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)

1. We investigated the relationship between circulating tumour necrosis factor-alpha concentrations, resting energy expenditure, cachexia and altered intermediary metabolism in patients with cystic fibrosis and chronic pulmonary infection. 2. Twenty adult patients with cystic fibrosis and chronic bronchial sepsis covering a spectrum of severity of lung disease (forced expiratory volume in 1 s 30-100% of predicted) were compared with 10 age matched, healthy, non-cystic fibrosis subjects. 3. Circulating tumour necrosis factor-alpha, C-reactive protein and neutrophil elastase-alpha 1-antiproteinase complex concentrations were determined simultaneously with glycerol, non-esterified fatty acids, catecholamines, anthropometric indices and resting energy expenditure (ventilated hood method). 4. Weight, body mass index and arm muscle mass were reduced in patients with cystic fibrosis compared with healthy control subjects (P < 0.01), whereas mean resting energy expenditure was increased [121 versus 101% predicted, mean difference 19.2% (95% confidence interval 11.0-27.4%), P < 0.001]. Circulating concentrations of glycerol (P < 0.01), non-esterified fatty acids (P < 0.01), adrenaline (P < 0.05), tumour necrosis factor-alpha, C-reactive protein and neutrophil elastase-alpha 1-antiproteinase complex (P < 0.01) were increased in patients compared with control subjects [tumour necrosis factor-alpha 96.9 versus 24.7 pg/ml, mean difference 72.2 pg/ml [95% confidence interval 27.7-116.7 pg/ml), P < 0.001]. Resting energy expenditure was significantly related to tumour necrosis factor-alpha levels and forced expiratory volume in 1 s. 5. In patients with cystic fibrosis and chronic pulmonary sepsis changes in resting energy expenditure, body composition and intermediary metabolism are consistent with the systemic effects of the host inflammatory response, which may be responsible for cachexia in adult patients. In particular these changes are consistent with the action of tumour necrosis factor-alpha, which was detected in the circulation during a period of apparent clinical stability.
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PMID:Tumour necrosis factor-alpha, resting energy expenditure and cachexia in cystic fibrosis. 828 44

The intensity of the host inflammatory response to pulmonary infection with Pseudomonas aeruginosa immediately prior to death was determined in six patients with cystic fibrosis (CF). Plasma concentrations of neutrophil elastase alpha 1-antiproteinase, tumour necrosis factor-alpha (TNF alpha) and serum C-reactive protein (CRP) were increased in the 7 days prior to death (P < 0.05) when compared with a period of clinical stability during the preceding 6 months. An increased inflammatory response was sustained for many weeks prior to death and was associated with poor symptom and lung function responses to apparently appropriate antibiotic treatment.
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PMID:The host inflammatory response prior to death in patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection. 829 Jul 44

Pseudomonas aeruginosa infection of the respiratory tract in patients with cystic fibrosis is a major determinant of morbidity and mortality. However, it has been postulated that the earliest phase of colonization is not associated with injury. To test this hypothesis we determined the association of the first recorded isolation of P. aeruginosa from the sputum on circulating markers of the inflammatory response in 6 patients with cystic fibrosis. At this time circulating C-reactive protein was increased in all 6 and neutrophil elastase alpha 1-antitrypsin complex (elastase-complex) was increased in 5 patients compared with healthy controls. This inflammatory response was associated with a reduction in the FEV1 and FVC of all patients [FEV1, 1.42 +/- 0.87 L (mean +/- SD) at first isolation vs. 2.08 +/- 0.74 L before isolation; P < 0.05; FVC, 1.94 +/- 0.93 L vs. 2.87 +/- 1.01 L, P < 0.05]. At a median interval of 10 months, 5 patients had raised titres of positive IgG antibody to P. aeruginosa, indicating significant exposure to this organism. At this time, lung function had returned to preinfection levels, whilst 3 patients showed continuing features of an inflammatory response, and the group mean value for elastase-complex was raised. Our findings demonstrate that at the time of first isolation of P. aeruginosa from the sputum of patients with cystic fibrosis, there is a concomitant systemic host response and an acute deterioration of pulmonary function.
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PMID:Host inflammatory responses to first isolation of Pseudomonas aeruginosa from sputum in cystic fibrosis. 832 87

Proteolytic enzymes derived from inflammatory cells or Pseudomonas aeruginosa may destroy lung matrix in cystic fibrosis (CF). Antielastases appear to be overwhelmed by large amounts of free neutrophil elastase (NE) activity in lower respiratory tract secretions, and proteolytic or oxidant stress is thought to account for such deficiency. The purpose of this study was to measure NE and myeloperoxidase activity in bronchoalveolar lavage fluid (BAL) from patients with CF and to correlate levels of these mediators with the degree of airflow obstruction and density of P. aeruginosa in BAL. We measured NE activity in BAL fluid from 14 patients with respiratory exacerbations of CF. NE complexed with alpha 1-antiprotease in peripheral blood was measured in 13 of the 14 patients subjected to BAL and in 21 additional patients who did not undergo BAL. Because oxidants generated by myeloperoxidase may contribute to increased elastase activity via inactivation of alpha 1-antiprotease, myeloperoxidase activity in BAL was also measured. We found that elastase activity in BAL correlated significantly with the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC ratio) (r = -0.80, p < 0.001) and FEV1 percent predicted (r = -0.62, p = 0.02). Myeloperoxidase activity also significantly correlated with airflow obstruction (FEV1/FVC ratio, r = -0.70, p = 0.005; FEV1 percent predicted, r = -0.52, p = 0.05). However, the degree of airflow obstruction, NE activity, myeloperoxidase activity, or total neutrophils in BAL did not correlate with the density of P. aeruginosa (CFU/ml) or total pathogen burden in BAL fluid.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neutrophil mediators, Pseudomonas, and pulmonary dysfunction in cystic fibrosis. 847 90

Human neutrophil elastase (NE) stimulates release of neutrophil chemotactic activity by a bronchial epithelial cell line and from nasal epithelial cells. In this article, we show that NE stimulates the production of neutrophil chemotactic activity by 2CFSMEo-cells, a transformed cystic fibrosis bronchial epithelial cell line. The production of chemotactic activity is dose- and time-dependent and can be blocked by preincubation of NE with alpha 1 antitrypsin (alpha1AT). Incubation of the NE-stimulated culture supernatant with neutralizing concentrations of rabbit anti-human interleukin 8 antibody completely neutralizes the chemotactic activity. Transfection of 2CFSMEo- cells with the eukaryotic expression vector pCMV4alpha1AT, complexed to cationic liposomes in a 1:3 wt/wt ratio, results in at least a 10-fold increase in measured human alpha1AT protein in culture supernatant. Detection of human alpha1AT mRNA by reverse transcriptase polymerase chain reaction in total RNA from transfected, but not untransfected cells, confirms successful gene transfer. Compared with untransfected cells, transfer of the human alpha1AT gene decreases chemotactic activity in culture supernatant and prevents cell detachment after NE exposure. Our data indicate that alpha1AT gene transfer is capable of blocking at least some of the biological effects of free elastase on cultured epithelial cells.
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PMID:Plasmid-liposome transfer of the alpha 1 antitrypsin gene to cystic fibrosis bronchial epithelial cells prevents elastase-induced cell detachment and cytokine release. 860 Sep 39

This study documents a difference between cystic fibrosis human (CF-HTG) and normal human (HTG) tracheal gland cells: the ability of histamine to induce an increase of intracellular free calcium concentration [Ca2+]i was abnormally reduced in CF-HTG cells. The magnitude of the [Ca2+]i peak rise in response to histamine is smaller in CF-HTG cells than in HTG cells, and the percentage of CF-HTG cells that increase [Ca2+]i is decreased compared with HTG cells. In contrast to histamine, the human neutrophil elastase (HNE) stimulation of both CF-HTG and HTG cells generated [Ca2+]i asynchronous oscillations and the magnitude of the peak [Ca2+]i response as well as the percentage of responding cells were similar for both groups. By videomicroscopy observations, the secretory response (exocytosis of secretion granules) of CF-HTG cells occurred with HNE, but not with histamine, thus suggesting that [Ca2+]i asynchronous oscillations may be linked to the exocytosis process in human tracheal gland cells.
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PMID:Intracellular free Ca2+ dynamic changes to histamine are reduced in cystic fibrosis human tracheal gland cells. 864 65

The interaction of alginate from Pseudomonas aeruginosa ATCC 39324 with human leukocyte elastase was studied by determining the effects of the polysaccharide on the amidolytic activity of the enzyme toward a range of synthetic peptide substrates of different length. The data support a model in which each elastase molecule interacts with a total of 19 uronic acid units on the alginate, primarily through electrostatic forces. Binding of alginate results in occlusion of distal subsites, most likely S4 and S5, of the enzyme's extended substrate-binding domain. As a result, alginate alone appears to be a weak inhibitor of the hydrolysis of long synthetic peptide substrates and [14C]elastin by elastase. Alginate also has effects on the antielastase function of naturally occurring protease inhibitors in the lung: It reduces the association rate of elastase and alpha 1-proteinase inhibitor, whereas it increases the association rate of elastase and secretory leukoprotease inhibitor. In the presence of 36 micrograms/ml alginate, the median concentration found in sputum from cystic fibrosis patients infected with mucoid strains of P. aeruginosa, the second-order rate constant for inhibition of elastase by secretory leukoprotease inhibitor is 2.6-fold greater than that for alpha 1-proteinase inhibitor. Alginate has only a minor effect on the antielastase activities of elafin and a recombinant form of the isolated C-terminal domain of secretory leukoprotease inhibitor. Based on these findings, alginate may be an important factor in determining the local distribution of leukocyte elastase and perturbing the overall protease-antiprotease balance in the infected lungs of cystic fibrosis patients.
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PMID:Alginate, the slime exopolysaccharide of Pseudomonas aeruginosa, binds human leukocyte elastase, retards inhibition by alpha 1-proteinase inhibitor, and accelerates inhibition by secretory leukoprotease inhibitor. 870 86

In cystic fibrosis (CF), neutrophil-dominated airway inflammation results in high levels of neutrophil elastase (NE). Some of these proteases are sequestered by the large amounts of deoxyribonucleic acid (DNA) present in purulent sputum. Recombinant human deoxyribonuclease (rhDNase), a new treatment in CF, depolymerizes DNA. Our concerns were that this might release proteases bound to DNA, which could be potentially harmful. The in vitro and in vivo effects of rhDNase on NE and interleukin-8 (IL-8) were evaluated. The acute effects of rhDNase were evaluated in CF patients during the first 6 days of treatment. Medium-term effects were evaluated in stable CF patients observed in rhDNase over 6 months. Sputum samples were collected at regular intervals and NE activity was measured by a fluorimetric assay and IL-8 with a radioimmunoassay. In vitro addition of rhDNase resulted in a twofold increase in protease activity and this was reflected in an acute transient rise on initiation of treatment with rhDNase. Medium-term treatment was associated with a decline in NE activity and IL-8. These in vivo results are encouraging, since the increase in protease activity was transient and the trend over 6 months was a reduction in both inflammatory markers.
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PMID:The effects of recombinant human DNase on neutrophil elastase activity and interleukin-8 levels in the sputum of patients with cystic fibrosis. 873 15

Lung inflammation in cystic fibrosis (CF) is associated with an increased release from activated neutrophils of oxidants and proteinases. Free radical generation is not efficiently neutralized, and the major anti-proteinase, alpha 1-proteinase inhibitor (alpha 1-PI) is thought to be oxidatively inactivated. We hypothesized that enhanced antioxidant protection could represent an additional long-term strategy to attentuate the host inflammatory response. The effect on plasma neutrophil elastase/alpha 1-PI (NE/alpha 1-PI) complex levels (as a marker of lung inflammation) and plasma malondialdehyde concentrations (as a marker of lipid peroxidation) of additional oral beta-carotene supplementation was studied in 33 CF patients who had already received long-term vitamin E supplementation. In the presence of a more than 10-fold increase in plasma beta-carotene concentrations (mean +/- SEM) (0.09 +/- 0.01 to 1.07 +/- 0.19 mumol/L; p < 0.0001), a small increase in plasma alpha-tocopherol concentrations (23.8 +/- 1.31 to 28.4 +/- 1.81 mumol/L; p = 0.02), and a more than 50% decrease in plasma malondialdehyde concentrations (1.00 +/- 0.07 to 0.46 +/- 0.03 mumol/L; p < 0.0001), plasma NE/alpha 1-PI complex levels decreased from 102.2 +/- 16.0 to 83.0 +/- 10.4 micrograms/L; (p = 0.02). Plasma retinol concentrations increased (1.05 +/- 0.06 to 1.23 +/- 0.07 mumol/L; p = 0.0001) due to conversion of beta-carotene to retinol, which could have contributed to the decrease in NE/alpha 1-PI complex levels. Based on these results, we speculate that efficient antioxidant supplementation could attenuate lung inflammation in CF.
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PMID:Neutrophil elastase/alpha 1-proteinase inhibitor complex levels decrease in plasma of cystic fibrosis patients during long-term oral beta-carotene supplementation. 879 58

Alpha-1-antitrypsin (a-1AT) is a natural inhibitor of the elastase that is released physiologically by neutrophils in the lung. As a result of the increased neutrophil degranulation secondary to chronic epithelial inflammation in cystic fibrosis patients with chronic infections by Pseudomonas aeruginosa, there are larger amounts of elastase in airway secretions. This results in the a-1AT concentration being insufficient to inhibit the destructive proteolytic degradation, culminating in a chronic epithelial burden and a worsening of the cystic fibrosis pulmonary disease. In this preliminary study, we have evaluated the results obtained from the sputum of 4 cystic fibrosis patients treated with a-1AT (Prolastina, Bayer) in aerosol. The levels of a-1AT, neutrophil elastase, antineutrophil elastase activity, IgG, albumin and clinical parameters were measured. The concentration of sputum a-1AT was increased when compared to the same patient after 8 days with treatment (we compared means with Student's t-test and p < 0.05 was considered significant). We did the same with the impairment of neutrophil elastase, although we found no significant results. Nevertheless, antineutrophil elastase activity increased (p < 0.05). These results encourage us to continue the same treatment for a longer period of time to prevent pulmonary disease in CF subjects.
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PMID:[An alpha 1-antitrypsin aerosol in the treatment of cystic fibrosis]. 883 May 66


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