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)

Human neutrophil elastase degraded tropoelastin approximately 9 times faster than it did solubilized elastin and approximately 19 times faster than it did lung elastin. When bound to alpha2-M, the enzyme retained approximately 6 per cent of its activity toward tropoelastin and solubilized latter observations suggest that alpha2-M--bound elastase, cleared slowly from lung extracellular tissue space, may participate normally in the turnover of soluble precursor (s) of elastin and may contribute to the development of emphysema in alpha1-antitrypsin deficiency.
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PMID:Degradation of tropoelastin and elastin substrates by human neutrophil elastase, free and bound to alpha2-macroglobulin in serum of the M and Z (Pi) phenotypes for alpha1-antitrypsin. 8 40

The important role that elastin plays in the development and proper function of lung has long been recognized. Also, the intimate connection between pulmonary emphysema and the destruction of alveolar elastin has been well established. Understanding the mechanisms regulating pulmonary elastin synthesis is crucial to fully understanding these normal and pathological processes. In this article, we review recent literature on elastin structure, the elastin gene and its multiple RNA transcripts, and the different tropoelastin isoforms that are translated from these mRNAs. The similarity of lung and aortic elastin and the cellular origin of lung elastin are also discussed. We next examine the few studies addressing regulation of elastin expression during lung development, maturation, and aging. The search for modulators of pulmonary elastogenesis, which has yielded mostly negative results, is then reviewed. Finally, we present a cell culture model that has been developed to study the molecular basis of lung injury in pulmonary emphysema.
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PMID:The regulation of lung elastin synthesis. 220 Feb 80

While elastin degradation is a hallmark of pulmonary emphysema, it is likely that elastin synthesis also occurs. However, the supramolecular structure and function of the newly synthesized elastin are abnormal. Very little is known about the regulation of elastin synthesis during the development of emphysema when prominent collections of mononuclear phagocytes are found in and near the alveolar interstitium. Transforming growth factor-beta (TGF-beta) is an important regulator of collagen and fibronectin production in wound healing, which is also accompanied by an influx of mononuclear phagocytes. We hypothesized that TGF-beta may influence elastin production by fibroblasts in the pulmonary interstitium. Therefore, we examined the influence of TGF-beta on the production of elastin by postconfluent cultures of neonatal rat lung fibroblasts. Elastin production was quantitated by analyzing the incorporation of [3H]valine into the soluble elastin precursor tropoelastin (TE). The incorporation of [3H]valine into TE was approximately 2-fold greater in the presence of 40 or 100 pM TGF-beta than in its absence. The intracellular, free [3H]valine pool was increased by 18% in the presence of TGF-beta. Therefore, TGF-beta-related differences in the precursor pool size were not solely responsible for the observed increase in [3H]valine incorporation. Northern analysis demonstrated that the increase in TE was accompanied by a smaller but significant increase in the steady-state level of elastin mRNA. Thus, the observed increase in TE production can be at least partially attributed to a pretranslational effect of TGF-beta.
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PMID:Transforming growth factor-beta increases elastin production by neonatal rat lung fibroblasts. 220 40

Disruption and degradation of interstitial elastic fibers are significant characteristics of pulmonary emphysema. In order to examine the responses of elastogenic cells to the conditions mimicking degradation of interstitial pulmonary elastin, rat pulmonary fibroblast cultures were used as an in vitro model. Second passage fibroblasts were divided into two different environmental situations to represent cells adjacent to and remote from the site of elastase-digested matrix. One set of cell cultures was briefly digested with pancreatic elastase. The resultant digest was then added back incrementally to the medium of elastase-digested cell cultures and to the medium of a second set of undigested cultures. Both sets of cell cultures remained viable and metabolically active during these treatments (96 h of incubation) as judged by protein synthesis, cell number, and steady-state levels of beta-actin mRNA. However, the two sets of cultures exhibited opposite responses in elastin gene expression with addition of increasing amounts of the elastase digest. The elastase-digested cultures exhibited a 200% increase in extractable soluble elastin and a 186% increase in tropoelastin mRNA with the addition of increasing amounts of the elastase digest to the medium. Conversely, the amount of soluble elastin recovered from the undigested cultures decreased 75%, and the steady-state level of tropoelastin mRNA decreased 63%. Soluble elastin peptides generated from oxalic acid treatment of purified elastin were shown to decrease tropoelastin mRNA in undigested cell cultures in the same manner as the elastase digest. Based on these data, we propose that pulmonary fibroblast elastin gene expression can be controlled coordinately by the state of the extracellular matrix and solubilized peptides derived from that matrix. Such integrated regulation may serve to localize elastin repair mechanisms.
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PMID:Pulmonary fibroblasts: an in vitro model of emphysema. Regulation of elastin gene expression. 239 39

Serum enzyme activity in 81 patients with various medical and dermatologic problems was determined with succinyl-(L-alanyl)3-p-nitroanilide as substrate. Values exceeding the limit of mean +/- 3 SD in healthy controls were detected in 16 patients. The highest activity, greater than 80 times the mean in the controls, was found in a 20-year-old patient with severe pulmonary emphysema and cutis laxa. The enzyme activity in the patient's serum was enhanced by Ca2+ and was inhibited by metal chelators but not by serine protease inhibitors. The pH optimum of the enzyme was 7.6. The enzyme was partially purified by gel filtration chromatography. Enzyme activity eluted in two major peaks with apparent molecular weights of greater than 10(7) daltons (peak I) and approximately 2.5 X 10(5) daltons (peak II). When compared with the elution patterns in the patient's mother and a healthy control, the elevated enzyme activity in the patient's serum was associated with peak I. The partially purified enzyme in peak I was not complexed with alpha 2-macroglobulin. The peak I enzyme was capable of degrading tropoelastin and a synthetic dinitrophenyl peptide at a glycyl-isoleucyl sequence, but not native or denatured collagen.
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PMID:Characterization and partial purification of a neutral protease from the serum of a patient with autosomal recessive pulmonary emphysema and cutis laxa. 388 13

A mild form of emphysema was produced in pigs raised on a copper-deficient, zinc-supplemented diet. The copper-requiring enzyme, lysyl oxidase, catalyzes the cross-linking of tropoelastin into mature elastin. Zinc further inhibits the activity of lysyl oxidase. Lungs from animals raised on copper-deficient, zinc-supplemented diets of demonstrate perforations in alveolar walls and diminished amounts of elastin bronchi and pulmonary arteries. Mean linear intercepts are greater and alveolar internal surface areas are less than those in control animals, fulfilling the generally accepted definition of emphysema. Physiologic confirmation is provided by a leftward shift of the saline volume-pressure curves when compared with those in control animals. Ultrastructurally, the alveolar walls are effaced and pores of Kohn are enlarged. There are areas in which elastin is absent leaving remnant microfibrils, and there are other changes consistent with active elastin synthesis. Biochemical data demonstrate no difference in elastin content as micrograms/ml of fat-free dry weight but do demonstrate increased collagen content in experimental animal lungs compared with that in control lungs. Ultrastructural similarities to enzyme-induced models of emphysema suggest the presence of elastin degradation in our model. We speculate that although the copper-deficient, zinc-supplemented state may stimulate protein synthesis in general, elastin is being degraded by endogenous means, but collagen is not.
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PMID:A copper-deficient, zinc-supplemented diet produces emphysema in pigs. 612 18

Water-soluble components of the gas phase of filtered cigarette smoke inhibit formation of covalent desmosine cross-links during conversion of tropoelastin to elastin in vitro. These same smoke components also suppress lysyl-oxidase-catalyzed oxidation of lysine epsilon-amino groups in tropoelastin (the chemical step preceding formation of all elastin cross-links, including desmosine) in a dose-dependent fashion. However, gas phase smoke does not block the oxidation of diaminopentane by lysyl oxidase. Thus, gas phase cigarette smoke may possess substrate-directed (rather than enzyme-directed) inhibitory components capable of interfering with elastin cross-linking in vitro. Similar effects occurring in smokers' lungs could impede elastin repair and contribute to the development of pulmonary emphysema.
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PMID:Cigarette smoke blocks cross-linking of elastin in vitro. 683 36

This study suggests one mechanism by which alveolar macrophages accumulate in the lung in pulmonary emphysema: elastin fragments generated at the diseased sites are potent chemoattractants for monocytes, the precursors of the macrophages. The most chemotactic elastin fragments have a molecular weight between 10,000 and 50,000 and are active at concentrations as low as 3 nanograms per milliliter. By comparison, elastin fragments with higher molecular weights and desmosines are active at concentrations greater than 0.3 microgram per milliliter. In addition, preincubation of monocytes with the 10,000- to 50,000-dalton elastin impairs the ability of the cells to migrate toward elastin fragments but not toward activated serum. Fragments of tropoelastin are not chemotactic for monocytes. Because elastin, but not tropoelastin, contains lysyl-derived cross-links, these structures may be the active chemotactic site on the elastin fragments.
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PMID:Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. 723 86

Elastic fibres are present in lung structures including alveoli, alveolar ducts, airways, vasculature and pleura. The rate of lung elastin synthesis is greatest during fetal and neonatal development, and is minimal in the healthy adult. We have determined that glucocorticoids up-regulate fetal lung tropoelastin expression while concomitantly accelerating terminal airspace maturation. Because there is minimal turnover of elastin in healthy adult lung, the elastin incorporated into the lung early in development supports lung function for the normal lifespan. However, in the adult lung, in pathological circumstances such as emphysema or pulmonary fibrosis there may be reactivation of elastin expression. We have found in silica-induced pulmonary fibrosis that expression of tropoelastin is primarily increased in the walls and the septal tips of the alveolus, with modest increases in other compartments which normally express tropoelastin during development. This finding suggests that the mesenchymal cell of the alveolar wall increases tropoelastin expression during fibrotic disorders. In emphysema and fibrosis, elastin is present in abnormal-appearing, probably non-functional, elastic fibres, suggesting that the adult lung cannot recapitulate the elastic fibre assembly mechanisms operative during normal lung growth.
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PMID:Elastin in lung development and disease. 857 58

PDGF-A(-/-) mice lack lung alveolar smooth muscle cells (SMC), exhibit reduced deposition of elastin fibres in the lung parenchyma, and develop lung emphysema due to complete failure of alveogenesis. We have mapped the expression of PDGF-A, PDGF receptor-alpha, tropoelastin, smooth muscle alpha-actin and desmin in developing lungs from wild type and PDGF-A(-/-) mice of pre- and postnatal ages in order to get insight into the mechanisms of PDGF-A-induced alveolar SMC formation and elastin deposition. PDGF-A was expressed by developing lung epithelium. Clusters of PDGF-Ralpha-positive (PDGF-Ralpha+) mesenchymal cells occurred at the distal epithelial branches until embryonic day (E) 15.5. Between E16.5 and E17.5, PDGF-Ralpha+ cells multiplied and spread to acquire positions as solitary cells in the terminal sac walls, where they remained until the onset of alveogenesis. In PDGF-A(-/-) lungs PDGF-Ralpha+ cells failed to multiply and spread and instead remained in prospective bronchiolar walls. Three phases of tropoelastin expression were seen in the developing lung, each phase characterized by a distinct pattern of expression. The third phase, tropoelastin expression by developing alveolar SMC in conjunction with alveogenesis, was specifically and completely absent in PDGF-A(-/-) lungs. We propose that lung PDGF-Ralpha+ cells are progenitors of the tropoelastin-positive alveolar SMC. We also propose that postnatal alveogenesis failure in PDGF-A(-/-) mice is due to a prenatal block in the distal spreading of PDGF-Ralpha+ cells along the tubular lung epithelium during the canalicular stage of lung development.
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PMID:Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development. 937 92


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