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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several lines of evidence indicate that neutrophil elastase and oxidants secreted by phagocytic inflammatory cells play key roles in the development of centrilobular emphysema. A recent report suggests that ethanol consumption may have a protective role against this disease in smokers. The aim of this study was to examine the effect of ethanol consumption on neutrophil elastase activity and superoxide production of peripheral blood neutrophils. These activities were measured in neutrophils from 52 male intoxicated patients and compared to activities in neutrophils from 20 male volunteers. Neutrophils from intoxicated patients contained 31% less elastase activity than that found in controls, 0.99 +/- 0.27 versus 1.44 +/- 0.23 micrograms/10(6) neutrophils (p less than 0.0001) and produced 25 to 27% less superoxide than controls in response to phorbol 12-myristate-13-acetate, 0.90 +/- 0.17 versus 1.2 +/- 0.21 nmol/min/10(6) PMN (p less than 0.0001) or N-formylmethionylleucylphenylalanine, 0.64 +/- 0.19 versus 0.88 +/- 0.24 (p less than 0.001). In follow-up studies of 10 patients admitted for acute alcoholism, elastase activity and superoxide production remained low for 2 to 4 days. After 6 to 10 days, elastase activity and superoxide production were significantly greater than they were at Day 0 and approached normal levels. Neutrophils isolated from blood samples of healthy abstaining donors, which had been exposed to ethanol or to plasma from inebriated patients for 16 to 20 h, showed no loss of elastase activity or superoxide production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neutrophil elastase activity and superoxide production are diminished in neutrophils of alcoholics. 216 Feb 12

Cigarette smoking is the major risk factor for development of emphysema. Many people are unable to stop smoking despite skilled support. The elastase-antielastase imbalance hypothesis for the pathogenesis of emphysema suggests that treatment with a supplemental elastase inhibitor might prevent development of emphysema in susceptible people. Many elastase inhibitors have been developed. Poorly soluble inhibitors do not prevent emphysema when tested in an animal model of elastase-induced emphysema. Irreversible inhibitors are effective in a dose-response manner. Reversible but tight-binding large molecular weight inhibitors, which clear slowly from the lungs, are effective in vivo. Small molecular weight, reversible inhibitors prevent haemorrhage after human neutrophil elastase instillation into the lungs but may potentiate emphysema. Only 15% of long-term smokers are susceptible to the development of emphysema. Susceptible smokers can be identified by the development of airflow obstruction. An outcome study of efficacy of elastase inhibitor therapy would be prohibitively expensive. However, a study of the process of development of elastase-induced emphysema is feasible. Measurement of alterations in elastase load of the lungs, elastase derived fibrinopeptides, circulating elastin peptides and urinary desmosines could be used for this purpose.
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PMID:The specific treatment of emphysema. 218 48

Current data suggest that emphysema in smokers is caused at least in part by the unrestrained action of neutrophil elastase on pulmonary tissues. Since colchicine reduces the secretion of enzymes from stimulated neutrophils, we designed a clinical trial to determine if colchicine could reduce the elastase load in the lungs or several putative indicators of elastin destruction. We carried out a prospective, double-blind, randomized, and placebo-controlled clinical trial. Outpatients seeking treatment for chronic obstructive pulmonary disease at the University of Texas Health Center at Tyler who met specific criteria were recruited into the study. A group of 46 cigarette smokers between 45 and 75 yr of age with chronic obstructive pulmonary disease (COPD) were studied. Colchicine or placebo was given orally in disguised capsules, 0.6 mg three times per day. Volunteers were placed on a baseline bronchodilator regimen of Theodur orally and albuterol by inhalation. Blood, urine, and bronchoalveolar lavage fluids were obtained after 1 wk of stabilization. The patients were then randomized and treated for 14 days with colchicine, and the measurements were repeated. Modifications in plasma elastin peptides and neutrophil elastase-generated fibrinopeptide A, urinary desmosines, and bronchoalveolar lavage fluid neutrophils or neutrophil elastase were the indicators of success or failure of the treatment. Pre- and posttreatment measurements in each patient and the difference between colchicine-treated and placebo-treated groups were compared. There were no statistically significant differences in either of the two types of analyses in any of the variables. We conclude that variables related to elastase load in the lungs were not modified by colchicine treatment. If a drug can be identified that is successful in modifying one of these variables, it would then have to be tested in a large-scale clinical trial in which the rate of decline in the FEV1.0 or mortality would be measured. The data presented here may provide useful information about the variability of key measurements of elastase load in the lungs and the breakdown of elastin and may aid investigators in designing similar trials in the future.
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PMID:A controlled trial of colchicine to reduce the elastase load in the lungs of cigarette smokers with chronic obstructive pulmonary disease. 219 34

Coal miners develop focal emphysema characterized by dilatation of second- and third-order respiratory bronchioles with coal mine dust-laden macrophages infiltrating the wall. A reticulin network with small amounts of collagen and atrophy of smooth muscle occurs. To evaluate the mechanisms of lung injury associated with this lesion, 17 long-term non- or ex-smoking West Virginia underground coal miners underwent bronchoalveolar lavage (BAL) and were compared to healthy nonsmoker and smoker controls. The coal miners had evidence of an alveolar macrophage-neutrophil alveolitis with a significant increase in neutrophils/microliter of epithelial lining fluid and an increased gallium lung scan index (206 +/- 26 units). Alveolar macrophages lavaged from coal miners spontaneously released exaggerated amounts of superoxide anion and hydrogen peroxide in vitro compared to nonsmoking controls. Coal workers had significantly elevated levels of neutrophil elastase in BAL fluid complexed with alpha 1-antitrypsin (P less than 0.01) and normal levels of alpha 1-antitrypsin. An accumulation of activated, dust-laden inflammatory cells with increased release of oxidants and elastase may contribute to the development of focal emphysema identified at postmortem in miners with coal workers' pneumoconiosis.
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PMID:Basic mechanisms leading to focal emphysema in coal workers' pneumoconiosis. 222 76

In solution, MeO-Suc-Ala-Ala-Pro-D,L-boro-Val pinacol ester (Boroval) is a highly effective but reversible inhibitor of both porcine pancreatic elastase and human neutrophil elastase (HNE) (50% inhibition with a 1.5 M ratio of Boroval to elastase). Boroval has been shown to prevent porcine-pancreatic-elastase-induced emphysema in hamsters. But with HNE-induced emphysema in hamsters, pretreatment with as much as a 170-fold M excess of Boroval, given intratracheally 1 h before 0.3 mg HNE, did not prevent emphysema. Indeed, lung volumes were larger after Boroval pretreatment than after HNE alone. Emphysema was also induced by instilling HNE that had been mixed with and inactivated by a 41-fold M excess of Boroval (a molar ratio of 42). When 0.25 or 0.5 mg of HNE were given mixed with a 41-fold M excess of Boroval, the emphysema was much more severe with the 0.5 mg dose. Two hours after instillation of 0.3 mg HNE inactivated with a 34-fold M excess of Boroval, bronchoalveolar lavage contained elastolytic activity but no evidence of hemorrhage. In contrast, hemorrhage was severe in hamsters that had been instilled with 0.3 mg HNE alone. We conclude that Boroval can enhance HNE-induced emphysema. We postulate that Boroval suppresses HNE-induced hemorrhage and the resultant influx of plasma protease inhibitors; the HNE-Boroval complex is transported into the alveolar interstitium, followed by dissociation of the inhibitor from the active site of HNE. Because of its small size, free Boroval is rapidly cleared, and the reactivated HNE attacks elastic fibers, giving rise to emphysema.
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PMID:Induction and exacerbation of emphysema in hamsters with human neutrophil elastase inactivated reversibly by a peptide boronic acid. 229 86

Studies were undertaken to evaluate the in vitro properties of recombinant human secretory leukocyte-protease inhibitor (rSLPI) that had been made in Escherichia coli in an inactive form and refolded, and to determine whether emphysema and bronchial secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be amelio-rated by prior intratracheal instillation of rSLPI. Chromatographic studies indicated that 3H-rSLPI formed a 1:1 complex with HNE. Blockage of the active site of HNE by a covalently bound tetrapeptide chloromethyl ketone reduced complex formation with 3H-rSLPI by more than 98%. Incubation of 3H-rSLPI-HNE complex with alpha 1-protease inhibitor for 3 hours at 37 degrees C decreased the amount of complex compared with incubation in the presence of bovine serum albumin (70% vs 27% dissociated). The calculated dissociation rate constant was 1.1 x 10(-4) sec-1, indicating a 1.8 hour dissociation half-life. Dissociated 3H-rSLPI retained its ability to recombine with HNE. rSLPI was as effective at inhibiting HNE released from stimulated neutrophils as 3H-rSLPI was at inhibiting purified HNE. Intratracheal pretreatment of hamsters with 3000 micrograms of rSLPI as long as 8 hours before the intratracheal instillation of 250 micrograms of HNE, resulted in significant protection against induction of emphysema and secretory cell metaplasia. One and 4 hours after instillation of rSLPI, 59% and 44%, respectively, of the initial functional activity was recovered in lung lavage supernatant, indicating a half-life of approximately 2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Recombinant human secretory leukocyte-protease inhibitor: in vitro properties, and amelioration of human neutrophil elastase-induced emphysema and secretory cell metaplasia in the hamster. 229 66

Intravenous augmentation therapy with human plasma alpha 1AT represents the current "state of the art" form of therapy for alpha 1AT deficiency. Augmentation therapy is directed towards specific correction of the central abnormality of alpha 1AT deficiency i.e., to correct the insufficient anti-neutrophil elastase screen of the lung. By augmenting lung levels of functional alpha 1AT, the anti-neutrophil elastase protective screen of the lower respiratory tract is re-established, and the delicate alveolar structures are protected from elastolytic degradation. Weekly, monthly and plasma exchange-alpha 1AT infusion all share the same basic approach to augmenting lung anti-elastase defenses, and appear to be equally effective in re-establishing the anti-elastase screen of the lower respiratory tract. One important issue concerning augmentation therapy is the question of when to initiate therapy. Because the goal of augmentation therapy is to prevent lung destruction, it is rational to initiate therapy prior to the onset of significant lung destruction. Traditionally, pulmonary function testing and chest X-rays have been used to determine the degree of emphysema, but these methods are relatively insensitive when compared to newer evaluative methods, including computed tomography and ventilation-perfusion scanning. In view of the availability of these newer diagnostic modalities, and the desire to maximally preserve the lung through early initiation of augmentation therapy, the traditional concepts requiring the presence of lung function abnormalities as evidence of lung destruction may need to be re-evaluated for individuals with alpha 1AT deficiency. Aerosol augmentation therapy with human plasma alpha 1AT or with rAAT are attractive possible alternative approaches to increasing lung anti-neutrophil elastase defenses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Augmentation therapy of alpha 1-antitrypsin deficiency. 234 51

Lung secretions contain several elastase inhibitors although alpha 1-antitrypsin (alpha 1AT) and antileukoprotease (ALP) are the major ones. Studies of lung alpha 1AT show that the inhibitor is usually partly inactive. In patients with established lung disease this is due to a combination of proteolytic degradation, complex with enzyme and oxidation at the active site. Studies in subjects with normal lungs demonstrate that the alpha 1AT is also partly inactivated although not by any of the recognised mechanisms. Furthermore no difference in function is found between current smokers and nonsmokers. ALP is largely an inhibitor of the major airways although it is still present in the lower airway secretions collected by lavage in healthy subjects. The proportions of alpha 1AT to ALP vary in patients with alpha 1AT deficiency (1:9), established emphysema (1:1) and subjects with healthy lungs (10:1). These differences affect the ability of the lavage fluids to inhibit neutrophil elastase during prolonged incubation with enzyme substrate. The results suggest that the relative concentrations of alpha 1AT and ALP, particularly in close proximity to lung substrates, may determine the degree of connective tissue destruction.
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PMID:Elastase inhibitors of the respiratory tract. 234 54

A study was undertaken to determine whether emphysema and airway secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be moderated by pretreatment with human alpha 1-protease inhibitor (API). API (4.9 mg) was given intratracheally to hamsters 1 h before 0.3 mg HNE. Eight weeks later, lung volumes and pressure-volume relationships were measured in the anaesthetized animals. Mean linear intercepts and secretory cell indices were measured in lung sections. API given 1 h before HNE moderated the development of bronchial secretory cell metaplasia. The severity of emphysema was reduced by 75%. Clearance studies indicated that 80% of the functional activity of instilled API could be lavaged from the lungs after 1 h, indicating a 4 h half-life in the lavageable compartment of the lungs. We calculate that for 50% protection from emphysema the molar ratio of lavageable API to HNE at the time of HNE instillation was 4.8 as compared with 0.78 for 50% inhibition of elastolytic activity in vitro, indicating that API is only 16% as efficient in vivo as compared with its in vitro HNE inhibitory effectiveness. Nevertheless, we conclude that human API given intratracheally is efficacious against HNE-induced emphysema and secretory cell metaplasia.
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PMID:Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters. 237 77

Much of the tissue damage associated with emphysema and other inflammatory diseases has been attributed to the proteolytic activity of neutrophil elastase, a major component of the azurophil granule. Recently, two additional azurophil granule proteins with NH2-terminal sequence homology to elastase were isolated (Gabay, J. E., Scott, R. W., Campanelli, D., Griffith, J., Wilde, C., Marra, M. N., Seeger, M., and Nathan, C. F. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 5610-5614) and designated azurophil granule protein 7 (AGP7) and azurocidin. Azurocidin and AGP7 represent significant protein components of the azurophil granule, together comprising approximately 15% of the acid-extractable protein as judged by reverse-phase high performance liquid chromatography analysis. AGP7 migrates on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as four distinct glycoforms of molecular mass 28-34 kDa, whereas azurocidin exhibits three predominant bands with molecular mass of 28-30 kDa. Treatment of intact azurophil granules with [3H]diisopropyl fluorophosphate resulted in labeling of elastase, cathepsin G, and AGP7, whereas azurocidin was not labeled. Tryptic mapping of 3H-labeled AGP7 allowed us to identify and sequence the active-site polypeptide that has 70% identity to elastase over 20 residues. The active site peptide of azurocidin was also identified by sequence analysis of tryptic fragments and showed 65% identity to the active site of elastase. Surprisingly, the catalytic serine of azurocidin is replaced by glycine, explaining its inability to label with [3H]diisopropyl fluorophosphate. Thus, we have identified two azurophil proteins closely related to neutrophil elastase, one of which has apparently lost its proteolytic activity due to mutation of the catalytic serine.
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PMID:Characterization of two azurphil granule proteases with active-site homology to neutrophil elastase. 240 77


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