Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the possible role of suppression of antiproteases by cigarette smoke in the pathogenesis of pulmonary emphysema in smokers, the following experiments were carried out. Elastin-agarose gels were impregnated with cigarette smoke condensate dissolved in dimethyl sulfoxide or with the solvent alone. This procedure affected neither local pH of the gel nor subsequent physical behavior (diffusion) of antiprotease. Elastases from various sources were then allowed to diffuse through the impregnated gels toward a counter-diffusing sample of antiprotease. The effectiveness of the antiprotease in blocking the enzyme was determined from the extent of elastolysis. The elastin substrates used included beef ligament elastin and dog lung elastin. The enzymes used were porcine pancreatic elastase and pure human leukocyte elastase. The antiproteases tested included human serum, pure human a1-antitrypsin, human bronchopulmonary lavage fluid, and a synthetic chloromethyl ketone inactivator of elastase. The results showed that whole, unfractionated cigarette smoke condensate suppressed all of the antiproteases tested, except for the chloromethyl ketone. These observations are discussed in terms of the protease-pathogenesis model of pulmonary emphysema.
 ...
PMID:Possible mechanisms of emphysema in smokers: cigarette smoke condensate suppresses protease inhibition in vitro. 30 25

The intratracheal injection of pancreatic elastase results in an acute loss of elastin from the lungs of hamsters and the development of emphysema. We used measurements of the unique covalent cross linking amino acids of elastin, desmosine and isodesmosine, to quantitate elastin. Direct measurements on the lungs estimated an average loss of elastin of 57% after elastase injection. Elastin breakdown products were also quantitated in the urine and feces after injection. An average of 8.8 nmol of desmosines was recovered from the urine of each hamster. This amount represented the desmosines from 61% of the elastin lost from the lungs. Desmosine and isodesmosine existed in the urine in peptide fractions that ranged from 9 to 27,000 daltons with an average of 13,000. Only trace quantities of desmosines could be detected in feces. Desmosines injected intraperitoneally were completely recovered in the urine, and radioactive tracer studies failed to reveal in vivo catabolism of injected desmosines. These results suggest that measurement of urinary desmosines holds promise for the study of elastin turnover.
 ...
PMID:Urinary excretion of elastin peptides containing desmosin after intratracheal injection of elastase in hamsters. 65 92

During pathologies such as arteriosclerosis and emphysema, degradation of elastin by elastases occurs and elastin peptides are produced. In order to evaluate elastin degradation, measurements of elastin peptide concentration in human blood were carried out. According to elastin peptides used for obtention of antibodies and for ELISA, the measured values are different. Elastin peptides have several biological effects: they are chemotactic, modify ion fluxes and several intracellular mechanisms.
 ...
PMID:[Elastin and arteriosclerosis: determination and characterization of elastin peptides in blood]. 130 Dec 21

Pulmonary emphysema is likely to be the result of elastic tissue digestion by unrestrained elastase activity in the lung. Elastin breakdown by elastases results in the release of soluble elastin fragments (EDP), which may be measured in plasma by an ELISA. Plasma EDP levels measured using an ELISA were determined in the following groups: disease-free children (n = 24), 0.162 +/- 0.082 ng/ml; disease-free adult nonsmokers (n = 114), 1.74 +/- 0.8 ng/ml; smokers (n = 68), 2.76 +/- 4.59 ng/ml; reformed smokers (n = 43), 1.91 +/- 1.14 ng/ml. Adults with established pulmonary emphysema (n = 50), as defined by bullous formation on the chest radiograph, had levels of 50.83 +/- 24.8 ng/ml, significantly higher than the disease-free groups at p < 0.01. Pulmonary emphysema can be reflected by pulmonary function tests, especially those that measure the pulmonary elastic properties, and by computed tomographic (CT) scan percent emphysema score. We therefore examined the relationship of plasma EDP to these other indicators of pulmonary emphysema in a separate group of 26 subjects using elastic recoil measurements (K), and a further group of 30 subjects with CT scan percent emphysema score. A significant correlation of p < 0.001 was shown for plasma EDP and K and a significant correlation of p < 0.01 was shown for plasma EDP and CT scan percent emphysema score, these correlations suggesting that plasma EDP levels are indicators of the loss of pulmonary distensibility and of mild to moderate pulmonary emphysema. These findings suggest that pulmonary emphysema is characterized by active elastin breakdown.
 ...
PMID:Plasma elastin-derived peptide levels in normal adults, children, and emphysematous subjects. Physiologic and computed tomographic scan correlates. 144 63

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.
 ...
PMID:Elastin decreases the efficiency of neutrophil elastase inhibitors. 199 Oct 75

Normal structure and function of the lung parenchyma depend upon elastic fibers. Amorphous elastin is biochemically stable in vitro, and may provide a metabolically stable structural framework for the lung parenchyma. To test the metabolic stability of elastin in the normal human lung parenchyma, we have (a) estimated the time elapsed since the synthesis of the protein through measurement of aspartic acid racemization and (b) modeled the elastin turnover through measurement of the prevalence of nuclear weapons-related 14C. Elastin purified by a new technique from normal lung parenchyma was hydrolyzed; then the prevalences of D-aspartate and 14C were measured by gas chromatography and accelerator-mass spectrometry, respectively. D-aspartate increased linearly with age; Kasp (1.76 x 10(-3) yr(-1) was similar to that previously found for extraordinarily stable human tissues, indicating that the age of lung parenchymal elastin corresponded with the age of the subject. Radiocarbon prevalence data also were consistent with extraordinary metabolic stability of elastin; the calculated mean carbon residence time in elastin was 74 yr (95% confidence limits, 40-174 yr). These results indicate that airspace enlargement characteristic of "aging lung" is not associated with appreciable new synthesis of lung parenchymal elastin. The present study provides the first tissue-specific evaluation of turnover of an extracellular matrix component in humans and underscores the potential importance of elastin for maintenance of normal lung structure. Most importantly, the present work provides a foundation for strategies to directly evaluate extracellular matrix injury and repair in diseases of lung (especially pulmonary emphysema), vascular tissue, and skin.
 ...
PMID:Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. 202 48

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.
 ...
PMID:Transforming growth factor-beta increases elastin production by neonatal rat lung fibroblasts. 220 40

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.
 ...
PMID:Biochemistry and turnover of lung interstitium. 228 53

Elastin in the most resistant fibrous protein of the organisms. Its degradation is catalysed by proteases designated as elastases. Elastic fibers appeared during phylogenesis at the level of the first Vertebrates and rendered possible the emergence of efficient circulatory and respiratory systems which were necessary for the development of the higher Vertebrates. Several pathological conditions, mostly age-dependent, are accompanied by the degradation of elastic fibers or their alteration due to increasing association with lipids and calcium salts. Several proteases (endopeptidases) of cellular origin were described over the last years, especially those of PMN leukocytes, platelets, monocytes-macrophages, smooth muscle cells and fibroblasts. Although less active on fibrous elastin than pancreatic elastase, these enzymes may well play an important role in the development of age-dependent pathologies such as athero-arteriosclerosis and emphysema. The involvement of cellular elastases in these pathologies is discussed in some detail. The age-dependent increase, both in vivo and in vitro of the elastase activity of fibroblasts and smooth muscle cells appears to play an important role in the modifications of cell behaviour observed in the above pathologies.
 ...
PMID:[Proteases of the elastase type]. 306 1

Elastin is an extracellular matrix protein critical to the normal structure and function of human lung. Recently reported data indicate that live human alveolar macrophages can degrade purified elastin in vitro. In this study, we directly compared the elastolytic activity of alveolar macrophages with that of human neutrophils. In the absence of proteinase inhibitors, human neutrophils degrade much more elastin than do human alveolar macrophages. However, macrophages cultured in 10% human serum and in contact with purified 3H-elastin degraded 4.7 micrograms elastin/10(6) cells per 24 h, as compared to less than 1 microgram/10(6) cells/24 h for neutrophils. We observed a similar pattern when the two cells were cultured in human alveolar fluid. We determined that the relative resistance of macrophage elastolytic activity to serum or alveolar proteinase inhibitors was not simply due to phagocytosis of substrate by the larger macrophages. Live macrophages as well as neutrophils degrade 125I-elastin coupled to noningestible sepharose beads. Again in serum-free media, neutrophils degraded eight-fold more elastin than macrophages but only macrophages degraded sepharose-coupled elastin in the presence of 10% serum. Because of these findings, we compared the enzymatic mechanisms of elastin breakdown by macrophages with that of neutrophils. Macrophage elastolytic activity is largely (65-80%) due to a cysteine proteinase(s), at least part of which is Cathepsin B. Approximately half of the cysteine proteinase activity appeared to be expressed at or near the cell surface. These experiments defined two enzymatically distinct pathways of elastin breakdown by human inflammatory cells: the classic, neutrophil derived soluble elastase(s) that is sensitive to serum and alveolar proteinase inhibitors, and a macrophage-mediated pathway that is largely cell associated and relatively resistant to inhibitors. The function of the two pathways depends on the relative excess or deficiency of soluble inhibitors. At inflammatory sites rich in proteinase inhibitors, tissue macrophages may degrade more extracellular matrix elastin than neutrophils. In smokers without antiproteinase deficiency, pulmonary macrophages, which are known to be increased in number, may be the more important cause of elastin breakdown and emphysema.
 ...
PMID:Comparison of live human neutrophil and alveolar macrophage elastolytic activity in vitro. Relative resistance of macrophage elastolytic activity to serum and alveolar proteinase inhibitors. 656 28


1 2 3 4 Next >>