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)

Syrian hamsters were exposed to the aerosol of a 5% solution of papain in the presence of cysteine and ethylenediamine-tetraacetic acid. Pulmonary emphysema in hamsters was observed after exposure to papain for two to three hours. There was no change with time in the severity of emphysema from the second through the fourth weeks after exposure to papain. Pathogenesis of pulmonary emphysema was discussed in relation to proteolysis of glycosaminoglycan-protein complex.
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PMID:Experimental pulmonary emphysema in Syrian hamsters. 82 20

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

Current theories of pathogenesis suggest that pulmonary emphysema develops in humans because of progressive loss or derangement of lung elastin through a process mediated by elastolytic enzymes released by inflammatory cells. Neutrophils are considered primary etiologic factors because these cells produce and release two potent serine proteinases that cause emphysema when instilled into the lungs of animals. It has been suggested that alveolar macrophages also contribute to the development of emphysema through production of several enzymes with elastolytic activity, including the lysosomal cysteine proteinases cathepsin B and cathepsin L, but this has not been verified experimentally. In the current study, we instilled 115 micrograms of active cathepsin B into the lungs of hamsters three times at 48-h intervals. After 6 wk microscopic evaluation revealed that lung sections of five of seven animals given cathepsin B contained focal areas of enlarged and distorted alveoli, in the absence of fibrosis, which were similar to changes seen in the lungs of animals given papain intratracheally. Morphometrically, mean linear intercept (micron) values were significantly higher (p less than 0.025) in animals given cathepsin B (204.4 +/- 20.8) as compared with control animals (173.2 +/- 7.8), and internal surface area (sqcm) values were significantly lower (935 +/- 120 versus 1,083 +/- 56 in control animals), thereby confirming that airspace enlargement had developed after instillation of the enzyme. Lung volumes (ml) and compliance (ml/cm H2O) were not significantly higher in animals given cathepsin B.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction of emphysema in hamsters by intratracheal instillation of cathepsin B. 154 48

Adult male Sprague-Dawley rats were exposed whole-body to mainstream cigarette smoke (CS) once daily for 40 consecutive days. Such a treatment resulted in a significant decrease of body weight growth and in intense histopathological changes of terminal airways, including a severe inflammation of bronchial and bronchiolar mucosae, with multiple hyperplastic and metaplastic lesions and foci of micropapillomatous growth as well as emphysema, with extensive disruption of alveolar walls. All histopathological changes were efficiently prevented by the daily administration of the thiol N-acetyl-L-cysteine (NAC) by gavage. Cytological and cytogenetical changes were monitored in bronchoalveolar lavage (BAL) fluid and bone marrow cells of groups of rats killed after 1, 3, 8, 28, or 40 days of treatment. From the first day of exposure, CS significantly enhanced the proportion of polymorphonucleates among BAL cells and the frequency of micronucleated (MN) bone marrow polychromatic erythrocytes. After 8 days, a reduction was observed in the polychromatic/normochromatic erythrocytes ratio and an increase in the frequency of MN pulmonary alveolar macrophages (PAM) was also recorded, followed, after 28 days, by an increase of binucleated PAM. All these alterations immediately reached a plateau and persisted unchanged until the end of the experiment. NAC administration exhibited a significant and considerable protective effect towards the CS-induced alterations of BAL cellularity, the increase of MN PAM and bone marrow cytotoxicity.
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PMID:Protection by N-acetylcysteine of the histopathological and cytogenetical damage produced by exposure of rats to cigarette smoke. 161 95

During their development, mononuclear phagocytes express a changing profile of proteinases that may participate in the degradation of elastin and other extracellular matrix components. Neutrophil elastase is produced and stored in azurophil-like granules in immature mononuclear phagocytes. Monocytes contain small amounts of neutrophil elastase but do not synthesize the enzyme. Macrophages neither synthesize nor contain neutrophil elastase, but they can internalize and secrete scavenged neutrophil elastase. Human alveolar macrophages synthesize cysteine proteinases including cathepsin L, a lysosomal enzyme with elastolytic activity at an acidic pH. Macrophages from several animal species synthesize an approximately 22-kD metalloelastase that, in the mouse, is secreted as a zymogen of about 36 kD. In addition to its direct elastolytic properties, this metalloelastase may also promote elastolysis by cleaving alpha 1-antiproteinase and thus protecting neutrophil elastase from inhibition. A human counterpart of this enzyme has not yet been purified; however, the elastolytic activity of human macrophages appears to depend predominantly on the activity of one or more metalloproteinases. Because elastin is intertwined with other matrix components in natural matrices, degradation of elastin in vivo probably involves cooperation of multiple proteinases to uncover macromolecules that mask the elastic fibers. Degradation of matrix may be localized to pericellular sites, where proteinases are protected from inhibitors and where potentially surface-bound enzymes may be concentrated. Complete breakdown of matrix may be completed within the cells after partially cleaved molecules are internalized. Growth and remodeling of the extracellular matrix must involve highly coordinated interactions between cells, cytokines, proteinases, proteinase activators and inhibitors, as well as the matrix itself. The intrapulmonary process resulting in emphysema probably involves equally complex interactions. Mononuclear phagocytes accumulate in large numbers in the lung in response to cigarette smoking, and they may play a role in the pathogenesis of the alveolar septal injury that characterizes pulmonary emphysema.
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PMID:Elastin degradation by mononuclear phagocytes. 206 50

Cathepsin B activity was quantitated in alveolar macrophages obtained from hamsters 10, 21, and 105 days after the intratracheal instillation of porcine pancreatic elastase, bleomycin, or normal saline. Alveolar macrophages lavaged from animals receiving elastase contained significantly higher enzyme levels at 21 and 105 days (16,200 and 17,000 U/mg protein/hr, respectively) as compared with saline-treated animals (12,300 units). In contrast, cells from animals receiving bleomycin showed a decrease in activity at 21 and 105 days (9700 and 9900 units, respectively). At 10 days enzyme levels did not differ significantly. The results suggest that cathepsin B levels in alveolar macrophages reflect differences in lung destruction and connective tissue repair in vivo. In addition, the finding of high cathepsin B activity in animals with emphysema suggests the possibility that cysteine proteases contribute to progressive lung destruction initiated by the intratracheal instillation of elastase.
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PMID:High cathepsin B activity in alveolar macrophages occurs with elastase-induced emphysema but not with bleomycin-induced pulmonary fibrosis in hamsters. 245 29

Oxidants derived from the atmosphere or from activated pulmonary phagocytes mediate functional inactivation of alpha-1-protease inhibitor (alpha-1-PI). Chronic exposure to these oxidants may cause emphysema. In this study we have investigated the effects of the antioxidants ascorbate, cysteine (10(-4) M to 10(-1) M), and dapsone (10(-6) M to 10(-3) M) on the oxidative inactivation of human alpha-1-PI by leukoattractant-activated polymorphonuclear leukocytes (PMNL) in vitro. During exposure of alpha-1-PI to stimulated PMNL in the presence of ascorbate and cysteine at concentrations of greater than 10(-4) M and dapsone at greater than 10(-6) M, the elastase inhibitory activity of alpha-1-PI was preserved. However, exposure of the alpha-1-PI to the antioxidants subsequent to PMNL-mediated oxidative inactivation was not associated with reactivation of elastase inhibitory capacity. Ascorbate, cysteine, and dapsone at concentrations that caused 50% protection of alpha-1-PI did not affect degranulation or the binding of radiolabeled leukoattractant to PMNL. It is suggested that the protective effects of the antioxidants are related to their ability to scavenge superoxide and oxidants generated by the PMNL-myeloperoxidase/H2O2/halide system. Because the effects of ascorbate and especially those of dapsone were observed at concentrations of these agents that are attainable in vivo, our results may have clinical significance.
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PMID:Investigation of the protective effects of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative inactivation of human alpha-1-protease inhibitor in vitro. 299 43

We propose that alpha-1-protease inhibitor (alpha 1 PI) can assume a major and beneficial role in preventing emphysema in alpha 1 PI-deficient individuals, and may also prove of value in the treatment of adult respiratory distress syndrome (ARDS). alpha 1 PI has a single, unusual disulfide bond that consists of a cysteine residue in the peptide chain covalently bound to a free amino acid cysteine. The linkage can be broken by reductants without adversely affecting the stability or the inhibitory activities of the protein. As a result of this property, alpha 1 PI can be effectively separated in solution from many other plasma proteins by salting out the contaminants in the presence of strong reductants. We have applied the technique of reductive-salting out, coupled with more conventional DEAE-anion exchange chromatography to isolate alpha 1 PI from Cohn Fraction IV-1, a relatively unused side product in the worldwide production of albumin and immunoglobulins. Furthermore, we have demonstrated that the product can be effectively pasteurized in the presence of various stabilizing additives. The necessary ingredients now exist for extensive clinical studies in the years ahead.
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PMID:Can alpha-1-protease inhibitor be used in replacement therapy? 660 Aug 94

The metabolic turnover of mature elastin fibers in adult animals is relatively slow. Although only small amounts of elastin are degraded normally, increased degradation and fragmentation of elastic fibers may play a significant role in disease processes. Elastinolytic enzymes are found in microorganisms, snake venoms, and in a number of mammalian cells and tissues, including pancreas, polymorphonuclear leukocytes, and macrophages. Elastinolytic enzymes fall into all 4 classes of proteinases (aspartic, cysteine, serine, and metallo) and show a spectrum of different specificities. All elastases studied to date have catalytic activity against protein and peptide substrates other than elastin. The presence of elastase activity is a virulence factor associated with the pathogenicity of Pseudomonas and other bacteria, dermatophytic fungi, and necrosis by rattlesnake venoms. Only elastinolytic enzymes are capable of inducing experimental pulmonary emphysema. Elastin degradation mediated by living macrophages and trophoblasts is confined to the immediate pericellular environment. Destruction of mature elastin by other mammalian elastases is probably the result of an imbalance in the normal inhibitor-proteinase ratio. The major plasma inhibitors contributing to the regulatory balance are alpha 1-proteinase inhibitor and alpha 2-macroglobulin.
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PMID:Elastases and elastin degradation. 704 42

Toxic oxygen free radicals are believed to play a role in the pathogenesis of a number of respiratory diseases. In particular, pulmonary emphysema may occur because of the oxidative impairment of alpha 1-proteinase inhibitor (alpha 1-PI). We report in vitro data on a new thiol agent, P 1507 [N-5-(thioxo-L-prolyl)-L-cysteine], obtained in a series of experiments designed in view of its therapeutic potential in these clinical conditions. We found that P 1507 at the concentration of 5 x 10(-6) M was able to almost fully abolish the PMA-triggered PMN-induced oxidative impairment of alpha 1-PI. Protection may be due to the radical scavenger ability of P 1507, that markedly reduced superoxide anion production from PMNs. We also found that P 1507 did not significantly impair other defence mechanisms of PMNs (i.e. phagocytosis, chemotaxis and bactericidal activity). The release of cytokines (TNF-alpha, IL-6 and IL-8) from monocytes was not altered in the presence of P 1507. We conclude that the compound P 1507 may be considered for treatment of clinical conditions characterized by overload of oxidants, on the basis of its ability in preventing the oxidative damage of alpha 1-PI and of a lack of unwanted inhibitory effects towards defence mechanisms of phagocytes.
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PMID:Interactions of P 1507, a new antioxidant agent, with phagocyte functions. 774 Oct 36


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