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

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

The tight-skin (Tsk) mouse is a model of genetically determined emphysema. The cause for the development of the lung lesion is unknown. In the present study we investigated the lung morphometry and the serum elastase inhibitory capacity (EIC) of Tsk mice. Mean interalveolar distance was significantly greater (+60%) in Tsk mice than in C57 Bl/6J, NMRI, and Balb/c mice, which have similar values. Serum of Tsk mice against mouse leukocyte elastase (MLE) has significantly lower EIC values than that of NMRI, Balb/c (-64%), and C57 Bl/6J (-50%) mice. Similar results were obtained when porcine pancreatic elastase (PPE) was used. Against human leukocyte elastase (HLE), however, there was no difference among the strains, all of which had high EIC values. Preincubation of mouse (C57 Bl/6J) serum with chloramine-T (CT) resulted in an almost complete inhibition of EIC against MLE and PPE but only in a 20% inhibition against HLE using a synthetic substrate. Using elastin Congo Red as substrate, CT inhibited EIC against MLE and PPE by approximately 70% but did not affect the EIC against HLE. These results indicate that (1) the Tsk mouse can be considered a model of severe inborn deficiency of serum antielastase activity which is associated with emphysema; and (2) MLE and PPE can be considered interchangeable in studies of serum EIC in the mouse. On the other hand, the differences between MLE and HLE preclude the use of HLE for EIC determination in this species.
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PMID:Serum antielastase deficiency in tight-skin mice with genetic emphysema. 230 13

The present study was aimed at testing whether alpha 1-proteinase inhibitor-sufficient patients with lung emphysema or idiopathic spontaneous pneumothorax have an impaired antielastase protection at the lung alveolar level. We have collected bronchoalveolar lavage fluids (BALF) from 20 PIMM emphysematous patients (44 +/- 12 yr), 24 patients with pneumothorax but no radiologic evidence of emphysema (30 +/- 11 yr), 32 healthy subjects (27 +/- 6 yr), and 56 patients with sarcoidosis (30 +/- 11 yr). The BALF were assayed for immunoreactive albumin, alpha 1-proteinase inhibitor (alpha 1PI), leukocyte elastase-alpha 1PI complex (LE-alpha 1PI), and mucus proteinase inhibitor (MPI) as well as for porcine pancreatic elastase inhibitory capacity, a measure of active alpha 1PI. The healthy subjects and the patients with emphysema or pneumothorax had comparable levels of total and active alpha 1PI and total MPI. In contrast, the levels of LE-alpha 1PI complex were elevenfold higher in patients with emphysema than in normal subjects (p = 0.021) and tended to increase with the severity of the disease because they were negatively correlated with FEV1/FVC% (r = -0.55; 0.05 less than p less than 0.1). They did not vary with age in a population of patients with sarcoidosis (r = 0.03), suggesting that their eleven-fold increase in emphysematous patients is not related to the age of these subjects. Patients with pneumothorax had levels of LE-alpha 1PI complex that did not significantly differ from those of normal subjects (p = 0.24).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The antielastase screen of the lower respiratory tract of alpha 1-proteinase inhibitor-sufficient patients with emphysema or pneumothorax. 232 50

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

Anti-elastase function in sputum sol-phase from patients with alpha 1-proteinase inhibitor (alpha 1PI) deficiency was compared with sol-phase from patients with cigarette smoke-induced bronchitis and emphysema. Both alpha 1PI (2P less than 0.01) and anti-leucoprotease (ALP) (2P less than 0.01) concentrations were lower in sol-phase from the alpha 1PI-deficient group, although alpha 2-macroglobulin (alpha 2M) levels were similar. There was no difference in alpha 1PI function between the two groups, but the inhibitor was only congruent to 30% active. The absolute neutrophil elastase (NE) inhibitory capacity was similar in both groups (median 185 micrograms of NE inhibited/ml of sputum, range 80-480, for the alpha 1PI-deficient group; median 175, range 80-300, for the bronchitic group). A substantial proportion of NE inhibition in secretions could not be accounted for by the amount of alpha 1PI, ALP and alpha 2M present (median 74.8%, range 43.2-97.4, for alpha 1PI-deficient sol-phase; median 50.0%, range 0-80.8, for bronchitic sol-phase). Gel filtration of sol-phase demonstrated the presence of NE inhibition in the low molecular weight fractions which was markedly sensitive to changes in substrate concentration and ionic strength, in contrast to purified alpha 1PI and ALP. Sputum sol-phase from both groups failed to prevent hydrolysis of elastin-fluorescein or succinyltrialanyl-p-nitroanilide by NE completely during prolonged incubation in the presence of an excess of functional inhibitors. This was more apparent in secretions from subjects with alpha 1PI deficiency and may explain why such patients have a more rapidly progressive form of emphysema.
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PMID:Elastase inhibitors in sputum from bronchitic patients with and without alpha 1-proteinase inhibitor deficiency: partial characterization of a hitherto unquantified inhibitor of neutrophil elastase. 244 Jun 36

Instillation of human neutrophil elastase (HNE) into hamster lungs produces milder emphysema but more pulmonary hemorrhage than an equivalent amount of porcine pancreatic elastase (PPE), whether equivalence is determined by elastolytic units or moles. We undertook a study of the mechanisms of these differences. 125I-HNE or 3H-PPE were instilled intratracheally into hamsters. The partitioning of radioactivity between bronchoalveolar lavage fluid (BAL) and lung tissue was similar for HNE and PPE as were the half-lives, 45 and 51 min, respectively, for uncomplexed, enzymatically active HNE and PPE. In BAL there was preferential binding and inactivation of HNE by the hamsters' alpha-1-protease inhibitor (a-1-PI) whereas PPE was preferentially bound by alpha-2-macroglobulin (a-2-M). This was also observed in vitro when HNE and PPE were incubated with plasma from untreated hamsters. Nevertheless, when the sum of the elastase binding capacity of a-1-PI and a-2-M was considered, hamster plasma had similar binding capacities for HNE and PPE. It is known that the enzymatic activity of elastases is inhibited by formation of a stable complex with a-1-PI. On the other hand, elastases bound to a-2-M are protected against a-1-PI inhibition but can free themselves by proteolysis and exhibit elastolytic activity. Preferential inactivation of HNE by a-1-PI may be one mechanism that accounts for the lesser emphysema-inducing potency of HNE than of PPE.
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PMID:Defenses of the hamster lung against human neutrophil and porcine pancreatic elastase. 246 16


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