Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:Mucus hypersecretion in bronchiectasis. The role of neutrophil proteases. 128 Sep 28

Cerebrospinal fluid (CSF) from 20 male patients with nonneurologic disease (age 64.5 +/- 2.8 SEM) was analyzed for the presence of the serpin alpha 1-antichymotrypsin (alpha 1-ACT). A chymotrypsin-specific chromogenic substrate (succinyl-Ala-Ala-Pro-Phe-p-nitroanilide) was used to examine the CSF samples. All CSF samples showed inhibitory activity ranging from 45 to 80% inhibition. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of the samples revealed the presence of a 68-kDa protein migrating identical to authentic human plasma alpha 1-ACT. Complex formation was performed with iodinated bovine chymotrypsin for several representative CSF samples having the highest chymotrypsin inhibitory activity. Comparison was made with complex formation performed with commercially available authentic human plasma alpha 1-ACT. These studies showed the formation of complexes at 37 degrees C, regardless of whether the sample was subsequently boiled or not. In the case of CSF, two complex bands, mass smaller than with plasma alpha 1-ACT, were formed at the lower temperature whereas a single higher Mr band was formed when the samples were boiled. To determine whether cleavage of the serpin occurred, these studies were repeated using human neutrophil cathepsin G as target protease. A complex of approximately 90 kDa was formed with human alpha 1-ACT under these same conditions. alpha 1-ACT has been detected in senile amyloid plaques in brains of Alzheimer's disease patients, the only plasma serine protease inhibitor localized to these structures. Another serpin, protease nexin I, is also found in these plaques, but this inhibitor does not circulate in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Characterization of the serpin, alpha 1-antichymotrypsin, in normal human cerebrospinal fluid. 172 48

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.
 ...
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.
 ...
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)
 ...
PMID:Mechanisms of extracellular matrix proteoglycan degradation by human neutrophils. 215 32

We examined the role of reactive oxygen metabolites in the degradation of human glomerular basement membrane (GBM) by stimulated human neutrophils. Neutrophils stimulated with phorbol myristate acetate (PMA) caused a significant degradation of GBM over 3 h resulting in 11.4 +/- 0.9% (SEM), n = 11 release of hydroxyproline compared with 0.3 +/- 0.09%, n = 11 release by unstimulated neutrophils. Superoxide dismutase, a scavenger of superoxide, did not inhibit the GBM degradation, whereas catalase, a scavenger of hydrogen peroxide, caused a marked inhibition (-60 +/- 7%, n = 4, P less than 0.001) of hydroxyproline release. Neither alpha-1 proteinase inhibitor, an inhibitor of elastase, nor soya bean trypsin inhibitor, an inhibitor of cathepsin G, caused any significant inhibition of GBM degradation. GBM degradation by cell-free supernatants obtained from stimulated neutrophils was markedly impaired in the presence of metal chelators EDTA (-72 +/- 7, n = 6, P less than 0.001) and 1,10,phenanthroline (-85 +/- 5%, n = 3, P less than 0.001). Considering these results, we postulated that reactive oxygen metabolites generated by the stimulated neutrophils activate a latent GBM degrading metalloproteinase(s). GBM degradation by supernatants obtained from incubations with catalase, azide, an inhibitor of myeloperoxidase, and methionine and taurine, scavengers of hypochlorous acid, was markedly reduced. Our data thus indicate that degradation of the GBM by PMA-stimulated neutrophils is due to activation of a latent metalloproteinase by hypochlorous acid or a similar oxidant generated by the myeloperoxidase-hydrogen peroxide-halide system.
 ...
PMID:Degradation of human glomerular basement membrane by stimulated neutrophils. Activation of a metalloproteinase(s) by reactive oxygen metabolites. 302 61

When polymorphonuclear neutrophil-platelet suspensions were stimulated by 0.5 microM N-formyl-Met-Leu-Phe in the presence of 40 U/mL of superoxide dismutase, a significant reduction of platelet secretion was observed (51.4 +/- 6.3% vs 62.4 +/- 4.6% for control; mean +/- SEM; N = 6; P < 0.01). This was due to the superoxide anion scavenging property of superoxide dismutase since neutrophil degranulation, cathepsin G and elastase enzymatic activities (the two main mediators of this cell-to-cell interaction) and platelet reactivity were not affected. Involvement of superoxide anions was confirmed using leukotriene B4, a neutrophil agonist which induces degranulation with minimal superoxide anion production. Indeed, serotonin release induced by this agonist was unchanged whether superoxide dismutase was added or not.
 ...
PMID:Modulation by superoxide anions of neutrophil-mediated platelet activation. 818 47

Plasma endothelin (ET) is increased in association with myocardial infarction. The aim of the present study was to get insight into the mechanisms behind this ischemia-induced increase in plasma ET. Since granulocytes increase ET production in vitro, we examined to what extent inhibition of granulocyte-derived proteases could reduce the increase in plasma ET observed in association with myocardial ischemia. We infused Eglin C, a selective inhibitor of the granulocyte-derived proteases elastase, cathepsin G, and chymotrypsin, in pigs subjected to 90 min left anterior descending coronary artery occlusion followed by 210 min reperfusion (n = 7). Arterial plasma ET increased in an untreated control group (n = 7) from 5.0 +/- 0.6 (mean +/- SEM) fmol . ml-1 before myocardial ischemia to 6.1 +/- 0.6 fmol . ml. at 90 min ischemia and reached a maximum of 6.8 +/- 0.9 fmol . ml-1 at 90 min reperfusion. The increase in plasma ET associated with myocardial ischemia was almost completely abolished in the Eglin C treated group (p = 0.005). Plasma ET in the Eglin C treated animals was 4.7 +/- 0.4, 4.7 +/- 0.4, and 4.6 +/- 0.4 fmol . ml-1 before myocardial ischemia, at 90 min ischemia, and at 90 min reperfusion, respectively. Our study suggests a role for granulocyte-derived proteases in the increase in plasma ET associated with myocardial ischemia. We have shown that the increase in plasma ET associated with myocardial ischemia was reduced by inhibition of granulocyte-derived proteases using the selective protease inhibitor Eglin C.
 ...
PMID:Inhibition of granulocyte-derived proteases reduces the increase in plasma endothelin associated with myocardial ischemia in the pig. 887 78