[[[(4-chlorophenyl)sulfonyl]amino]carbonyl]phenyl] oxomethyl]-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]amide (20i; BI-RA-260) (IC50 = 0.084 microM). Compound 20i was also tested in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 20i, 5 min prior to HLE challenge, effectively inhibited hemorrhage in a dose-dependent manner with an ED50 of 4.8 micrograms. The inhibitor 20i, 20 micrograms administered it. 24, 48, and 72 h prior to HLE challenge, exhibits significant inhibition against hemorrhage at all time points (97%, 64% and 49%, respectively). In a 21-day chronic model of emphysema in hamsters, 200 micrograms of HLE administered it. caused an elastase-induced emphysema in the lungs which can be quantitated histologically utilizing image analysis. In this assay, 20i significantly inhibited pulmonary lesions associated with septal destruction and increased alveolar spaces, when dosed at 20 micrograms it. 5 min prior to challenge with HLE.
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PMID:Inhibition of human leukocyte elastase (HLE) by N-substituted peptidyl trifluoromethyl ketones. 154 92

A large series of variously substituted anthraquinones has been synthesized and assayed for inhibitory capacity against human leukocyte elastase (HLE) and cathepsin G (CatG), two serine proteinases implicated in diseases characterized by the abnormal degradation of connective tissue, such as pulmonary emphysema and rheumatoid arthritis. It was found that 2-alkyl-1,8-dihydroxyanthraquinone analogues are competitive inhibitors of HLE with IC50 values ranging from 4 to 10 microM, and also inhibit CatG with IC50 values ranging from 25 to 55 microM. Consequently, analogues containing the 2-alkyl-1-hydroxy-8-methoxyanthraquinone substitution pattern inhibit HLE to the same magnitude as for the compounds above, but show very little inhibition of CatG. Anthraquinones containing long, hydrophobic n-butyl carbonate moieties in the 1- and 8-positions in conjunction with a third hydrophobic substituent in the 2- or 3-position are highly selective for HLE, with Ki values in the range of 10(-7) M. All of the inhibitors described are completely reversible, with no evidence of acyl-enzyme formation detected.
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PMID:Novel anthraquinone inhibitors of human leukocyte elastase and cathepsin G. 157 86

The mammalian pulmonary blood-gas barrier is well known to be extremely thin. For example, in the human lung, half of the area of the barrier (the 'bulging' part) has a thickness of only 0.2-0.4 micron. We show here that the barrier is also immensely strong. This is an essential requirement because the capillary wall stresses during heavy exercise become very large (about 7 x 10(4) N/m2 = 70 kPa) when capillary pressure increases to 30 mmHg. Stress failure of the pulmonary capillary wall consistently occurs in experimental rabbit preparations at abnormally high pressures exceeding 40 mmHg and may be the cause of bleeding into the lung in galloping racehorses. The great strength of the thin side of the blood-gas barrier can be attributed to the extracellular matrix, especially the type IV collagen which is predominantly located in the very thin lamina densa. The alveolar wall is therefore particularly vulnerable to injurious agents which attack type IV collagen such as autoantibodies in Goodpasture's Syndrome and perhaps neutrophil elastase in emphysema. The combination of extreme thinness and great strength of the blood-gas barrier poses a unique design requirement.
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PMID:Strength of the pulmonary blood-gas barrier. 162 33

Repeated intratracheal instillations of E. coli lipopolysaccharide (LPS) in hamster lungs cause an influx of polymorphonuclear leukocytes (PMNs) into the alveolar walls, with concomitant development of severe emphysema. It has been suggested that elastase, released by these PMNs, is involved in the development of emphysema. This study demonstrates the release of elastase from recruited PMNs in cryostat sections of hamster lungs, after being treated once, twice, or thrice with LPS, intratracheally. Elastase activity was visualized using two elastase-specific synthetic substrates, to which a methoxynaphthylamine (MNA) group had been bound covalently. Liberated MNA, when made insoluble by coupling with 5-nitrosalicylaldehyde, fluoresces strongly. The authors observed that the interval between start of incubation and appearance of fluorescence and the intensity of fluorescence correlated with the number of LPS administrations. Fluorescence was observed to be located in or in close vicinity to alveolar walls. No fluorescence was observed in sections of untreated hamsters. Liberation of MNA from synthetic substrates was delayed strongly by the addition of a recombinant secretory leukocyte proteinase inhibitor or a substituted cephalosporin neutrophil elastase inhibitor. The authors conclude that LPS-mediated PMN influx into the lung is accompanied by release of elastase from these cells and speculate that this PMN-elastase is involved in the development of LPS-mediated emphysema.
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PMID:Detection of extracellular neutrophil elastase in hamster lungs after intratracheal instillation of E. coli lipopolysaccharide using a fluorogenic, elastase-specific, synthetic substrate. 163 60

Exposure to silica can induce fibrosis and/or emphysema. Various factors such as proteases, other hydrolases and oxidants may be involved in the destruction of lung parenchyma. On the other hand, antiproteases play an important role in the protection of lung parenchyma against the action of proteases. We have developed an animal model of silicosis in monkey Macacus cynomolgus and followed these factors by bronchoalveolar lavage (BAL). We have studied glycosidases activities, elastase-like activity, immunoreactive alpha 1-protease inhibitor (alpha 1PI), neutrophil elastase inhibitory capacity (NEIC) and myeloperoxidase. Bronchoalveolar cells in serial BAL were also studied. Six monkeys were exposed to quartz aerosols (100 mg.m-3) for 18 wks. They were followed until they developed X-ray changes, which occurred between 21-64 wks after the end of the dust exposure. Cellular "silicotic nodules" were observed in lung biopsies. A control animal underwent serial BAL. Changes were seen in the differential cell count. The release of superoxide anion by bronchoalveolar cells obtained during the experiment was increased. Separation on a gradient of Percoll showed the presence of young macrophages, which exhibited enhanced release of superoxide anion as compared to the totality of bronchoalveolar cells. The biochemical analysis of BAL fluids obtained during and after the period of dust exposure showed an increase in glycosidases, alpha 1PI and NEIC. Some free elastase-like activity was simultaneously detected in BAL fluids from exposed animals but not from the control. This elastase-like activity was very low compared to NEIC. The increase in enzymatic and antiprotease activities occurred at different points in time for each animal, suggesting large differences in individual responses to dust, but occurred before the chest X-ray abnormalities.
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PMID:An attempt to evaluate lung aggression in monkey silicosis: hydrolases, peroxidase and antiproteases activities in serial bronchoalveolar lavages. 164 17

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