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)

Thioglycolate-stimulated mouse peritoneal macrophages secrete a Proteinase which degrades insoluble elastin. There is little elastase activity in cell lysates but the bulk of the enzyme accumulates extracellularly during culture in serum-free medium. The secretion of elastase is sustained for over 12 days in culture and continued secretion of elastase requires protein synthesis. Unstimulated macrophages secrete very little elastase activity but can be triggered to secrete higher levels of this enzyme by phagocytosis and intracellular storage of latex particles. The macrophages elastase is a distinctive proteinase differing from the elastases of pancreas and granulocytes and is distinct from the other secreted proteinases of macrophages, namely, collagenase and plasminogen activator. The macrophages elastase is a serine proteinase and is inhibited by di-isopropyl phosphoro-fluoridate, ovoinhibitor, EDTA, dithiothretiol, and serum. Its activity is little affected by soybean trypsin inhibitor, turkey ovomucoid and chloromethyl ketones derived from tosyl lysine, tosyl phenylalanine, and acetyltetra alanine. Hydrolysis by macrophage elastase of chromogenic ester substrates for pancreatic elastase could not be detected. Elastase secretion by stimulated macrophages exceeds that by primary and established fibroblast cell strains. It is likely that elastase secretion by macrophages plays a major role in the pathogenesis of chronic destructive pulmonary diseases such as emphysema.
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PMID:Elastase secretion by stimulated macrophages. Characterization and regulation. 16 96

Human polymorphonuclear neutrophilic leukocytes (PMNs) contain large amounts of neutral proteases that can degrade elastin, collagen, proteoglycan, and basement membrane. The instillation of one of the purified enzymes (elastase) into dog lungs in vivo causes degradation of elastic fibers and other alveolar septal components and results in anatomic changes similar to those of human pulmonary emphysema. Cigarette smoking is a major risk factor associated with pulmonary emphysema in man. One mechanism for this association may be interference with the regulation of PMN elastase activity by alveolar antiproteases. This possibility is supported by the observation that the oxidizing activity of tobacco smoke inactivates alpha 1-proteinase inhibitor in vitro. Macrophages also secrete an elastolytic protease, albeit at low levels. The short-term exposure of cultured mouse macrophages to cigarette smoke augments the rate of elastase secretion by these cells. Mouse macrophage elastase is not inhibited by alpha 1-proteinase inhibitor or alpha 2-macroglobulin. This unusual property of macrophage elastase may facilitate its attack upon elastin over prolonged intervals despite very low levels of macrophage elastase production. A unified hypothesis of lung injury in pulmonary emphysema is presented, involving both PMN and macrophage elastases and the actions of cigarette smoke. (Am J Pathol 97:111--136, 1979).
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PMID:Lung injury induced by leukocytic proteases. 49 91

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

A deficiency of alpha 1 antiproteases is associated with severe and early emphysema. This emphysema can be experimentally produced in animals by endotracheal instillation of elastolytic proteases. Thus it would seem that emphysema is linked to an imbalance between proteases and antiproteases at the pulmonary level. This work studies the proteases, whose role in the genesis of emphysema is highly probable in view of the data in the literature (leukocyte elastase), disputed (macrophage elastase) or transitory (microbial elastases). We contrast the main agents capable of inhibiting these proteases (alpha 1 antiprotease and bronchial inhibitors) or of changing their activity (alpha 2 macroglobulins). The relative importance of these antiproteases is discussed in the light of studies made on bronchial secretions and bronchoalveolar lavage. These irritants may influence the protease - antiprotease equilibrium and favour the development of emphysema by increasing the proteases or decreasing the antiproteases. It appears that tobacco, as well as infection and anything which sets in motion the pulmonary phagocytes favour the liberation of leucocyte elastase. These attacks inactive the alpha 1 antiproteases in addition to the bronchial inhibitor. They may be recognized by a change in elastolytic and anti-elastolytic activity observed in bronchial secretions and in bronchoalveolar lavage (which is more disputed in the latter).
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PMID:[Proteases, antiproteases and pulmonary emphysema]. 618 52

Thioglycollate-elicited mouse peritoneal macrophages were cultured in contact with the mixture of extracellular matrix proteins produced by rat smooth muscle cells in culture. Both live macrophages and their conditioned media hydrolyzed glycoproteins, elastin, and collagen. Live macrophages also degraded extracellular connective tissue proteins secreted by endothelial cells and fibroblasts. The glycoproteins in the matrix markedly inhibited the rate of digestion of the other macromolecules, particularly elastin. When plasminogen was added to the matrix, activation of plasminogen to plasmin resulted in the hydrolysis of the glycoprotein components, which then allowed the macrophage elastase easier access to its substrate, elastin. Thus, although plasmin has no direct elastinolytic activity, its presence accelerated the rate of hydrolysis of elastin and therefore the rate of matrix degradation. These findings may be important in an understanding of disease states, such as emphysema and atherosclerosis, that are characterized by the destruction of connective tissue.
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PMID:Degradation of connective tissue matrices by macrophages. II. Influence of matrix composition on proteolysis of glycoproteins, elastin, and collagen by macrophages in culture. 645 Feb 58

Inflammatory mouse peritoneal macrophages secrete a metalloproteinase that is not inhibited by alpha 1-proteinase inhibitor. This proteinase, macrophage elastase, recognizes alpha 1-proteinase inhibitor with macrophage elastase does not involve a stable proteinase-inhibitor complex and results in the proteolytic removal of a peptide of apparent molecular weight 4,000-5,000 from the inhibitor. After degradation by macrophage elastase, alpha 1-proteinase inhibitor is no longer able to inhibit human granulocyte elastase, a serine proteinase implicated in the pathogenesis of emphysema. Macrophage elastase apparently does not degrade human granulocyte elastase-alpha 1-proteinase inhibitor complexes or release active granulocyte elastase from these complexes. The ability of macrophage elastase to degrade alpha 1-proteinase inhibitor is inhibited by EDTA and alpha 2-macroglobulin.
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PMID:Limited proteolysis by macrophage elastase inactivates human alpha 1-proteinase inhibitor. 696 73

The matrix metalloproteinases (MMP) are a multigenic family involving 14 enzymes which can cleave most, if not all, the components of the extracellular matrix (interstitium and basement membranes). The present work reports on the main structural characteristics, the substrate preference and the site synthesis of these proteinases and their inhibitors (TIMP). Human MMPs are produced by various cell types and are involved in the remodelling of the extracellular matrix in many physiological and pathophysiological circumstances. Elastolytic MMPs produced by monocytes and/or macrophages (matrilysin, gelatinases, macrophage elastase) are likely to be implicated in the development of acquired pulmonary emphysema.
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PMID:[Metalloproteinases in the extracellular matrix: structure and activity]. 908

To determine which proteinases are responsible for the lung destruction characteristic of pulmonary emphysema, macrophage elastase-deficient (MME-/-) mice were subjected to cigarette smoke. In contrast to wild-type mice, MME-/- mice did not have increased numbers of macrophages in their lungs and did not develop emphysema in response to long-term exposure to cigarette smoke. Smoke-exposed MME-/- mice that received monthly intratracheal instillations of monocyte chemoattractant protein-1 showed accumulation of alveolar macrophages but did not develop air space enlargement. Thus, macrophage elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke.
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PMID:Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. 930 97

In the mouse, macrophage elastase is critical to macrophage proteolysis. The use of gene-targeting has uncovered both pathological roles, including destructive effects in aneurysm formation and emphysema, and physiological roles, such as tumor growth inhibition and regulation of inflammation. Translation of findings from mouse to human biology depends upon how well the disease models replicate the human conditions and the similarity of enzyme profile between species. We know that human MMP-12 is associated with these diseases, but as opposed to the mouse, other MMPs may also be of importance (MMP-9, and perhaps MMP-7, in particular). Our interpretation is that findings in mice reflect the critical role of macrophage proteolysis in these disease processes.
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PMID:Diverse roles of macrophage matrix metalloproteinases in tissue destruction and tumor growth. 1060 92

Targeted ablation of the surfactant protein D (SP-D) gene caused chronic inflammation, emphysema, and fibrosis in the lungs of SP-D (-/-) mice. Although lung morphology was unperturbed during the first 2 weeks of life, airspace enlargement was observed by 3 weeks and progressed with advancing age. Inflammation consisted of hypertrophic alveolar macrophages and peribronchiolar-perivascular monocytic infiltrates. These abnormalities were associated with increased activity of the matrix metalloproteinases, MMP2 and MMP9, and immunostaining for MMP9 and MMP12 in alveolar macrophages. Hydrogen peroxide production by isolated alveolar macrophages also was increased significantly (10-fold). SP-D plays a critical role in the suppression of alveolar macrophage activation, which may contribute to the pathogenesis of chronic inflammation and emphysema.
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PMID:Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. 1080 80


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