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)

Pulmonary emphysema is a disease in which peptides formed by the enzymatic degradation of the amorphous component of interstitial elastin may be release from the lung. In order to provide a test that can monitor the destruction of lung elastin invivo, we developed a hemagglutination inhibiton assay that specifically and quantitatively measure elastin-derived peptides in serum. Using this method, was measured the concentration of elastin-derived peptides in the serums of dogs developing emphysema through the administration of porcine pancreatic elastase. Elastin-derived peptides could be detected in the serums for a period of 12 days after the administration of a single 25- or 50-mg dose of elastase, and for at least 40 days after a 100-mg dose. There was a good correlation between the maximal concentration of elastin derived peptides found in the serums and the amount of elastase administered to the animal. This immunologic method may be useful in following the progression of experiment emphysema.
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PMID:Immunologic identification of elastin-derived peptides in the serums of dogs with experimental emphysema. 690 15

Elastin-derived peptides, produced by digesting human aortic elastin and bovine ligament elastin with human neutrophil elastase, were tested for chemotactic activity. At 100 micrograms protein/ml, elastin digests were nearly as active for monocytes as saturating amounts of complement-derived chemotactic activity. Neutrophils and alveolar macrophages showed less response to elastin peptidces than did monocytes. Fractionation of the digests by gel filtration chromatography disclosed that maximal chemotactic activity eluted in fractions corresponding to 14,000-20,000 mol wt containing most of the desmosine cross-links in the digests. Whole human serum and rabbit anti-elastin immunoglobulin inhibited the chemotactic activity. Purified desmosine also showed chemotactic activity for monocytes, maximal at 10 nM. These findings suggest that elastin-degradation products enriched in cross-linking regions recruit inflammatory cells in vivo and that elastin proteolysis, characteristic of emphysema, may be a signal for recruitment of mononuclear phagocytes into the lungs.
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PMID:Chemotactic activity of elastin-derived peptides. 690 89

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

Elastin is known to occur in the lung parenchyma and pleura as well as in the pulmonary vessels, but no detailed studies of this elastin's linkage between them have been done in three dimensions. For many years we have known that there is abundant elastin in the mammalian lungs, which may be associated with etiology of causing emphysema. We have developed selective casting methods to allow us to determine the location where elastin is found morphologically. The method involves casting either the vasculature via the right ventricle, or the airways via the trachea in the air sacs. Studies of the vasculature were done with the lung inflated to 80% of the vital capacity. The casted lungs were then put in 0.1 N NaOH at 75 degrees C for 48 hours, turning them frequently. THis method removed all non-elastin tissues. The scanning electron microscopy (SEM) was used to reveal the three dimensional pictures of elastin structures from both lung parenchyma and pulmonary vessels. Elastin was seen as fenestrated sheets and some fibers in both the vessels and the airways. Elastin in the two different locations was often interconnected. Studies on 6 dogs, 8 rabbits, and 2 pigs showed no significant species difference at the level of resolution of the SEM, which was used to study the specimens after they had been freeze-dried.
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PMID:Three dimensional structures of pulmonary elastin; airway vs vascular elastin. 787 52

Nitrogen dioxide (NO2), an air pollutant produced by burning fossil fuels and a component of cigarette smoke, is thought to contribute to the pathogenesis of pulmonary diseases, such as emphysema. In order to gain information on the mechanism by which NO2 damages the lung and proteins vital to its function, as well as its reaction with proteins in general, in vitro exposures of alpha-1-proteinase inhibitor (alpha 1PI), elastin, poly-L-lysine, and poly-L-arginine were performed. The ability of alpha 1PI to inhibit its natural physiological target, human neutrophil elastase (HNE), declined with exposure to 54% of the control value at molar ratios of NO2:alpha 1PI of 400:1 and greater. Exposure of alpha 1PI to NO2 resulted in a 50% loss of immunoreactivity with either monoclonal or polyclonal antibodies in an enzyme-linked immunosorbent assay at molar ratios of NO2:alpha 1PI of 100:1 and greater. The results of parallel O-phthalaldehyde and bicinchoninic acid protein assays as well as amino acid analysis on control and NO2-exposed alpha 1PI suggested a reactivity of NO2 with lysine residues. Elastin and poly-L-lysine were labeled by reductive methylation of amino groups with [3H]HCHO prior to treatment with NO2 in aqueous solutions at physiological pH. NO2 exposure of elastin resulted in the solubilization of 84% of the associated radioactivity of which 79% was identified as [3H]methyllysine by amino acid analysis. After NO2 exposure of poly-L-[3H]lysine, gel filtration chromatography revealed that the 50,000 M(r) poly-L-[3H]lysine had been degraded to small peptides of 1-3000 M(r). Similarly, after NO2 exposure of unlabeled poly-L-arginine, gel filtration chromatography, and total peptide analysis revealed that the 47,500 M(r) peptide was also partially degraded to peptides. These results suggest that NO2 reacts with the epsilon-amino groups of Lys residues (primary amines) and with the amide nitrogen (secondary amines) of surface-exposed Lys and Arg residues in the peptide backbone to result in peptide bond cleavage. These findings are the first indication of NO2-mediated peptide degradation and provide additional data on the potential of NO2 to damage proteins vital to the function of the lung in an in vitro exposure system.
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PMID:Nitrogen dioxide reactivity with proteins: effects on activity and immunoreactivity with alpha-1-proteinase inhibitor and implications for NO2-mediated peptide degradation. 832 82

Studies of collagen and elastin in pulmonary emphysema have been controversial. The problems involve methodologic differences; often whole lungs have been sampled and the types of emphysema have not been classified. Quantification of collagen and elastin is important since the increase in collagen supports the inflammatory-repair hypothesis of emphysema, which has been recently revived. On the other hand, loss of elastin supports the protease-antiprotease hypothesis. Accordingly, we measured collagen (hydroxy-proline) and elastin (desmosine) in 147 small samples of human lungs removed for cancer. The amount and type of collagen were also assessed histochemically in tissue blocks adjacent to the tissue used for the biochemical analysis. We found that collagen in the homogenates was increased only in irregular airspace enlargement, but histochemically, collagen was consistently increased in centriacinar, distal acinar, and irregular air-space enlargement sections. Elastin was decreased in all grades of panacinar air-space enlargement and also in severe centriacinar air-space enlargement. Our data support both the protease-antiprotease imbalance hypothesis in panacinar and the inflammatory-repair hypothesis in centriacinar, distal acinar, and irregular air-space enlargement.
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PMID:Collagen and elastin in human pulmonary emphysema. 817 82

Treatment of hamster lungs with porcine pancreatic elastase (PPE) causes emphysema and a decrease in lung elastin content, which returns to control level by Day 30. To explore the mechanism of alveolar wall remodeling after elastolytic injury, we examined the expression of elastin and alpha1(I) collagen mRNAs by in situ hybridization at 1, 2, 3, 5, 7, and 30 d after intratracheal PPE. The lungs of control animals displayed weak signals for elastin and alpha1(I) collagen mRNA in pleura, large arteries, veins, and airways. There was little or no signal in respiratory air space walls. Increased expression of elastin and alpha1(I) collagen mRNA began by Day 1 after PPE and reached an asymptote by Day 3 that was maintained by elastin until Day 7; expression of alpha1(I) collagen mRNA waned earlier. Elastin and, to a lesser extent, alpha1(I) collagen mRNA were heavily expressed in pleura, blood vessels, and airways. Analysis of serial sections showed elastin message was minimal in the walls of respiratory air spaces and when present, at 3, 5, and 7 d, was primarily found at the free margins of alveolar septa. Collagen message was very sparse in respiratory air space walls. By 30 d, elastin mRNA expression was reduced but still above control levels and emphysema was widespread and severe. Rank score of elastin mRNA expression in individual subpleural air spaces showed a positive correlation with air space size. In conclusion, most expression of elastin and alpha1(I) collagen mRNA occurs in the pleura, airway, and vascular walls. In respiratory air space walls, expression of elastin mRNAs occurs in damaged tissue at free septal margins.
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PMID:Remodeling of alveolar walls after elastase treatment of hamsters. Results of elastin and collagen mRNA in situ hybridization. 970 Jan 35

The aim of this study was to investigate the extracellular degrading proteolytic cascade proteins referred to as matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-9, membrane-type matrix metalloproteinase-1 (MT1-MMP), tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), TIMP-2, neutrophil elastase, and alpha1-antitrypsin in human pulmonary emphysema. Localization of MMP-1, MMP-2, MMP-8, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 was verified by immunohistochemical analysis. The results of our study indicated that the immunoreactivity of MMP-1, MMP-8, MMP-9, and TIMP-1 was absent, whereas MT1-MMP and MMP-2 were mainly observed in pneumocytes, fibroblasts, and alveolar macrophages. Although MT1-MMP and MMP-2 were observed both in emphysematous and normal lung tissue, these immunoreactivities were intense in the emphysematous samples. The presence of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 was confirmed at mRNA level by reverse transcription-PCR analysis and enzyme immunoassay (EIA). However, the only statistical difference that was observed was in MMP-2 and MMP-9 (MMP-2: emphysematous samples, 19.1+/-2.1 versus control samples, 5.2+/-0.60 microg/g protein, p < 0.05; MMP-9: emphysematous samples, 18.4+/-5.6 versus control samples, 8.1+/-2.7 microg/g protein, p < 0.05). Results of the neutrophil elastase as analyzed by EIA, and alpha1-antitrypsin levels as detected by laser nephelometric immunoassay, indicated no statistical difference between the emphysematous and control groups. In addition to the presence of mRNA levels, the level of MT1-MMP according to immunoblot analysis increased in the emphysematous samples. Gelatin zymographic analysis confirmed the presence of both pro and active forms of MMP-2, and the increased ratio of the active form of MMP-2 in emphysematous samples (25.9%+/-2.0% versus 11.2%+/-3.3%, p < 0.05), indicated in situ activation of MMP-2 by MT1-MMP. Elastin zymographic analysis showed elastolytic activity by MMP-2 and MMP-9 but not the reported band of macrophage metalloelastase (MMP-12). The data suggest that the MT1-MMP/MMP-2/TIMP-2 system plays a significant role in the MMP-mediated extracellular matrix degradation and tissue remodeling of emphysematous lungs, and thus may contribute to the weakening of lung parenchyma and lead to the formation of emphysema.
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PMID:Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. 975 52

Elastin is a major component of the mammalian lung, predominantly found in the alveoli. Destruction of alveolar elastic fibers is implicated in the pathogenic mechanism of emphysema in adults. These data define a role for elastin in the structure and function of the mature lung, and suggest that elastin is important for alveogenesis. To investigate the role of elastin in lung development, we examined mice lacking elastin (Eln-/-). At birth, the distal air sacs of Eln-/- lungs dilate to form abnormally large cavities. This phenotype appears before the synthesis and deposition of alveolar elastin, a process mediated by myofibroblasts and initiated after postnatal Day 4. Morphometric analyses demonstrate that the perinatal development of terminal airway branches is arrested in Eln-/- mice. The branching defect is accompanied by fewer distal air sacs that are dilated with attenuated tissue septae, a condition reminiscent of emphysema. Elastin expression in the lung parenchyma before alveogenesis is localized to the mesenchyme surrounding the developing airways, supporting a role for elastin in airway branching. Thus, in addition to its role in the structure and function of the mature lung, elastin is essential for pulmonary development and is important for terminal airway branching.
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PMID:Impaired distal airway development in mice lacking elastin. 1097 Aug 22

Mice lacking macrophage elastase (matrix metalloproteinase-12, or MMP-12) were previously shown to be protected from the development of cigarette smoke-induced emphysema and from the accumulation of lung macrophages normally induced by chronic exposure to cigarette smoke. To determine the basis for macrophage accumulation in experimental emphysema, we now show that bronchoalveolar lavage fluid from WT smoke-exposed animals contained chemotactic activity for monocytes in vitro that was absent in lavage fluid from macrophage elastase-deficient mice. Fractionation of the bronchoalveolar lavage fluid demonstrated the presence of elastin fragments only in the fractions containing chemotactic activity. An mAb against elastin fragments eliminated both the in vitro chemotactic activity and cigarette smoke-induced monocyte recruitment to the lung in vivo. Porcine pancreatic elastase was used to recruit monocytes to the lung and to generate emphysema. Elastin fragment antagonism in this model abrogated both macrophage accumulation and airspace enlargement.
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PMID:Elastin fragments drive disease progression in a murine model of emphysema. 1647 Feb 45


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