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)

Hamsters were intratracheally instilled with saline solutions containing a high dose (145 to 220 micrograms) or a low dose (1.3 to 1.5 micrograms) of 3H-methylated pancreatic elastase or N-acetyl-(L-alanyl)3-L-alanine chloromethyl ketone-inactivated 3H-methylated pancreatic elastase. Only the lysyl residues of the elastase molecule were methylated and radiolabeled in a nonlabile manner. The 3H-methylated elastase preparation exhibited esterolytic and elastolytic activity, spectral properties, and emphysema-inducing properties indistinguishable from those of unmodified pancreatic elastase. There was no detectable hemorrhagic or emphysematous reaction with the inactivated 3H-methylated elastase, and this material was cleared from the lungs 11 times faster than the corresponding enzymatically active high dose of 3H-methylated elastase and 18 times faster than the corresponding enzymatically active low dose of 3H-methylated elastase. There were correspondingly higher amounts of radioactivity in the urine of hamsters treated with the inactivated elastase. All of the 3H radioactivity recovered from the urine was associated with epsilon-N-methyllysyl and epsilon-N,N-dimethyllysyl residues. Significant levels of radioactivity were found in the cells, primarily alveolar macrophages, lavaged from the lungs. The low dose of enzymatically active elastase caused neither detectable hemorrhage nor emphysema, both of which were associated with the high dose. At 144 days significant radioactivity (1,200 cpm) remained in the lungs of animals treated with high or low doses of enzymatically active elastase, whereas virtually no radioactivity (100 cpm) was found in the lungs of those treated with high or low doses of inactivated elastase. The data presented support the hypothesis that the formation of elastase complexes with alpha 1-protease inhibitor and alpha 2-macroglobulin is associated with the slower clearance and the retention of significant amounts of radioactivity in the lungs. Some of the residual radioactivity found in the hamster lungs might represent enzymatically active elastase complexed with alpha 2-macroglobulin and might offer an explanation for the progressive nature of emphysema induced by a single dose of elastase.
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PMID:The dose-dependent fate of enzymatically active and inactivated tritiated methylated pancreatic elastase administered intratracheally in the hamster. 9 Apr 69

Thioglycolate-stimulated mouse peritoneal macrophages secrete a Proteinase which degrades insoluble elastin. There is little elastase activity in cell lysates but the bulk of the enzyme accumulates extracellularly during culture in serum-free medium. The secretion of elastase is sustained for over 12 days in culture and continued secretion of elastase requires protein synthesis. Unstimulated macrophages secrete very little elastase activity but can be triggered to secrete higher levels of this enzyme by phagocytosis and intracellular storage of latex particles. The macrophages elastase is a distinctive proteinase differing from the elastases of pancreas and granulocytes and is distinct from the other secreted proteinases of macrophages, namely, collagenase and plasminogen activator. The macrophages elastase is a serine proteinase and is inhibited by di-isopropyl phosphoro-fluoridate, ovoinhibitor, EDTA, dithiothretiol, and serum. Its activity is little affected by soybean trypsin inhibitor, turkey ovomucoid and chloromethyl ketones derived from tosyl lysine, tosyl phenylalanine, and acetyltetra alanine. Hydrolysis by macrophage elastase of chromogenic ester substrates for pancreatic elastase could not be detected. Elastase secretion by stimulated macrophages exceeds that by primary and established fibroblast cell strains. It is likely that elastase secretion by macrophages plays a major role in the pathogenesis of chronic destructive pulmonary diseases such as emphysema.
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PMID:Elastase secretion by stimulated macrophages. Characterization and regulation. 16 96

Methods are described for the covalent attachment of succinoyl-Ala-Ala-Pro-ValCH2Cl, an active site-directed inhibitor of human leukocyte elastase (EC 3.4.21.11), to microspheres of human albumin. The insertion of side arms of various lengths revealed that maximum inhibition of this enzyme was obtained when the spacer arm was at least 24.3 A in length. Approximately 30 molecules of the inhibitor could be attached to each molecule of albumin. Such derivatized microspheres were capable of inhibiting approximately one mole of elastase per mole of albumin, which is comparable to the inhibitory activity of alpha 1-antitrypsin. Experiments in vivo in which rats were injected intravenously with radiolabeled microspheres to which the inhibitor had been attached showed a rapid and exclusive uptake by the lungs. About 40--50% of the injected microspheres subsequently remained in the lungs with a half-life of approximately 17 days. These derivatized microspheres thus appear to offer promise as a therapeutic agent for emphysema.
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PMID:Albumin microspheres as carrier of an inhibitor of leukocyte elastase: potential therapeutic agent for emphysema. 28 51

A series of tripeptides possessing trifluoromethyl or aryl ketone residues at P1 were prepared and evaluated both in vitro and in vivo as potential inhibitors of human leukocyte elastase (HLE). Tripeptides containing non naturally occurring N-substituted glycine residues at the P2-position have been demonstrated to be potent in vitro inhibitors of HLE, with IC50 values in the submicromolar range. Sterically demanding substituents on the P2-nitrogen have no detrimental effect on in vitro potency. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing trifluoromethyl functionality. Deletion of the amino acid at the P3-subsite region affords inactive compounds. Valine is the preferred residue at the P1-position, whereas the corresponding glycine, alanine, alpha,alpha-dimethylglycine, or phenylalanine analogues are all inactive. The compounds described herein all confer a high degree of in vitro specificity when tested against representative cysteine, aspartyl, metallo, and other serine proteases. One of the most potent in vitro inhibitors is (3RS)-N-[4-[[[(4-chlorophenyl)sulfonyl]amino]carbonyl]phenyl] oxomethyl]-L-valyl-N-(2,3-dihydro-1H-inden-2-yl)glycine N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]amide (20i; BI-RA-260) (IC50 = 0.084 microM). Compound 20i was also tested in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal (it.) administration of 20i, 5 min prior to HLE challenge, effectively inhibited hemorrhage in a dose-dependent manner with an ED50 of 4.8 micrograms. The inhibitor 20i, 20 micrograms administered it. 24, 48, and 72 h prior to HLE challenge, exhibits significant inhibition against hemorrhage at all time points (97%, 64% and 49%, respectively). In a 21-day chronic model of emphysema in hamsters, 200 micrograms of HLE administered it. caused an elastase-induced emphysema in the lungs which can be quantitated histologically utilizing image analysis. In this assay, 20i significantly inhibited pulmonary lesions associated with septal destruction and increased alveolar spaces, when dosed at 20 micrograms it. 5 min prior to challenge with HLE.
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PMID:Inhibition of human leukocyte elastase (HLE) by N-substituted peptidyl trifluoromethyl ketones. 154 92

Elastase inhibitors are potential drugs for the control of lung emphysema. Since neutrophils may release elastase in the lung interstitium, elastin and inhibitors may complete locally for the binding of enzyme. To better evaluate the potential activity of antielastases, we have run experiments that mimic this in vivo competition. Elastase was added to mixtures of human lung elastin and inhibitor, and the solubilization of the fibrous substrate was measured as a function of time. Controls in which a synthetic substrate was used instead of elastin were run under identical conditions. We show that the rate constants for the irreversible inhibition of elastase by methoxysuccinyl-Ala2-Pro-Val-chloromethylketone and L-657,229, a substituted beta lactam, are 28- and 63-fold lower with elastin than with a synthetic substrate, respectively. The rate constant decreases with increasing concentrations of elastin, indicating that the inhibition is competitive. Elastin also impairs the potency of the following reversible inhibitors: trifluoroacetyl-Lys-Ala-NH-C6H4-p-C6H11, trifluoroacetyl-Lys-Ala-NH-C6H4-pN(C2H5)2, methoxysuccinyl-Ala2-Pro-Boro-Val-OH, and mucus proteinase inhibitor whose Ki values are 29- to 127-fold higher with elastin than with a synthetic substrate. Again the inhibition is competitive. We conclude that association rate constants of irreversible inhibitors and Ki values of reversible ones may be measured accurately using elastin as a substrate. The kinetic constants measured with elastin and not those determined with synthetic substrates should be used to decide whether a given inhibitor is potent enough to be a physiologic antielastase or a potential antielastase drug.
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PMID:Elastin decreases the efficiency of neutrophil elastase inhibitors. 199 Oct 75

Proteinase 3 (PR-3) is a human polymorphonuclear leukocyte (PMNL) serine proteinase that degrades elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters (Kao, R. C., Wehner, N. G., Skubitz, K. M., Gray, B. H., and Hoidal, J. R. (1988) J. Clin. Invest. 82, 1963-1973). We have determined the primary structure of several PR-3 peptides and have analyzed catalytic properties of the enzyme. The enzyme has considerable amino acid sequence homology with two other well characterized PMNL neutral serine proteinases, elastase and cathepsin G. Furthermore, the NH2-terminal amino acid sequence of PR-3 is identical to that of the target antigen of the anti-neutrophil cytoplasmic autoantibodies associated with Wegener's granulomatosis. PR-3 degrades a variety of matrix proteins including fibronectin, laminin, vitronectin, and collagen type IV. It shows no or minimal activity against interstitial collagens types I and III, respectively. The analysis of peptides generated by PR-3 digestion of insulin chains and the activity profile against a panel of chromogenic synthetic peptide substrates show that PR-3 prefers small aliphatic amino acids (alanine, serine, and valine) at the P1 site. The elastase-like specificity of PR-3 is consistent with its striking sequence homology to elastase at substrate binding sites. PR-3 is inhibited by alpha 1-proteinase inhibitor (ka = 8.1 x 10(6) M-1 S-1; delay time = 25 ms) and alpha 2-macroglobulin (ka = 1.1 x 10(7) M-1 S-1; delay time = 114 ms) but not by alpha 1-anti-chymotrypsin. In contrast to elastase and cathepsin G, PR-3 is not inhibited by secretory leukoprotease inhibitor and is weakly inhibited by eglin c. Thus, PR-3 is distinct from the other PMNL proteinases.
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PMID:Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase. Structural and functional properties. 203 50

A novel beta-lactam derivative, N-(2-chloromethylphenyl) 3,3-difluoroazetidin-2-one, which behaves as a time-dependent inactivator of leukocyte elastase, has been tested in biological models designed to detect its potential therapeutic value in the treatment of emphysema. Its effect on two types of leukocyte elastase, purified human leukocyte elastase and elastase freshly discharged upon stimulation of guinea pig polymorphonuclear neutrophils, was examined using three methods: the cleavage of a chromogenic peptide substrate, MeO-Suc-Ala-Ala-Pro-Val-NA, the lysis and solubilization of tritiated elastin and the microscopic examination of the damage to lung elastic network. The inhibitor was shown to be effective at preventing proteolysis due to leukocyte elastase. Besides its low cellular toxicity, no apparent hindrance of its efficiency was found in the above quasi in vivo environment. This suggests that this inhibitor may be of potential therapeutic value in elastase-related pathology.
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PMID:Biological evaluation of the inhibition of neutrophil elastase by a synthetic beta-lactam derivative. 208 24

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

The in vitro and in vivo effects of heparin fragments (CY 216; CY 222) towards elastase(s) and elastase inhibitor (alpha 1 Pi) were studied. Heparin as well as its lower Mr fragments were shown to inhibit rat leucocyte elastase. The interaction between this enzyme and heparins appears to occur via electrostatic forces. Porcine pancreatic elastase is unaffected by heparin(s) but CY 216 and CY 222 could partly abolish the hydrolytic activity of hamster serum on Suc-Ala-Ala-Ala-N-PhNO2. N desulphated N acetylated CY 142 and CY 143 had no effect. CY 216 and CY 222 decreased in vitro the inhibitory potential of alpha 1 proteinase inhibitor (alpha 1 Pi) as well as the elastase inhibitory capacity of hamster serum. Maximum effect (30% decrease) was observed at ng concentrations of CY 216 and CY 222. Their N desulphated N acetylated counterparts (CY 142 and CY 143), but not heparin, exhibited similar effects. CY 216 and CY 222 were administered daily subcutaneously to hamsters and blood was collected 1, 2, 4, 7 and 24 hr after treatment for determining both serum elastase activity (E.A.) and serum elastase inhibitory capacity (E.I.C.). E.A. levels dropped by 30% 2 hr after CY 216 or CY 222 injection but returned to original values 4-7 hr later. This effect is independent of the duration of the treatment. Hamster serum E.I.C. was significantly increased (greater than 30%) after 3-4 weeks of treatment with CY 216 and CY 222. These findings point towards the potential use of these compounds in elastase-related diseases such as emphysema.
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PMID:Influence of heparin fragments on the biological activities of elastase(s) and alpha 1 proteinase inhibitor. 284 23

Human neutrophil elastase (HNE) has been implicated as a major contributor to tissue destruction in various disease states, including emphysema. The structure of HNE, at neutral pH, in complex with methoxysuccinyl-Ala-Ala-Pro-Ala chloromethyl ketone (MSACK), has been solved and refined to an R factor of 16.4% at 1.84-A resolution. Results are consistent with the currently accepted mechanism of peptide chloromethyl ketone inhibition of serine proteases, in that MSACK cross-links the catalytic residues His-57 and Ser-195. The structure of the HNE-MSACK complex is compared with that of porcine pancreatic elastase in complex with L-647,957, a beta-lactam inhibitor of both elastases. The distribution of positively charged residues on HNE is highly asymmetric and may play a role in its specific association with the underlying negatively charged proteoglycan matrix of the neutrophil granules in which the enzyme is stored.
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PMID:Structure of human neutrophil elastase in complex with a peptide chloromethyl ketone inhibitor at 1.84-A resolution. 291 84


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