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)

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

To study the pulmonary structural remodeling in pulmonary lymphangiomyomatosis, electron microscopy and light and electron microscopic immunohistochemical observations for elastin and alpha 1-antitrypsin were performed on five open lung biopsy samples. Lung specimens showed emphysema-like changes in areas of abnormally accumulated smooth muscle cells. In the alveolar walls having accumulated smooth muscle cells, elastic fibers were decreased in number, disrupted, granular, and occasionally accumulated. Ultrastructurally, elastic fibers in areas of smooth muscle cell accumulation showed poorly outlined amorphous components and a few microfibrils, and occasionally showed electron-dense granular deposits in and around the amorphous components. Spiraling collagen fibrils were frequently found associated with these abnormal elastic fibers. Immunohistochemistry for elastin showed even staining of amorphous components of elastic fibers in the areas of smooth muscle cell accumulation. alpha 1-Antitrypsin was also detected evenly in amorphous components of elastic fibers in the areas of smooth muscle cell accumulation. It is proposed that the emphysema-like lesions of lymphangiomyomatosis are mediated by the degradation of elastic fibers, and these degraded elastic fibers are related to an imbalance of the elastase/alpha 1-antitrypsin system similar to the probable pathogenesis of emphysema.
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PMID:Role of elastic fiber degradation in emphysema-like lesions of pulmonary lymphangiomyomatosis. 207 Nov 16

The lung contains a host of extracellular matrix components that comprise the supporting and adhesive elements of conducting airways, alveoli and the vascular tree. While none of these components is unique to the lung, their peculiar distribution determines the architecture and function of this gas exchange organ. Cells and tissues of the lung interact with the matrix through a variety of surface receptors, especially the integrins and adhesive molecules, some of which may play important roles in lung injury and repair. Collagen type I is the predominant determinant of tensile strength, but as many as 11 other genetic types of collagen with specialized adhesive and connecting functions can be found in various lung structures, including cartilage and basement membranes. Excessive matrix accumulation in the lung is the result of a complex set of influences on gene regulation, part of which may be due to the presence of inflammatory cytokines that directly stimulate matrix synthesis. However, degradation and turnover of the matrix are also critical processes influenced by many of the same mediators. Collagenase and gelatinase (type IV collagenase) are tightly-regulated metalloenzymes that, together with a set of specific inhibitors of metalloproteinases, determine the net abundance and distribution of collagen. Elastases of several biochemical types are also under tight regulation by proteinase inhibitors. Elastin is essential to lung function at the level of alveolar wall resiliency and patency, and loss of elastin in emphysema appears to be due to uncontrolled degradation of the embryologically-established pattern of elastic fibres accompanied by nonfunctional replacement as a response to injury. Injury to the vascular endothelium of the lung, as well as other physiological insults that elevate pulmonary blood pressure, can lead to the excessive accumulation of collagen and elastin in the conductance and resistance arteries of the pulmonary circulation. Mechanical stress and endothelial injury may mediate the medial hypertrophy of these vessels. Extracellular matrix components are critically involved in every stage of lung biology: development, normal function and acute and chronic disease states. To date, only glucocorticoids, cross-linking inhibitors, and protease inhibitors have been used in a general attempt to suppress either excessive matrix accumulation or loss. More detailed understanding of the regulation and specific interactions of matrix components is central to the analysis of disease states and the development of appropriate therapeutic strategies.
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PMID:Biochemistry and turnover of lung interstitium. 228 53

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

Human leukocyte elastase (HLE) has been demonstrated on lung elastic fibers in areas of pulmonary emphysema. In vitro studies in our laboratory have shown that HLE-elastin complexes may be remarkably stable. We tested the possibility that elastin-bound HLE may retain catalytic activity in the presence of inhibitors that are effective against free HLE and found: (1) alpha-1-proteinase inhibitor (alpha 1PI), antileukoprotease (ALP), and eglin C inhibited free HLE on an approximately 1:1 molar basis, measured with either 3H-elastin or a synthetic peptide substrate; (2) the ability of each inhibitor to control catalytic activity of HLE when complexed with elastin was impaired (e.g., in a 24-h assay, a 70-fold molar excess of alpha 1PI gave only 93% inhibition of HLE); and (3) a chloromethyl ketone inhibitor of HLE gave qualitatively similar results, although at the low enzyme concentrations used it was a less effective inhibitor of free and elastin-bound enzyme than were the polypeptide inhibitors. Further, we found evidence for two distinct mechanisms of inhibition of elastin-bound HLE. alpha 1PI and eglin C prevented elastin solubilization largely by enhancing net dissociation of HLE from the complexes; enzyme remaining bound to the substrate retained essentially full activity. In contrast, ALP and the chloromethyl ketone prevented elastin solubilization by binding to the complexes and inhibiting the enzyme in situ. These results may have implications regarding progressive elastin solubilization in vivo and should stimulate further investigation of enzyme activity in heterogeneous systems in which one or more reactants are insoluble.
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PMID:Inhibition of human leukocyte elastase bound to elastin: relative ineffectiveness and two mechanisms of inhibitory activity. 231 May 84

The phorbol myristate acetate (PMA)-differentiated myelomonocytic cell line, THP-1, and human alveolar macrophages contain the cysteine proteinase cathepsin L. This enzyme is synthesized as a 43-kD proenzyme and processed to the active 25-kD form. Differentiation of THP-1 cells in the presence of human serum resulted in an increase in the size of the vacuolar compartment and the accumulation of more 25-kD cathepsin L antigen, as compared with THP-1 cells differentiated in the presence of fetal calf serum. Cells cultured in both types of sera have equivalent levels of cathepsin L mRNA. Metabolic labeling experiments demonstrated equivalent rates of synthesis, processing to the active form, and persistence in both culture conditions. An extracellular source of enzyme was documented by immunoblotting human serum which demonstrated 25-kD cathepsin L antigen; furthermore, we demonstrated that both THP-1 cells, differentiated in human serum, and human alveolar macrophages take up the 43-kD proenzyme and process it to the 25-kD form. Thus, human serum contains a factor(s) that induces both a marked increase in the size of the vacuolar compartment in differentiated THP-1 cells and a novel pathway that is responsible for the uptake and processing of extracellular cathepsin L. The activity of this inducible pathway is a major determinant of levels of intracellular cathepsin L. Cathepsin L is a potent elastase and the regulation of its uptake and processing may play a role in the pathogenesis of disease processes characterized by the destruction of elastin, such as pulmonary emphysema.
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PMID:Uptake of extracellular enzyme by a novel pathway is a major determinant of cathepsin L levels in human macrophages. 236 15

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

Elastase activity directed against lung extracellular matrix is currently believed to be important in the pathogenesis of pulmonary emphysema. Although human alveolar macrophages degrade elastin when in direct contact with this substrate in vitro, studies of free elastase activity in medium conditioned by human alveolar macrophages have yielded variable results. As human alveolar macrophages secrete the tissue inhibitor of metalloproteinases (TIMP), an inhibitor of collagenase and of other connective-tissue-derived mammalian metalloproteinases, we speculated that this inhibitor's effects might extend to macrophage elastase. Using metalloproteinase elastase from the murine macrophagelike cell line P388D1, we observed that human alveolar macrophage conditioned medium inhibits metalloproteinase elastase and that this inhibitory activity could be blocked by specific antibody to TIMP. Alpha 2-macroglobulin, another proteinase inhibitor secreted by alveolar macrophages, also inhibited metalloproteinase elastase, but its inhibitory capacity was not blocked by antibody to TIMP. Because detergents are often included in elastase assays, we examined the effects of sodium dodecyl sulfate (SDS). Buffers containing SDS and SDS-treated elastin were found to exert diverse effects on metalloproteinase elastase, TIMP, and alpha 2-macroglobulin activities, including a marked inhibition of metalloproteinase elastase activity by SDS-containing buffers. These findings suggest that detection of secreted metalloproteinase elastase activity by human alveolar macrophages is complicated by the concomitant release by these cells of inhibitors of metalloproteinases, and that assay conditions can markedly influence the results.
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PMID:Human alveolar macrophages secrete an inhibitor of metalloproteinase elastase. 243 67

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


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