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

Research on the pathogenesis of experimental emphysema has involved studies of the distribution of and destruction of elastin in the alveolar interstitium. The ill-defined organization of elastin in the alveolar interstitium makes it difficult to identify the elastin specifically by staining procedures ordinarily used for electron microscopy. This problem becomes more significant when the elastic tissue is fragmented during emphysema development and localization of the elastin fragments is essential. Therefore, a specific technique using high-titer antibodies against purified canine lung elastin was developed. The primary antibody was used on preembedded or etched postembedded sections. Localization of the antielastin IgG was accomplished with ferritin-labeled rabbit antisheep IgG as the secondary antibody. Treatment with the preimmune serum gave negligible ferritin background staining. The antielastin antibody did not react with lung connective tissue proteins such as the microfibrillar component of elastin or collagen or proteoglycan. The antielastin antibody appeared to be species specific. The method may be useful for studies of experimental emphysema.
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PMID:Immunologic localization of elastin by electron microscopy. 8 14

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

Both clinical and experimental evidence implicate proteolytic enzymes active against elastin in the pathogenesis of emphysema. Paradoxically, however, the elastin content of emphysematous human lungs at autopsy has been normal. When emphysema was produced in hamsters by a single intratracheal injection of 25 units of porcine pancreatic elastase, the elastin content of the lungs was reduced from 1.40 +/- 0.22 mg. in controls to 0.43 +/- 0.10 mg. 24 hours after injection, and histologic sections showed that many elastic fibers had disappeared. The elastin content of the lungs gradually increased, approaching normal values by 2 months after injection. The incorporation of 14C-proline into elastin was markedly elevated during the first 2 weeks after injection, decreasing nearly to normal by 2 months. The synthesis of collagen was also increased, indicated by an increase in the collagen content of the lung, an increase in the prolyl hydroxylase activity, and an increase in incorporation of labeled proline into collagen. During the period of active resynthesis of elastin, small clumps of microfibrils and elastic fibrils were visible by electron microscopy within grooves on the surface of septal connective tissue cells in the lungs. Many elastic fibers seen in histologic sections up to 4 months after injection were of abnormal configuration and disorganized.
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PMID:The induction of emphysema with elastase. II. Changes in connective tissue. 17 9

Based on the hypothesis that cross-linked elastin is critical for normal lung structure, lung tissue from copper-deficient rats was studied. Copper deficiency was induced in the second generation by feeding dams a milk-based diet low in copper (less than 1 ppm) during gestation and lactation. The weanlings were fed the same diet until they showed severe signs of deficiency between 6 and 10 weeks of age. Controls animals received the basal diet supplemented with 10 ppm copper. Liver cytochrome oxidase activity, which served as the chief index of deficiency, decreased from a normal level of approximately 80 to 15 mumole/min/g. The lungs of the deficient animals contained 17% less elastin and had 35% larger alveolar spaces (34.7 vs 47.7 intercepts), as determined by the mean alveolar intercept method. The ultrastructure of elastin in the bronchi, arterioles, and alveolar ducts had a "washed out" appearance. To determine the reversibility of the pathology, deficient animals, 5 to 10 weeks of age, were repleted by feeding a copper-supplemented diet for 1, 2, and 3 months. During this period growth resumed, anemia disappeared, and liver cytochrome oxidase returned to normal. There was no improvement in lung structure with regard to alveolar size (28.4 intercepts compared with 43.6 in controls and 35.1 in deficient littermates killed at the start of repletion). The ultrastructure and electron density of pulmonary elastin was restored to near normal. The lung of the copper-deficient rat is proposed as a model for developmental pulmonary emphysema.
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PMID:The lung of the copper-deficient rat. A model for developmental pulmonary emphysema. 20 87

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.
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PMID:Possible mechanisms of emphysema in smokers: cigarette smoke condensate suppresses protease inhibition in vitro. 30 25

We assayed protease and elastase activity of lysosomal granules of purified neutrophil suspensions in 58 patients with chronic irreversible airflow obstruction and compared them to 26 healthy control subjects. Denatured hemoglobin and tritiated elastin were used as substrates for protease and elastase assays. Forty-two patients had M antitrypsin phemotype, five had MS, and 11 had Z variant (five were homozygotes and six were heterozygotes). We did not find significant differences in mean lysosomal elastase or protease activity between patients with normal antitrypsin and control subjects; however, a few patients had concentrations of neutrophil elastase that exceeded the range among control subjects. There was no significant correlation between neutrophil protease or elastase activity and age, smoking, degree of airway obstruction, diffusing capacity, lung elastic recoil, or radiologic presence of emphysema in patients with M and MS antitrypsin. In patients with Z variant antitrypsin, protease and elastase concentrations per unit of lysosomal protein were not significantly different from those in control subjects or M patients; however, both elastase and protease content per 108 neurtophils was significantly higher in homozygous and heterozygous Z patients as compared to normalsubjects and M patients, which suggest an increase in the neutrophil content of protease and elastase in patients with Z antitrypsin deficiency. These results suggest that hte concentrations of protease and elastase in neutrophils do not appear to interact as additive risk factors in the pulmonary impairment of most patients with chronic airflow obstruction, but may be of importance as risk factors in patients with Z or MZ phenotype and in a few patients with M phenotype.
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PMID:Interrelationships between neutrophil elastase, serum alpha, -antitrypsin, lung function and chest radiography in patients with chronic airflow obstruction. 31 28

There is now overwhelming evidence that lung destruction resulting in emphysema is largely due to enzymatic action on pulmonary connective tissues, mainly elastin. These enzymes are probably derived from neutrophil polymorphonuclear leucocytes and alveolar macrophages. Arguments are advanced to show that release of these enzymes is related to cigarette smoking. This explanation for the pathogenesis of emphysema is compatible with the distribution of the disease within the lung noted in epidemiological studies. If this conclusion with regard to the role of cigarette smoking is correct it must follow that, apart from patients with alpha 1-antitrypsin deficiency, emphysems is a disease which could be almost entirely eliminated if the smoking habit was abandoned.
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PMID:Aetiology of emphysema. 31 6

Two of the major enzymes present in an released from neutrophil granulocytes are the endoproteinases elastase and cathepsin G. While the former is believed to be one of the major causative agents responsible for tissue destruction in emphysema and rheumatoid arthritis, little is known about the function of cathepsin G. We have recently developed simple procedures for isolating the isoenzymes of each type of proteinase as well as for their specific controlling plasma inhibitors. We have also prepared synthetic substrates and inhibitor analogues. Some sequence studies have been initiated and the results indicate homology of these enzymes not only with each other and with the pancreatic proteinases but also between cathepsin G and proteolytic enzymes present in muscle and mast cell tissue. Significantly, both types of enzyme can degrade the structural protein myosin, as well as elastin and proteoglycan. However, their relative importance in muscle protein turnover or muscle disease has not yet been clarified.
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PMID:Human leucocyte elastase and cathepsin G: structural and functional characteristics. 39 98

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


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