Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Secretory leukocyte protease inhibitor (SLPI) and elafin are structurally similar, low-molecular-weight antiproteases produced in the lung. We have developed a simple method for distinguishing the antiprotease activities of SLPI and elafin in lung lavage fluid from those of alpha 1-antitrypsin (alpha 1-AT) that is based on the resistance of the low-molecular-weight antiproteases to inactivation by cetyltrimethylammonium bromide. In a study of 23 healthy, nonsmoking volunteers, we found that the low-molecular-weight antiproteases accounted for 22 +/- 2% (mean +/- SEM, n = 23) of the total neutrophil elastase-inhibitory capacity of human bronchoalveolar lavage fluid (BALF). Elafin activity was below the limit of detection. SLPI activity (as measured by inhibition of alpha-chymotrypsin) accounted for 72 +/- 4% (mean +/- SEM, n = 23) of the low-molecular-weight antiprotease activity in BALF. Measurements of SLPI in the lavage fluid samples by enzyme-linked immunosorbent assay (ELISA) agreed closely with values obtained by measuring the activity of this inhibitor. The activity of the low-molecular-weight antiproteases decreased significantly (p < 0.05), from 9.0 +/- 0.8 to 7.0 +/- 0.6 pmol of neutrophil elastase inhibited per mL (mean +/- SEM, n = 23), following acute ozone exposure.
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PMID:Contribution of secretory leukocyte proteinase inhibitor to the antiprotease defense system of the peripheral lung: effect of ozone-induced acute inflammation. 758

A growing body of evidence suggests that neutrophil-derived proteinases play a major role in lung tissue damage in cystic fibrosis (CF). Most previous studies have focused on serine proteinases such as neutrophil elastase, providing no information on the extent to which metalloproteinases participate in proteolytic processes in CF. To address this issue, we evaluated the contribution of one of the major neutrophil metalloproteinases, i.e., 95 kDa gelatinase (type IV collagenase), to the total gelatinolytic activity measured in sputum specimens from 27 patients with CF. Compared with asthmatic children (n = 9), CF patients had a 6.7 times greater level of total gelatinase activity in sputum revealed by zymography. The 95 kDa gelatinase was increased 3.7-fold in the CF subjects (2,441 +/- 411 [SEM] arbitrary units [AU] x 10(6) per ml of sputum versus 665 +/- 201 in asthmatics) and the 88-kDa active form 23.2-fold (2,272 +/- 372 AU x 10(6) per ml of sputum versus 98 +/- 43, respectively). Using radiolabeled 3H-gelatin as the substrate, we demonstrated uninhibited gelatinolytic activity in all CF patients; this activity was significantly correlated to disease severity as assessed by pulmonary function tests. Western blotting using anti-tissue inhibitor of metalloproteinase (anti-TIMP) and anti-95/88-kDa gelatinase antibodies demonstrated a more than 10-fold excess of 95/88 kDa gelatinase over TIMP. Bacterial proteinases from Pseudomonas aeruginosa were shown to contribute little to the gelatinolytic activity measured in sputum supernatants from patients with CF, although culture supernatants from various P. aeruginosa strains expressed gelatinolytic activity in vitro. Finally, lung damage, as assessed by increased type IV collagen degradation products in sputum, was significantly correlated to concentrations of active 88 kDa gelatinase. These data argue for a significant role of 95/88 kDa gelatinase in airway damage in CF.
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PMID:Imbalance between 95 kDa type IV collagenase and tissue inhibitor of metalloproteinases in sputum of patients with cystic fibrosis. 763 40

An ex vivo whole blood model of meningococcal bacteraemia was developed to examine the total bactericidal activity of blood. Using a single defined donor and strains belonging to serogroups A, B and C and an unencapsulated strain, we demonstrated that the bactericidal mechanisms operating in whole blood varied with anticoagulant, serogroup and bacterial growth conditions. The choice of anticoagulant had a major effect on the survival of the serogroup A strain with 94% (SEM 7.6) survival in citrated blood compared to 19.7% (SEM 19.6) survival in heparinised blood after 60 min incubation. The serogroup C strain showed enhanced survival when grown in liquid medium compared to growth on solid medium (73.5%, SEM 7.5, and 8.2%, SEM 3.1, respectively, in citrated blood after 60 min). The pattern of survival of serogroup B and the unencapsulated strain were largely unaffected by these variables. Comparison with cell free conditions allowed the contribution of cellular components in meningococcal killing to be determined. Secreted levels of tumour necrosis factor and neutrophil elastase secreted during whole blood assays did not correlate with bacterial growth or viability indicating a lack of relationship between killing and activation of phagocytes.
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PMID:Whole blood model of meningococcal bacteraemia--a method for exploring host-bacterial interactions. 764 46

Although activation of formed blood elements during cardiopulmonary bypass has been examined, its presumed procoagulant role has not been identified or quantified. We evaluated the effects of iloprost, an inhibitor of platelet and leukocyte function, on subclinical coagulation during simulated extracorporeal circulation. We determined that a heparin dose of 1 U/ml prevented clot formation in this model, but resulted in elevated plasma levels of fibrinopeptide A, the first cleavage product of fibrinogen. Human blood was recirculated with 1 U/ml heparin using a roller pump and pediatric reversed hollow fiber oxygenator (0.8 m2) for 2 hr at 37 degrees C. Iloprost (1 ng/ml, n = 5) reduced platelet adhesion, with platelet counts of 78 +/- 7% (mean +/- SEM) of baseline during 2 hr of simulated extracorporeal circulation, compared to 36 +/- 6% in control circuits (CONT: n = 6, P < 0.05). Plasma levels of platelet factor 4 and beta-thromboglobulin were also reduced by iloprost (486 +/- 116 ng/ml vs CONT, 2933 +/- 275 ng/ml, P < 0.05, and 938 +/- 274 ng/ml vs CONT, 5700 +/- 1109 ng/ml, P < 0.05, respectively). Circulating leukocyte counts were maintained in iloprost circuits (6.4 +/- 0.6 x 10(3)/mm3 vs CONT, 4.2 +/- 0.3 x 10(3)/mm3, P < 0.05), and neutrophil elastase levels rose to only 0.4 +/- 0.1 ng/ml in iloprost circuits, compared to 0.8 +/- 0.1 ng/ml in CONT (P < 0.05). Finally, iloprost treatment reduced fibrinopeptide A levels to 102 +/- 28 ng/ml (CONT, 793 +/- 337 ng/ml, P < 0.05) after 2 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Iloprost reduces procoagulant activity in the extracorporeal circuit. 769 41

In an attempt to further evaluate the role of neutrophil elastase (NE) in the development of emphysema, we examined the immunologic quantity of NE bound to alpha 1-protease inhibitor (PI), the NE inhibitory activity, and the molecular pattern of alpha 1-PI in unconcentrated bronchoalveolar lavage fluid (BALF) supernatant from 36 community-based older volunteers. They were classified into three groups: 10 current smokers with low attenuation areas (LAAs) on the lung computed tomography (CT) scans who were considered to have subclinical emphysema, 13 current smokers who had a comparable smoking history but no LAA, and 13 noncurrent smokers without LAA. The concentration of NE-alpha 1-PI complex was significantly increased in the subjects with subclinical emphysema when compared not only with the noncurrent smokers (0.52 +/- 0.10 versus 0.21 +/- 0.03 SEM micrograms/mg albumin, p < 0.01) but also with the LAA(-) current smokers (0.52 +/- 0.10 versus 0.23 +/- 0.07 SEM micrograms/mg albumin, p < 0.01). NE inhibitory activity measured by a spectrophotometric method using methoxysuccinyl-alanyl-alanyl-prolyl-valyl-paranitroanilide did not show any significant difference between the two groups of current smokers. There was no difference in the pattern or density of native and proteolysed alpha 1-PI bands between the three groups by Western blotting. We conclude that NE-alpha 1-PI complex in BALF is a factor that may differentiate smokers who are potentially developing emphysema from those who are not.
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PMID:Excessive neutrophil elastase in bronchoalveolar lavage fluid in subclinical emphysema. 852 Jul 85

Bronchiectasis is associated with sputum containing high levels of the proteolytic enzyme elastase, which is thought to be involved in the pathogenesis of the disease. Agents which inhibit neutrophil function and interfere with neutrophil elastase release may have a beneficial effect on the development and progression of such diseases. We have studied the effects of the nonsteroidal anti-inflammatory agent indomethacin on neutrophil function in nine patients with clinically stable bronchiectasis. All patients remained clinically stable during the study. We observed a significant reduction in peripheral neutrophil chemotaxis to 10 nmol.L-1 N-formyl-methionyl-leucyl-phenylalanine (FMLP) from a mean of 19.86 (SEM 1.35) to 8.46 (0.68) cells.field-1 after 4 weeks of therapy. There was also a significant reduction in fibronectin degradation both by resting and FMLP-stimulated neutrophils, from a mean of 1.90 (0.19) micrograms x 3 x 10(5) cells at the start of therapy to 0.87 (0.08) micrograms after 4 weeks, and from 3.17 (0.35) micrograms to 1.48 (0.05) micrograms, respectively. There was no effect on spontaneous or stimulated superoxide anion generation by neutrophils. Despite the marked changes in peripheral neutrophil function, no adverse effect was observed on viable bacterial load in the bronchial secretions. In addition, there was no difference in sputum albumin, elastase or myeloperoxidase levels, and only minor changes in the chemotactic activity of the sputum. These results suggest that nonsteroidal anti-inflammatory agents have a major effect on peripheral neutrophil function but do not appear to have an adverse effect on bacterial colonization of the airways.
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PMID:In vivo study of indomethacin in bronchiectasis: effect on neutrophil function and lung secretion. 857 72

This study was designed to determine the effects of inhaled human neutrophil elastase (HNE) on airway constriction and airway responsiveness, and to examine the protection by an intravenous recombinant half-length secretory leukoprotease inhibitor, r1/2SLPI in guinea pigs. Aerosol inhalation of HNE (250 microgram/ml, for 3 min) caused a transient but significant airway constriction, in which lung resistance (RL) increased from 194 +/- 18 (mean +/- SEM) to 461 +/- 42 cm H2O/L/s (p < 0.001). Thirty minutes after the end of HNE inhalation, airway responsiveness to intravenous 5-hydroxytryptamine (5-HT) was significantly increased. The provocative dose causing a 200% increase in RL (PD200) was significantly decreased from 10.0 +/- 1.2 to 6.5 +/- 0.8 microgram/kg (p < 0.001). Forty-five minutes after the end of HNE inhalation, total cells in bronchoalveolar lavage fluid (BALF) were significantly increased (p < 0.05). Histologic study of intrapulmonary bronchi demonstrated an acute inflammatory response characterized by damage to the epithelium, airway obstruction by mucus plugs, and recruitment of mononuclear and polymorphonuclear cells to the bronchial epithelium. r1/2SLPI (30 mg/kg) injected 5 min before the initiation of HNE inhalation significantly inhibited the airway constriction (p < 0.05), the airway hyperresponsiveness (p < 0.01), and the increase of cells in BALF (p < 0.05). The present data suggest that HNE plays a role in the induction of airway constriction and airway hyperresponsiveness in various inflammatory lung diseases with pulmonary neutrophil infiltration, such as chronic obstructive pulmonary diseases (COPD) and possibly bronchial asthma. r1/2SLPI may be useful as an antiprotease treatment.
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PMID:Aerosolized human neutrophil elastase induces airway constriction and hyperresponsiveness with protection by intravenous pretreatment with half-length secretory leukoprotease inhibitor. 861 73

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

Reperfusion injury has been implicated in the development of primary graft dysfunction (PGD) after liver transplantation. Neutrophil migration and activation may be involved in the pathogenesis of this injury. We studied neutrophil activation and its role in the etiology of PGD by measuring neutrophil elastase by radioimmunoassay, in serial blood samples of 19 patients before, during, and for 24 hr after transplantation. In a subgroup of patients, we also measured soluble thrombomodulin at the same time points as a marker of endothelial damage. The pretransplant elastase level was significantly raised (40.13+/-4.84 ng/ml, mean+/-SEM) compared with levels of healthy controls (18.7+/-5.6 ng/ml, P<0.05). A marked increase in elastase activity followed reperfusion, with a peak at 2 hr (370+/-50.5 ng/ml, P<0.01). Thereafter, there was a decline, but elastase remained elevated at 24 hr (186+/-60.94 ng/ml). The mean increase in neutrophil elastase after reperfusion correlated significantly with markers of graft function (P<0.05) and with the mean rise in soluble thrombomodulin (P=0.042), which increased from a pretransplant level of 81.2+/-11.32 to 186+/-50.4 ng/ml, 6 hr after reperfusion (P<0.05). The results of this study indicate that marked neutrophil activation and endothelial cell damage occurs after graft reperfusion during orthotopic liver transplantation, and the degree of activation correlates with markers of graft function, which may suggest a role in the etiology of PGD.
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PMID:Neutrophil elastase: a determinant of endothelial damage and reperfusion injury after liver transplantation? 887 84

Chest radiography in patients with cystic fibrosis (CF) frequently shows more severe changes in the upper lobes. We performed bronchoalveolar lavage (BAL) on 12 clinically stable, young adult patients with CF to determine whether inflammation varies significantly among geographically distinct areas of the lung. We found that absolute numbers of neutrophils were generally greater in BAL fluid from the upper lobe (25.7 +/- 7.9 x 10(5) neutrophils/ml [mean +/- SEM]) of the right lung than that obtained from the right lower lobe (6.8 +/- 2.8 x 10(5) neutrophils/ml; p < 0.01). The mean value of unopposed neutrophil elastase activity in upper-lobe BAL fluid (227 +/- 91 nmol peptide hydrolyzed/ml/min) was also significantly greater than that in lower-lobe BAL fluid (84 +/- 43 nmol/peptide hydrolyzed/ml/ min; p < 0.01), and similar differences were found for myeloperoxidase activity and DNA content. Neutrophil influx and unopposed neutrophil elastase for a given region correlated inversely with lung function or percentage of ideal body weight, and upper-versus lower-lobe differences were more pronounced in subjects with better preservation of lung function. Our findings suggest that regional variation in inflammation must be considered when utilizing BAL to study lower respiratory tract inflammation in CF or to monitor responses to therapeutic interventions that can potentially diminish lung inflammation. Our findings may also have implications for the study of the natural history of lung inflammation and infection in neonates, infants, and young children with CF.
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PMID:Regional variability of lung inflammation in cystic fibrosis. 937 72


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