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 mechanisms by which cigarette smoking lead to bronchopulmonary diseases are incompletely understood. The most characteristic lesion is a chronic macrophage-alveolitis accompanied by slight fibrosis and emphysema. The macrophages contain a ceroid-like granular autofluorescent pigment in their lysosomes. Using immunohistochemical methods, open lung-, transbronchial biopsies and cells obtained by broncho-alveolar lavage from cigarette smokers were studied: anti-human macrophage serum and anti-human elastase, immune sera against type I, type III collagens and fibronectin were used in the demonstration of the cellular components of alveolitis and the connective tissue constituents of fibrosis. The characteristic red-brown autofluorescent pigment of the macrophages was also found in an extra-alveolar location mainly in peribronchial, septal and pleural scars. Similar emission colour occurred focally in the elastic laminae of fibrotic alveoli and sclerotic arteries. Granular fluorescent pigment was found in many bronchial epithelial cells. The epithelial pigmentation was associated with increased transcription of nucleic acid proteins, revealed by colloid silver (AgNOR) reaction. The results suggest that the autofluorescent pigment substances in macrophages may indicate or also play a role in the development of pathological connective tissue and epithelial changes of smoker's lung, in addition to the known mediators and enzymes.
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PMID:Cellular autofluorescent pigment and interstitial fibrosis in smoker's lung. 144 83

We studied changes in rat lung fibronectin (FN) content and synthesis after endobronchial administration of elastase. A severe hemorrhagic neutrophilic alveolitis ensued with plasma protein leakage, initial rise in tissue FN content, and sustained rise in FN synthesis. Unlike fibrotic models where initial rises in tissue FN levels are sustained, levels in this model normalized promptly. This, in the setting of increased synthesis is consistent with increased degradation. This degradation of tissue FN may result in the disruption of the lung architecture, interfere with the deposition of newly synthesized matrix and could partly explain the development of emphysema in a model where excess fibronectin synthesis is observed.
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PMID:Changes in tissue fibronectin in elastase induced lung injury. 174 1

Proteinase 3 (PR-3) is a human polymorphonuclear leukocyte (PMNL) serine proteinase that degrades elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters (Kao, R. C., Wehner, N. G., Skubitz, K. M., Gray, B. H., and Hoidal, J. R. (1988) J. Clin. Invest. 82, 1963-1973). We have determined the primary structure of several PR-3 peptides and have analyzed catalytic properties of the enzyme. The enzyme has considerable amino acid sequence homology with two other well characterized PMNL neutral serine proteinases, elastase and cathepsin G. Furthermore, the NH2-terminal amino acid sequence of PR-3 is identical to that of the target antigen of the anti-neutrophil cytoplasmic autoantibodies associated with Wegener's granulomatosis. PR-3 degrades a variety of matrix proteins including fibronectin, laminin, vitronectin, and collagen type IV. It shows no or minimal activity against interstitial collagens types I and III, respectively. The analysis of peptides generated by PR-3 digestion of insulin chains and the activity profile against a panel of chromogenic synthetic peptide substrates show that PR-3 prefers small aliphatic amino acids (alanine, serine, and valine) at the P1 site. The elastase-like specificity of PR-3 is consistent with its striking sequence homology to elastase at substrate binding sites. PR-3 is inhibited by alpha 1-proteinase inhibitor (ka = 8.1 x 10(6) M-1 S-1; delay time = 25 ms) and alpha 2-macroglobulin (ka = 1.1 x 10(7) M-1 S-1; delay time = 114 ms) but not by alpha 1-anti-chymotrypsin. In contrast to elastase and cathepsin G, PR-3 is not inhibited by secretory leukoprotease inhibitor and is weakly inhibited by eglin c. Thus, PR-3 is distinct from the other PMNL proteinases.
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PMID:Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase. Structural and functional properties. 203 50

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

Chronic exposure to coalmine dust is associated with the accumulation of inflammatory leukocytes in the bronchoalveolar region of the lung and, in the long term, with fibrosis and emphysema of the lung parenchyma. Degradation of connective tissue by inflammatory leukocytes has been implicated in the parenchymal damage that precedes the development of fibrotic or emphysematous lesions in the lung. The ability of inflammatory leukocytes obtained by bronchoalveolar lavage from rats inhaling coalmine dust to degrade fibronectin in vitro was assessed. The animals were exposed to an airborne mass concentration of dust similar to the maximum permissible level in United Kingdom collieries. The bronchoalveolar lavage cell population showed changes with duration of dust exposure; there were increases in the total number of leukocytes and in the percentage of polymorphonuclear leukocytes, and the macrophage component of the lavage became increasingly activated, as assessed by the ability of these cells to spread on glass. In addition, degradation of a radiolabelled fibronectin matrix by the coalmine dust exposed bronchoalveolar leukocytes increased with duration of dust exposure. Thus exposure to airborne coalmine dust causes an influx of inflammatory leukocytes to the alveolar region. These cells have enhanced ability to degrade fibronectin and this may be important in subsequent disease development.
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PMID:Inflammatory responses in lungs of rats inhaling coalmine dust: enhanced proteolysis of fibronectin by bronchoalveolar leukocytes. 269 94

1. Neutrophils from patients with chronic obstructive bronchitis and emphysema or age-matched control subjects were cultured on a substrate of 125I-fibronectin. The neutrophils from patients with lung disease digested significantly more fibronectin and released more elastase into the culture supernatant than did cells from control subjects. Preincubation of neutrophils from emphysematous patients with plasma from control subjects significantly inhibited fibronectin digestion by the patients' neutrophils by, on average, 10%. Preincubation of control subjects' neutrophils with plasma from emphysematous patients had no effect on fibronectin digestion. 2. Tumour necrosis factor increased fibronectin digestion in a dose-dependent manner when the cytokine was added to the adherent cells but not when preincubated with the polymorphonuclear leucocytes in suspension. Bacterial endotoxin in concentrations above 6 micrograms/ml significantly increased fibronectin digestion by neutrophils, but leukotriene B4, interferon-gamma and interleukin-1 alpha had no significant effects. 3. Dexamethasone inhibited fibronectin digestion by neutrophils in a dose-dependent manner, from 11% at 10(-10) mol/l to 68% at 10(-3) mol/l.
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PMID:Effects of plasma, tumour necrosis factor, endotoxin and dexamethasone on extracellular proteolysis by neutrophils from healthy subjects and patients with emphysema. 275 60

Peripheral polymorphonuclear leucocytes (PMN) from subjects with emphysema or bronchiectasis digested significantly more iodine-125-labelled fibronectin (on average, 250% and 280%, respectively) than did those from control subjects. PMN from patients with bronchiectasis contained significantly more of the serine proteinase elastase than did the control cells, which may have contributed to their greater extracellular proteolysis. PMN from patients with emphysema, but not those with bronchiectasis, showed enhanced chemotaxis (on average 260%) in response to a chemotactic peptide compared with control cells. Thus, PMN from subjects with chronic obstructive lung diseases can digest more extracellular connective tissue protein than PMN from healthy subjects. This behaviour suggests a mechanism for the pathological tissue damage associated with these disorders. Furthermore, the sensitivity to chemotactic factors of PMN from emphysematous patients would contribute to the larger numbers of these cells in their lung tissues, thus increasing further the proteolytic burden in the lungs.
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PMID:Neutrophils from subjects with chronic obstructive lung disease show enhanced chemotaxis and extracellular proteolysis. 288 63

Recent concepts on the mechanisms of aging of extracellular matrix (EM) are reviewed as well as its involvement in age-associated diseases. Cell differentiation, histogenesis and organogenesis can be analyzed in terms of the program of the biosynthesis of EM macromolecules during development, maturation and aging. The most important biological role of EM is the integration of cells in tissues, of tissues in organs and of organs in the whole organism. EM can directly influence cell behavior through the contact between EM and the genome mediated by structural glycoproteins (fibronectin, laminin, elastonectin, etc.) interacting with other EM macromolecules (collagen, proteoglycans, elastin) and the cytoskeleton by trans-membrane receptors (integrins). Most age-associated diseases exhibit a deviation (qualitative or quantitative) from the normal program of EM biosynthesis. Three examples are analyzed in some detail: atherosclerosis, diabetes and malignant tumors. The degradation of elastic fibers catalyzed by cellular elastase-type enzymes is observed in atherosclerosis and also in emphysema and skin aging. Several of these enzymes were isolated and characterized from platelets, fibroblasts, smooth muscle cells and lipoproteins. The biosynthesis of some of them increases with age and facilitates cell migration. Plasma fibronectin increases with age exponentially. This increase is absent or strongly attenuated in diabetes and some cancers. Tissue fibronectin increases in diabetes, Werner syndrome and in the peritumoral desmoplastic reaction while most tumor cells can no more retain fibronectin on their membrane facilitating their movement in the organism. These examples demonstrate the importance of the study of cell matrix interactions for gerontology.
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PMID:Aging of the extracellular matrix and its pathology. 328 58

Polymorphonuclear leukocytes have been implicated in connective tissue injury in a variety of disease processes. To gain insight into mechanisms by which neutrophils might degrade connective tissue macromolecules in the presence of proteinase inhibitors, we have used a model system that allows neutrophils to be held in vitro under physiologic conditions in close proximity to a very proteinase-sensitive substrate, (125)I-labeled fibronectin. We have found: (a) neutrophils spread rapidly on the fibronectin substrate; (b) fibronectin proteolysis by neutrophils is largely attributable to released elastase, and is linearly related to cell number over the range of 2,000 to 30,000 cells per assay; (c) oxidants released from neutrophils stimulated by opsonized zymosan or phorbol myristate acetate do not protect released elastase from inhibition by alpha(1)-proteinase inhibitor or alpha(2)-macroglobulin; (d) neutrophil myeloperoxidase and enzymatically generated superoxide anion render alpha(1)-proteinase inhibitor ineffective against fibronectin proteolysis when neutrophils are added 30 min later; and (e) alpha(1)-proteinase inhibitor and alpha(2)-macroglobulin incompletely inhibit fibronectin proteolysis by neutrophils (79.8+/-6.3 and 73.5+/-12.0%, respectively.) The data suggested that proteolysis due to neutrophils that are in contact with susceptible macromolecules may occur due to partial exclusion of inhibitors from the cell-substrate interface. Although confirming that alpha(1)-proteinase inhibitor is ineffective against neutrophil-derived proteolysis after exposure to oxidants, these studies did not support the hypothesis that oxidants released from stimulated neutrophils enhance activity of proteinases they release in the presence of alpha(1)-proteinase inhibitor. We anticipate that further studies with this test system will be helpful in defining conditions that modulate inflammatory connective tissue injury in diseases such as pulmonary emphysema and rheumatoid arthritis.
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PMID:Proteolysis by neutrophils. Relative importance of cell-substrate contact and oxidative inactivation of proteinase inhibitors in vitro. 618 Oct 97

The pulmonary influx of cytotoxic inflammatory cells, normally, in response to external toxins, is now thought to be etiologic in many of the disease syndromes of man, such as bronchitis and emphysema. Many types of effector inflammatory cells are involved, e.g., eosinophils, neutrophils, T-lymphocytes, monocytes. The diseases are characterized either by tissue destruction or by tissue hyperplasia. Agents which initiate the influx and cytotoxic secretions by these cells are legion and in general are not cell-specific. They include agents, such as phorbol esters, formyl peptides-complement fragments, elastin fragments, fatty acids (leukotrienes) as well as many uncharacterized excretions of inflammatory cells themselves, which react with specific receptors on the inflammatory cells, and secreted proteins such as fibronectin. Other agents, such as linoleic acid, digitonin and hydroxy fatty acids which are not bound by specific receptors also activate motility of inflammatory cells. The precise role of the above multiple cytotoxins in specific cellular fluxes in most pulmonary disease remains undefined. Similarly, the mechanism of cytotoxicity used by specific invading cells in specific pulmonary syndromes remains unclear. In general, macrophages are thought to destroy using specific proteases, neutrophils use oxidant radicals and proteases and eosinophils use basic surface active peptides. T-cells kill by unknown mechanisms. However, in specific clinical syndromes, it is usually not clear which cell is the cytotoxic culprit, nor is the mechanism of destruction usually known.
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PMID:Control of cellular influx in lung and its role in pulmonary toxicology. 637 3


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