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)

Plasma neutrophil elastase-alpha 1 antiproteinase complex, lactoferrin and C-reactive protein (CRP) were determined over a 15-month period in 26 patients with cystic fibrosis, of whom 21 were chronically infected with Pseudomonas aeruginosa. Median concentrations of both neutrophil products and CRP were greater in patients who were clinically stable than in healthy subjects without cystic fibrosis. CRP concentrations increased further at the onset of symptomatic exacerbations. Thirty-five courses of intravenous antibiotics and 22 courses of oral ciprofloxacin were reviewed and revealed similar improvements in clinical scores and lung function tests for both forms of treatment. Intravenous antibiotics reduced the plasma concentrations of both neutrophil products and CRP, while oral ciprofloxacin only significantly reduced the concentration of neutrophil elastase-alpha 1 antiproteinase complex. Plasma concentrations of inflammatory markers were significantly greater in exacerbations associated with fever and leukocytosis. Statistical modelling demonstrated negative within-patient relationships between lung function and both CRP and lactoferrin, and positive relationships between the three inflammatory markers. Neutrophil granule products and CRP reflect the pulmonary inflammatory state in cystic fibrosis and may be of value in monitoring treatment.
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PMID:Inflammatory markers in cystic fibrosis. 188 31

In cystic fibrosis (CF), extracellular lung matrix is progressively damaged, neutrophils invade the air spaces, and activated neutrophils may release large amounts of neutrophil elastase (NE). Although alpha 1-antiprotease (alpha 1-AP) binds and inactivates NE and is the major antielastase of the lower respiratory tract, antielastase defenses may be overwhelmed in CF, leading to progressive lung damage. To determine whether the ability of alpha 1-AP to neutralize NE is impaired in CF, we compared NE activity in bronchoalveolar lavage (BAL) fluid and human neutrophil elastase/alpha 1-antiprotease (NE/alpha 1-AP) complex in both BAL fluid and peripheral blood serum from patients with CF, normal volunteers, and patients with interstitial lung disease. We detected a considerable amount of NE activity in BAL fluid from all but one patient with CF but none in that from normal volunteers or from patients with interstitial lung disease. Although in interstitial lung disease there was a significant correlation between increased NE/alpha 1-AP complex in BAL or peripheral blood and the degree of neutrophil influx, NE/alpha 1-AP complex was disproportionately low in CF BAL compared with significantly elevated values in serum. These data suggest that in CF, alpha 1-AP-mediated defense against free NE in the lower respiratory tract is significantly impaired, and high levels of uncomplexed, enzymatically active, NE are present in CF respiratory secretions. To determine whether intravenously administered antipseudomonal antibiotic therapy for exacerbations of CF lung disease diminished the amount of free NE in respiratory secretions, we used BAL to investigate the effect of such therapy on neutrophils and NE in patients with CF colonized with pseudomonads.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human neutrophil elastase and elastase/alpha 1-antiprotease complex in cystic fibrosis. Comparison with interstitial lung disease and evaluation of the effect of intravenously administered antibiotic therapy. 189 98

To investigate the hypothesis that mast cell and neutrophil proteases stimulate airway gland secretion, we studied the effects of two mast cell proteases (tryptase and chymase) and two neutrophil enzymes (human neutrophil elastase and cathepsin G) on secretion of 35S-labeled macro-molecules from cultured bovine airway gland serous cells. Tryptase had no effect, but the other three enzymes stimulated secretion. Threshold concentrations of the enzymes (greater than or equal to 10(-10) M) were lower by two orders of magnitude than other agonists (e.g., histamine, prostaglandins, beta-adrenergic agonists). Only proteases induced maximal secretory response (greater than or equal to 80% depletion of 35S-labeled macromolecules), and these responses were greater than 10-fold larger than those of other agonists. The active catalytic sites of the enzymes are required for their secretory activities. These findings suggest a role for these enzymes in the pathogenesis of inflammatory airway diseases associated with hypersecretion, and they suggest that the use of selective site-directed inhibitors of these enzymes may provide a novel strategy for intervention in inflammatory diseases of the airways associated with hypersecretion (e.g., cystic fibrosis, chronic bronchitis).
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PMID:Role of mast cell and neutrophil proteases in airway secretion. 189 27

It has been suggested that proteinase enzymes could play an important role in the pathogenesis of chronic bronchial infections including bronchiectasis and cystic fibrosis (CF). Because Pseudomonas aeruginosa frequently colonizes the respiratory tract in bronchiectasis and CF, we examined the in vitro effects of human neutrophil elastase (HNE) and proteinase enzymes produced by P. aeruginosa (elastase: PE; alkaline proteinase: PAP) on the ciliary beat frequency (CBF) and ultrastructure of human nasal ciliated respiratory epithelium. HNE (500 micrograms/ml) progressively reduced CBF and caused marked epithelial disruption; lower concentrations (100 and 20 micrograms/ml) also caused epithelial disruption but without slowing CBF. The effects of HNE (500 micrograms/ml) were completely abolished by adding alpha 1-antitrypsin (5 mg/ml). There was no synergy between HNE and pyocyanin, a product of P. aeruginosa which slows CBF. PE in phosphate-buffered saline also caused epithelial disruption without slowing CBF; however, PE in medium containing divalent metal ions caused CBF slowing as well as epithelial disruption at 100 micrograms/ml. PAP (500 micrograms/ml) had almost no effect on ciliated epithelium. The effects of HNE and PE on nasal and bronchial epithelium obtained from the same patient were similar. Light and transmission electron microscopy revealed that HNE and PE were cytotoxic and caused detachment of epithelial cells from neighboring cells and the basement membrane. There was cytoplasmic blebbing of the cell surface and mitochondrial damage; however, no increase of abnormalities in the ultrastructure of cilia on living cells was seen. These results support the hypothesis that HNE and PE contribute to the delayed mucociliary clearance and epithelial damage that is observed in patients with chronic bronchial infection.
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PMID:Effects of human neutrophil elastase and Pseudomonas aeruginosa proteinases on human respiratory epithelium. 189 52

Plasma tumour necrosis factor alpha (alpha) concentration is increased in acute Gram negative sepsis, but the effect of chronic infection on plasma concentrations is unknown. A study was carried out in patients with cystic fibrosis to determine the effect of chronic lung infection with Pseudomonas aeruginosa on the plasma concentration of tumour necrosis factor and two other indicators of the inflammatory response, circulating C reactive protein and neutrophil elastase-alpha 1 antiproteinase complex (elastase complex). The concentration of immunoreactive tumour necrosis factor in plasma was greater than the upper 95% confidence interval for healthy subjects (2.6 U/ml) on 129 out of 189 occasions in 14 patients observed for about a year. The increase in tumour necrosis factor was associated with increased circulating C reactive protein and elastase complex. Twelve patients with an exacerbation of respiratory symptoms were studied before and after two weeks' treatment with anti-pseudomonal antibiotics. All three indicators of the inflammatory response fell after treatment, though median tumour necrosis factor (4.8 U/ml) and elastase complex (0.41 microgram/ml) concentrations remained above the upper limits for healthy subjects. During a period of clinical stability plasma tumour necrosis factor was increased in 10 of the 12 patients, elastase complex was increased in 10 of the 12, and C reactive protein was increased in seven. Increased plasma immunoreactive tumour necrosis factor was a feature of the near continuous inflammatory response to chronic P aeruginosa infection in cystic fibrosis and may be a factor contributing to the progressive lung destruction seen in this disease.
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PMID:Plasma tumour necrosis factor alpha in cystic fibrosis. 201 8

The chronic, progressively destructive bronchitis of patients with cystic fibrosis (CF) is characterized by an important imbalance between tissue destroying granulocyte proteases such as granulocyte elastase (GE) and its physiological inhibitors in bronchial secretions. Recent in vitro studies suggest, that proteases derived from bacteria or endogenous proteases may contribute to inactivation of physiological inhibitors of GE. Since only trypsin-unreactive alpha 1-proteinase inhibitor (alpha 1-PI) was detected in CF bronchial secretions, we attempted to identify the mechanism of inactivation of alpha 1-PI. We found a heat stable, serine protease-like enzymatic activity capable of degrading 125I-labelled alpha 1-PI extensively in 22 infected but not in one non-infected CF bronchial secretion. In infected secretions, only degraded alpha 1-PI, which did not migrate like oxidized alpha 1-PI in tandem-crossed immunoelectrophoresis, was detectable. We conclude, that free GE in excess as well as GE bound to bronchial mucosal inhibitor may partly account for the alpha 1-PI-cleaving activity, but that other yet unknown bacterial or host serine proteases also contribute to alpha 1-PI inactivation.
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PMID:Proteolytic inactivation of alpha 1-proteinase inhibitor in infected bronchial secretions from patients with cystic fibrosis. 202 37

To examine the pathogenetic role of neutrophil elastase in airway hypersecretion, we have studied the novel inhibitor of this enzyme, [4-(4-bromophenylsulfonylcarbamoyl)benzoyl-L-valyl-L-proline 1 (RS)-(1-trifluroacetyl-2-methylprolyl)amide] (ICI 200, 355). This compound was a potent (Ki = 0.6 +/- 0.22 nM) inhibitor of human neutrophil elastase and a much weaker inhibitor of other hydrolases. ICI 200,355 also inhibited the ongoing destruction of insoluble elastin by human neutrophil elastase. ICI 200,355 produced a concentration-dependent inhibition of the secretory response induced by human neutrophil elastase (10(-8) M), with an IC50 of 1.6 x 10(-8) M. ICI 200,355 had no effect on baseline secretion or on the secretory response to chymase, cathepsin G or Pseudomonas aeruginosa elastase. Thus, ICI 200,355 appears to be a useful tool for investigating the role of human neutrophil elastase in inflammatory disorders associated with hypersecretion, such as cystic fibrosis, chronic bronchitis, and asthma.
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PMID:Inhibition of human neutrophil elastase by ICI 200,355. 205 Jan 95

Neutrophil elastase has been implicated as a factor that impairs local host defenses in chronic Pseudomonas aeruginosa (Pa) lung infection in cystic fibrosis (CF). We recently showed that this enzyme cleaves the C3b receptor, CR1, from neutrophils (PMN) in the lungs of infected CF patients. The C3bi receptor on these cells, CR3, is resistant to elastase. We now show that purified neutrophil elastase markedly impairs complement-mediated PMN-Pa interactions including phagocytosis of opsonized Pa, stimulation by opsonized Pa of PMN superoxide production, and killing of opsonized Pa by PMN. When PMN and opsonized Pa were treated separately with elastase, additive levels of inhibition were observed in each of the above assays. The effects on the bacteria were due to cleavage of the bound C3bi from the surface of opsonized Pa by neutrophil elastase. C3bi was also cleaved by pseudomonas elastase, or bronchoalveolar lavage fluid from CF patients with chronic Pa lung infection. Inhibitors of neutrophil elastase eliminated C3bi cleavage by BAL fluid, while inhibitors of pseudomonas elastase had no effect. Blocking CR1 and CR3 on PMN with specific monoclonal antibodies reduced phagocytosis of opsonized Pa to an extent similar to that caused by elastase cleavage of CR1 on PMN and C3bi on Pa. We conclude that neutrophil elastase in the lungs of chronically infected CF patients cleaves C3bi from opsonized Pa as well as CR1 from PMN, creating an "opsonin-receptor mismatch" that severely impairs complement-mediated phagocytic host defenses against these bacteria.
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PMID:Neutrophil elastase cleaves C3bi on opsonized pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. 216 45

Pseudomonas aeruginosa elastase has recently been shown to inactivate bronchial inhibitor, the major leukoproteinase inhibitor of the bronchial tree. To test if this in vitro finding is relevant to pathology, we have measured the leukocyte elastase inhibitory capacity and the immunoreactive levels of bronchial inhibitor in the acidified and neutralized sputum specimens from 15 patients with cystic fibrosis, 11 of whom were infected by P. aeruginosa and 10 of whom exhibited free bacterial elastase activity. The percentage of functionally active bronchial inhibitor in these acid-treated sputum specimens (i.e., concentration of active inhibitor/concentration of immunoreactive inhibitor X 100) was found to be 125 +/- 17%. It was positively correlated with the free leukocyte elastase concentration (r = 0.77, p less than 0.001) but not with the free bacterial elastase concentration (r = 0.46, p greater than 0.05). Therefore, in an in vivo situation, P. aeruginosa elastase does not necessarily inactivate the bronchial inhibitor. Experiments using pure proteins show that the inactivation process does not take place when leukocyte and P. aeruginosa elastase are added simultaneously to the inhibitor. This suggests that the bronchial inhibitor reacts preferentially with leukocyte elastase and that in its complexed form it is shielded from the inactivating action of P. aeruginosa elastase. In addition, the inhibitor recovered from the acid-induced dissociation of the leukocyte elastase-inhibitor complexes, exhibits a substantially higher specific activity than does the native molecule. This explains why the average functional activity of the bronchial inhibitor is significantly higher than 100% in sputum samples from patients with cystic fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence that Pseudomonas aeruginosa elastase does not inactivate the bronchial inhibitor in the presence of leukocyte elastase. Studies with cystic fibrosis sputum and with pure proteins. 241 73

Patients with cystic fibrosis suffer from a chronic, progressively destructive bronchitis characterized by colonization of the airways by Pseudomonas aeruginosa. Cell wall lipopolysaccharides from P. aeruginosa may stimulate secretion of cytokines such as tumor necrosis factor alpha (TNF alpha) by monocytes/macrophages. We found elevated levels of TNF alpha (150 +/- 60 pg/ml), interleukin-1 alpha (144 +/- 205 pg/ml), and interleukin-1 beta (62 +/- 100 pg/ml) in plasma from 25 patients with cystic fibrosis. In patients with less advanced disease, elevated plasma levels of TNF alpha correlated with high levels of complexes between neutrophil elastase and alpha 1-proteinase inhibitor, suggesting that TNF alpha may be a mediator of neutrophil degranulation. TNF alpha, by its chemotactic effect on neutrophils, may also contribute to the massive influx of neutrophils into and around the bronchial tree. Our findings raise the questions whether in patients with cystic fibrosis TNF alpha acts as cachectin and whether it mediates the anorexia that often results in weight loss.
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PMID:Relation between tumor necrosis factor-alpha and granulocyte elastase-alpha 1-proteinase inhibitor complexes in the plasma of patients with cystic fibrosis. 222 2


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