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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the role of neutrophil proteases in the pathogenesis of mucus hypersecretion in bronchiectasis, we collected sputum samples from seven patients with bronchiectasis and measured their secretagogue activity by examining secretion of radiolabeled macromolecules by bovine airway submucosal gland cells incubated with sputum supernatants. There was marked secretagogue activity in bronchiectasis sputum, reaching a maximum of 1,963 +/- 292% (mean +/- SEM) above baseline at 1:15 dilution. Addition of ICI 200,355 (10(-5) M), a selective human neutrophil elastase inhibitor, decreased the secretory response markedly (72.53 +/- 5.89% reduction). The combination of aprotinin, an inhibitor of cathepsin G, and ICI 200,355 caused significantly more reduction in the secretory response than ICI 200,355 alone (89.12 +/- 3.8 versus 72.53 +/- 5.89% reduction, p < 0.05). We conclude that bronchiectasis sputum causes a large secretory response from tracheal submucosal glands due mostly to neutrophil proteases.
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PMID:Mucus hypersecretion in bronchiectasis. The role of neutrophil proteases. 128 Sep 28

It has been suggested that leucocytes play an important role in the pathogenesis of complicated pancreatitis. Indeed, increased plasma concentrations of neutrophil elastase as a marker of neutrophil activation could be detected in patients with a severe course of the disease. Recently, interleukin-8 (IL-8) has been described as a novel neutrophil activating peptide. To determine the role of IL-8 in acute pancreatitis we measured its serum concentrations by a specific enzyme-linked immunosorbent assay in 10 patients with acute pancreatitis daily during the first week of hospitalization. IL-8 levels were compared with plasma concentrations of neutrophil elastase and the clinical course of the disease. Three of the patients had uncomplicated pancreatitis, while seven showed various extrapancreatic complications. Patients with complicated pancreatitis had statistically significant (P less than 0.05) higher mean values of IL-8 (121 +/- 41 pg/ml-1 vs. 13 +/- 6 pg ml-1, mean +/- SEM) and neutrophil elastase (547 +/- 35 ng ml-1 vs. 250 +/- 20 ng ml-1) than patients with uncomplicated disease. There was a positive correlation (r = 0.52, P less than 0.0001) between IL-8 and neutrophil elastase in the lower concentration range of IL-8 (less than 100 pg ml-1). At IL-8 levels greater than 100 pg ml-1 neutrophil elastase was always greatly elevated; however, under these conditions the relationship between IL-8 and elastase was no longer linear. No measurable IL-8 concentrations were found when plasma elastase was less than 200 ng ml-1. During follow-up, initially elevated IL-8 concentrations decreased in correlation with clinical improvement.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interleukin-8 and neutrophil activation in acute pancreatitis. 158 45

The accuracy of methods employed to measure the elastin-specific crosslinks, desmosine (DES) and isodesmosine (IDES), has been called into question because contaminants in the urine may cause elevated values. In the present study urine samples were spiked with a known amount of [14C]DES and refluxed in 6 N HCl. Sephadex G-15 chromatography of the hydrolyzed urine employed to remove contaminants. DES and IDES were quantified by high performance liquid chromatography (HPLC) as well as by amino acid analysis. The amount of isotope recovered was used to determine losses during the overall procedure and the isotope dilution to calculate the amounts of endogenous DES and IDES originally present in the urine. Because similar values were obtained by both methods, the more rapid HPLC method was used for all succeeding analyses. In one experiment, the DES amounts in urine collected from hamsters for 3 days after intratracheal treatment with human neutrophil elastase (300 micrograms) or porcine pancreatic elastase (300 micrograms) were 0.212 +/- 0.012 (mean +/- SEM, two measurements on a single pool) and 0.816 +/- 0.005 (two measurements) microgram per hamster per day, respectively. Urine from control hamsters had a mean value of 0.074 +/- 0.008 (eight measurements) microgram per hamster per day. The HNE- and PPE-treated hamsters had mean linear intercept values of 119 and 159% of control values, respectively, giving a positive correlation between increase in airspace size and elevation of urinary DES.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Measurement of urinary desmosine by isotope dilution and high performance liquid chromatography. Correlation between elastase-induced air-space enlargement in the hamster and elevation of urinary desmosine. 185 49

We examined the roles of enzymes from mast cells and from neutrophils in stimulating airway submucosal gland secretion. To avoid effects on surface epithelial cells and goblet cells, we studied a line of cultured bovine tracheal gland serous cells. We discovered that mast cell chymase and neutrophil elastase are the most potent secretagogues of airway submucosal glands described. Mast cell chymase markedly stimulated serous cell secretion in a concentration-dependent fashion with a threshold of 10(-10) M, whereas tryptase had no effect. The response to 10(-8) M chymase (1,530 +/- 80% over baseline; mean +/- SEM) was approximately 10-fold higher than that evoked by other agonists such as histamine and isoproterenol. Both neutrophil proteases also stimulated secretion in a concentration-dependent fashion with a threshold of greater than 10(-10) M. Elastase was more potent than cathepsin G, causing a maximal secretory response of 1,810 +/- 60% over baseline at 10(-8) M. Secretion by the 3 proteases was noncytotoxic and required catalytically active enzymes. These findings suggest a potential role for neutrophil and mast cell proteases in the pathogenesis of increased and abnormal submucosal gland secretions in diseases associated with inflammation of the airways.
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PMID:Role of enzymes from inflammatory cells on airway submucosal gland secretion. 192 74

The granule proteases of human neutrophils are thought to be responsible for the connective tissue destruction associated with certain inflammatory diseases. Using a model system for the degradation of a macromolecular connective tissue substrate, purified neutrophil elastase and cathepsin G were both individually able to degrade cartilage matrix proteoglycan and this degradation was blocked by the appropriate specific inhibitors. Neutrophil granule lysate also produced cartilage matrix degradation but little inhibition of degradation occurred when either elastase or cathepsin G inhibitor was used alone. However, a combination of elastase and cathepsin G inhibitors each at 100 microM or each at 10 microM blocked cartilage matrix degradation by 89% +/- 1 and 65% +/- 9 (mean +/- SEM, n = 3), respectively. The magnitude of the cartilage degradation mediated by neutrophil lysate, and its sensitivity to specific inhibitors, was reproduced using purified elastase and cathepsin G at the concentrations at which they are present in neutrophil lysate. Human neutrophils stimulated with opsonized zymosan degraded cartilage matrix in a dose-dependent manner in the presence of serum antiproteases. Supernatants from stimulated neutrophils cultured in the presence of serum did not degrade cartilage matrix, indicating that neutrophil mediated degradation in the presence of serum was confined to the protected subjacent region between the inflammatory cell and the substratum. A combination of elastase and cathepsin G inhibitors each at 500 microM or each at 100 microM blocked subjacent cartilage matrix degradation by stimulated human neutrophils by 91% +/- 3 and 54% +/- 8 (mean +/- SEM, n = 5), respectively, whereas either the elastase or cathepsin G inhibitor alone was much less effective. These studies demonstrate that neutrophil-mediated cartilage matrix degradation is produced primarily by elastase and cathepsin G. Furthermore, these results support the hypothesis that inflammatory neutrophils form zones of close contact with substratum that exclude serum antiproteases and that this subjacent degradation of cartilage matrix by stimulated neutrophils can be blocked by a combination of synthetic elastase and cathepsin G inhibitors.
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PMID:Degradation of cartilage matrix proteoglycan by human neutrophils involves both elastase and cathepsin G. 203 61

Alterations in proteoglycans (PG) located in the pulmonary interstitium may influence extracellular matrix (ECM) structure and assembly during the development of diseases in which increased numbers of neutrophils enter the lung. To evaluate potential mechanisms of PG degradation, neutrophils or purified neutrophil products were incubated with ECM that had been produced by cultured neonatal rat vascular smooth muscle cells (SMC) or lung fibroblasts (LF) and metabolically labeled with 35SO4. Matrix PG solubilization was expressed as a percentage of the spontaneous [35SO4]PG solubilization that occurred in the presence of buffer alone. Solubilization by unstimulated neutrophils was 105.8 +/- 3.1% (mean +/- SEM, n = 6) and 101.7 +/- 3.05 (n = 8) using ECM that had been produced by LF and SMC, respectively. Solubilization by neutrophils that had been stimulated with formyl-methionine-leucine-phenylalanine (FMLP) in the presence of cytochalasin B (CB) was 189.7 +/- 5.8% and 298.2 +/- 26.2% using ECM produced by LF and SMC, respectively. Matrix that had been produced by SMC was used to evaluate which neutrophil products were responsible for the degradation of PG. Addition of a specific inhibitor of neutrophil elastase (NE) to stimulated polymorphonuclear leukocytes (PMN) reduced PG solubilization by 88.3 +/- 4.8% (n = 8). Addition of an inhibitor of cathepsin G (CG), as well, did not further reduce PG degradation. Purified CG and myeloperoxidase solubilized significantly more PG, 125.8 +/- 6.2% (n = 9) and 143.2 +/- 8.1% (n = 6), respectively (P less than 0.01), than was solubilized spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of extracellular matrix proteoglycan degradation by human neutrophils. 215 32

Neutrophils contribute to the healing of and scar formation in myocardium after ischemic injury. Many recent studies indicate that neutrophils may be involved in the genesis and propagation of myocardial ischemia. To characterize neutrophil function in ischemic heart disease, neutrophil chemotaxis, leukotriene B4 (LTB4) generation, and elastase release in plasma were measured in 20 patients with stable angina, 17 patients with unstable angina or acute myocardial infarction (AMI), and 20 age-matched control subjects. Neutrophils from patients with stable angina exhibited markedly increased chemotactic activity and LTB4 generation as compared with the age-matched control subjects (p less than 0.01). Neutrophils of nine of 17 patients with unstable angina or AMI clumped spontaneously ex vivo and exhibited marked pseudopod formation and granule extrusion on electron microscopy. Subsequent chemotactic activity and LTB4 generation by neutrophils from these patients was less than in patients with stable angina, suggesting previous in vivo activation. Plasma levels of peptide B beta, a product of fibrin degradation by human neutrophil elastase, were approximately 15-fold higher (p less than 0.001) in patients with unstable angina or AMI (588 +/- 171 pmol/l, mean +/- SEM) compared with those in patients with stable angina (37 +/- 25 pmol/l) or control subjects (40 +/- 22 pmol/l), confirming intense in vivo neutrophil activation. Our study shows enhanced neutrophil function in patients with ischemic heart disease. The increased neutrophil chemotactic activity and LTB4 generation may be markers of stable angina pectoris. Intense neutrophil activation in unstable angina or AMI, as manifested by morphologic changes in neutrophils and elastase release, may relate to ongoing in vivo cellular activation.
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PMID:Neutrophil function in ischemic heart disease. 253 59

To explore the time course and the mechanism of development of bronchial secretory cell metaplasia (SCM) induced by human neutrophil elastase (HNE), anesthetized hamsters were injected intratracheally with 300 micrograms highly purified HNE in 0.5 ml saline solution; saline-injected and untreated animals served as controls. At 3, 8, 16, and 21 days after treatment, animals were killed and their lungs fixed by vascular perfusion. Samples from the hilar region of the left lung, containing the main axial airway and its proximal branches, were embedded in Epon-Araldite, and 1 micron sections were stained with methylene blue. Epithelial cells with a luminal border were categorized into three cell types and expressed as a percent of total cells counted (mean 1900 per animal); cells containing at least three mucin granules were classified as secretory, ciliated cells displayed cilia or basal bodies, and cells with none of these characteristics were classified as indeterminate. Percentages of the three cell types in saline-treated animals, at all time points, were comparable to those in the untreated controls. With HNE treatment the secretory cell percentages were higher at 16 days (mean +/- SEM, 36.4% +/- 3.2%) and at 21 days (35.7% +/- 2.9%) than in the untreated animals (18.2% +/- 1.8%, P less than 0.05). The percentage of the indeterminate cells in the HNE group was decreased at days 8, 16, and 21 (7.2% +/- 1.6%, 5.0% +/- 1.4%, and 8.2% +/- 2.5%, respectively) compared with that in the untreated group (21.7% +/- 2.5%, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Quantitative study of secretory cell metaplasia induced by human neutrophil elastase in the large bronchi of hamsters. 384 55

The authors wished to determine whether secretory cell metaplasia (SCM) induced in the bronchi of hamsters by human neutrophil elastase (HNE) was enzymatically mediated. We also wished to determine whether SCM could be induced by a proteolytic enzyme devoid of elastolytic activity. Accordingly, groups of weight-matched hamsters were given a single intratracheal instillation of 0.5 ml of saline solution containing one of the following: 300 micrograms of HNE purified from blood neutrophils, n = 14; 300 micrograms of HNE inactivated with Suc-Ala-Ala-Pro-Val chloromethyl ketone (CMK), n = 10; 500 micrograms of porcine pancreatic trypsin treated with CMK to eliminate residual active elastase, n = 10; 500 micrograms of trypsin inactivated by tosyl lysine chloromethyl ketone, n = 10; 2 micrograms CMK, n = 10; and saline alone, n = 10. Seven untreated animals served as additional controls. Twenty-one days post treatment, 5-6 micron paraffin-embedded sections, from the left lung hilar region, stained by Alcian blue and periodic acid-Schiff reaction were graded on a five-point scale for determination of the secretory cell index, which reflects SCM. Both elastase and trypsin produced severe SCM: mean +/- SEM secretory cell indices were 2.96 +/- 0.11 and 2.72 +/- 0.19, respectively, compared with values of 0.90 +/- 0.35 for the untreated group and 0.93 +/- 0.46 for the saline group (p less than .05). The secretory cell indices of the groups treated with inactivated elastase or trypsin were comparable to those of the saline-treated and untreated groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Proteolytic activity of human neutrophil elastase and porcine pancreatic trypsin causes bronchial secretory cell metaplasia in hamsters. 390 65

We determined L-selectin expression and elastase levels in neutrophils obtained from patients receiving granulocyte colony-stimulating factor (G-CSF) either alone (given for increasing peripheral progenitor cells for harvest) or in combination with high-dose chemotherapy with autologous bone transplantation support (BMT). Administration of G-CSF alone for 3-5 days produced a decrease in L-selectin expression in neutrophils (25 +/- 4 versus 7 +/- 1, mean +/- SEM; mean channel fluorescence, n = 10) with no effect on neutrophil elastase activity (3.1 +/- 0.3 versus 3.4 +/- 0.6; micrograms elastase/million cells; n = 9). In contrast, in patients in the BMT group the L-selectin expression was increased (26 +/- 2 versus 38 +/- 3; n = 20) and elastase activity was markedly decreased (2.9 +/- 0.2 versus 1.4 +/- 0.2, n = 12) compared with values before BMT. The changes in L-selectin expression correlated with the ability of neutrophils to adhere to human umbilical vein endothelial cells. The decrease in the neutrophil elastase activity was not associated with an increase in the plasma elastase/alpha 1-antitrypsin complex levels, indicating that the decrease in the neutrophil elastase activity is not caused by activation of neutrophils and release of the enzyme into the plasma. Administration of G-CSF alone did not cause a decrease in the neutrophil elastase activity but increased plasma elastase/alpha 1-antitrypsin complex levels. There was no change in CR3 expression on neutrophils under any of these conditions. These observations suggest that the changes seen in neutrophils during BMT are influenced by various factors associated with BMT other than the administered cytokine alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in L-selectin expression and elastase activity in neutrophils from patients receiving granulocyte colony-stimulating factor alone or in conjunction with high-dose chemotherapy with autologous bone marrow transplantation. 753 70


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