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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A great deal of experimental evidence suggests that emphysema in smokers is caused by the action of neutrophil elastase on lung elastin. In order to test this hypothesis, it is necessary to find a drug that reduces the load of neutrophil elastase in the lungs of patients with emphysema. In a previous study we treated smokers with emphysema with colchicine, a drug that prevents neutrophil elastase secretion, to determine if it would reduce the elastase burden in the lungs. Colchicine was unable to reduce the elastase load while the stimulus of smoking continued. In this study we treated ex-smokers with emphysema to determine if colchicine could reduce the elastase burden in the lungs. The objective of the study was to determine if colchicine can reduce the elastase load and putative indicators of elastase load in the lungs of patients with chronic obstructive pulmonary disease. The study was a prospective, double-blind, randomized, and placebo-controlled clinical trial. The subjects were outpatients seeking treatment at the University of Texas Health Center at Tyler. We studied 16 ex-cigarette smokers between 45 and 75 yr of age with lung disease defined by FEV1 less than 70% of predicted but greater than 1.2 L whose airflow obstruction was less than 20% reversible with bronchodilators. Colchicine or placebo was taken by mouth in disguised capsules, 0.6 mg three times per day. Volunteers were placed on a baseline bronchodilator regimen of theodur by mouth and albuterol by inhalation. Blood, urine, and bronchoalveolar lavage fluids were obtained after 1 wk of stabilization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A controlled trial of colchicine to reduce the elastase load in the lungs of ex-cigarette smokers with chronic obstructive pulmonary disease. 202 12

Antileucoprotease (ALP), a potent inhibitor of human neutrophil elastase (HNE), may be a modulating factor in the pathogenesis of emphysema. Investigating the clearance of intratracheally-instilled ALP in hamsters, we observed a rapid clearance from the airway lumen within 60 min, whereafter the remaining 40% slowly decreased with a calculated half-life (T0.5) of 2.8 h. Lung tissue-associated ALP showed a peak at 40 min and slowly decreased (T0.5 approximately 3 h). In vivo efficacy of ALP on HNE-induced pulmonary lesions was studied by instillation of either 365 micrograms or 730 micrograms ALP, followed after 1 h by 420 micrograms HNE. Emphysema, haemorrhage and secretory cell metaplasia (SCM) were quantified 21 days after instillations. ALP was found to be able to inhibit emphysema and haemorrhage in a dose-related way, the decrease of haemorrhage being less pronounced. SCM was minimally affected. These results show that ALP inhibits efficiently the development of HNE-induced emphysema and, to a lesser extent, haemorrhage. We speculate that tissue-associated ALP might be responsible for this protection.
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PMID:Effect of human antileucoprotease on experimental emphysema. 202 36

Emphysema in humans takes several different forms: centrilobular, panacinar, paraseptal, and airspace enlargement with fibrosis. The varying morphologic and background features of these forms of emphysema suggest that they differ in pathogenesis. Elastic fiber rupture and fraying are a feature of emphysema. Experimental emphysema may be induced by human neutrophil elastase and other elastolytic enzymes but not by nonelastolytic proteases. Disruption of elastic fibers also appears to be the underlying feature of lathyrogen-induced airspace enlargement and of the emphysema in the blotchy mouse. However, there is no evidence of elastic fiber destruction in cadmium-induced airspace enlargement with fibrosis or in emphysema associated with hyperoxia or severe starvation. Thus, elastic fiber disruption is not common to all forms of experimental emphysema. We posit that airspace enlargement may be a stereotyped response of the lungs to different injuries. Emphysema can be induced in experimental animals by repeated induction of pulmonary neutrophilia. However, the evidence for involvement of neutrophil elastase in human emphysema is not clear: there are studies using a variety of approaches that weigh on both sides of the question. There is also in vitro evidence that alveolar macrophages can degrade elastin or elastic fibers with which they are in contact by means of a metalloelastase or the cooperative action of plasminogen activator and an acid cysteine protease. We conclude that the pathogenesis of emphysema is complex. Neutrophil elastase likely plays a major role in the development of some forms of emphysema, but our understanding of the interactions between the alveolar walls and neutrophils is still fragmentary.
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PMID:Putative role of neutrophil elastase in the pathogenesis of emphysema. 206 48

During their development, mononuclear phagocytes express a changing profile of proteinases that may participate in the degradation of elastin and other extracellular matrix components. Neutrophil elastase is produced and stored in azurophil-like granules in immature mononuclear phagocytes. Monocytes contain small amounts of neutrophil elastase but do not synthesize the enzyme. Macrophages neither synthesize nor contain neutrophil elastase, but they can internalize and secrete scavenged neutrophil elastase. Human alveolar macrophages synthesize cysteine proteinases including cathepsin L, a lysosomal enzyme with elastolytic activity at an acidic pH. Macrophages from several animal species synthesize an approximately 22-kD metalloelastase that, in the mouse, is secreted as a zymogen of about 36 kD. In addition to its direct elastolytic properties, this metalloelastase may also promote elastolysis by cleaving alpha 1-antiproteinase and thus protecting neutrophil elastase from inhibition. A human counterpart of this enzyme has not yet been purified; however, the elastolytic activity of human macrophages appears to depend predominantly on the activity of one or more metalloproteinases. Because elastin is intertwined with other matrix components in natural matrices, degradation of elastin in vivo probably involves cooperation of multiple proteinases to uncover macromolecules that mask the elastic fibers. Degradation of matrix may be localized to pericellular sites, where proteinases are protected from inhibitors and where potentially surface-bound enzymes may be concentrated. Complete breakdown of matrix may be completed within the cells after partially cleaved molecules are internalized. Growth and remodeling of the extracellular matrix must involve highly coordinated interactions between cells, cytokines, proteinases, proteinase activators and inhibitors, as well as the matrix itself. The intrapulmonary process resulting in emphysema probably involves equally complex interactions. Mononuclear phagocytes accumulate in large numbers in the lung in response to cigarette smoking, and they may play a role in the pathogenesis of the alveolar septal injury that characterizes pulmonary emphysema.
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PMID:Elastin degradation by mononuclear phagocytes. 206 50

Inherited or "acquired" deficiency of alpha 1-antitrypsin (believed to be the cause of pulmonary emphysema) will probably be treated in the future by replacement with alpha 1-antitrypsin purified from human plasma or produced by recombinant DNA, which seems promising because it permits site-specific mutagenesis in the oxidizable active site of the normal human alpha 1-antitrypsin. The aim of this in-vitro study was to investigate the elastase inhibitory activity and the resistance to oxidizing agents of normal human alpha 1-antitrypsin, a recombinant yeast-produced variant (VAL 358) and a recombinant E. coli-produced variant (LEU 358). The inhibitors were exposed to chemical oxidants (NCS, H2O2, xanthine/xanthine oxidase, chloramine-T) and to PMA-activated neutrophils. The elastase inhibitory activity was assayed on porcine pancreatic elastase and neutrophil elastase. Normal alpha 1-antitrypsin and VAL 358 variant were good inhibitors of both elastases. LEU 358 variant was the best inhibitor for neutrophil elastase, but it poorly inhibited the porcine pancreatic elastase. Normal alpha 1-antitrypsin was affected by all oxidants; both variants were almost totally resistant to chemical oxidants and to activated neutrophils. We conclude that recombinant alpha 1-antitrypsin variants differ in their elastase inhibitory activity and offer increased resistance to oxidant agents.
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PMID:Alpha 1-antitrypsin variants produced by recombinant DNA: differences in elastase inhibitory activity and resistance to oxidant agents. 210 1

The author reviews the early history of alpha 1-antitrypsin (AAT) deficiency; the biochemical characterization of this inborn error of metabolism, its pattern of inheritance, frequency and predisposition to early, panacinar emphysema. The importance of the destructive element in emphysema and the gradual focusing on neutrophil elastase as a key enzyme in the pathogenesis of emphysema in alpha 1-antitrypsin deficiency is emphasized. The deficiency state as a prototype of an endoplasmic reticulum storage disease is discussed.
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PMID:Discovery of alpha 1-antitrypsin deficiency. 211 60

Antitrypsin is the predominant protease inhibitor in human plasma. Despite its name, its prime function is an inhibitor of neutrophil elastase. It is the archetype of a family of protease inhibitors (serpins) characteristically with a MW 50,000 and a highly ordered tertiary structure. Its role is as a protector of vulnerable tissues against digestion by leukocyte enzymes, and plasma deficiency predisposes to premature emphysema. Northern Europeans are uniquely susceptible to deficiency due to the frequency of two mutants (Z & S) both having substitutions at glutamic acids that form key salt bridges in the molecule. In the reactive center of antitrypsin is a labile methionine which allows leucocytes to switch off inhibitory activity but this contributes to the accelerated lung degeneration in cigarette smokers. Although plasma replacement therapy is one option for treatment a first approach is to avoid smoking and other environmental irritants.
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PMID:The molecular structure and pathology of alpha 1-antitrypsin. 211 61

Critical elements of the mechanisms of emphysema remain to be clarified. However, taken together, the existing evidence supports the concept that alveolar matrix destruction ensues as the regulatory interplay between oxidant and protease expression is subverted. The final common pathway of matrix destruction links the inherited and acquired forms of emphysema through the ultimate expression of unimpeded neutrophil elastase.
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PMID:The protease-antiprotease balance within the human lung: implications for the pathogenesis of emphysema. 211 64

Alpha 1-antitrypsin (AAT) deficiency is a genetic disease in which low serum and lung levels of the antiprotease AAT cause a deficiency of the anti-elastase defensive screen of the lower respiratory tract such that neutrophil elastase is free to degrade the connective tissue of the lung, eventually resulting in emphysema. Intravenous AAT infusion therapy restores lung levels of AAT, but is inefficient, costly and a demanding form of therapy. As an alternative, we evaluated aerosol delivery of human plasma AAT (pAAT) and recombinant DNA-produced AAT (rAAT), as a means of providing anti-elastase protection to the lower respiratory tract. In vitro studies demonstrated that both pAAT and rAAT can be aerosolized into droplets suitable for alveolar deposition without loss of antiprotease activity. When administered by aerosol to individuals with AAT deficiency, pAAT and rAAT each significantly raised lung epithelial lining fluid levels of AAT and anti-neutrophil elastase capacity, with the likelihood that twice daily administration of 100 mg of either form would result in normalization of lung anti-elastase defenses at the alveolar surface. Studies in sheep further demonstrated that the aerosolized pAAT and rAAT were each able to pass through alveolar epithelium and gain access to the interstitial compartment of the lung, thus increasing anti-elastase defenses of the lung interstitium. Therapy was safe and well tolerated in all cases. Aerosol therapy with pAAT or rAAT is a safe, feasible, and likely a biochemically efficacious alternative to intravenous AAT augmentation therapy and merits further long-term studies for clinical therapy.
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PMID:Strategies for aerosol therapy of alpha 1-antitrypsin deficiency by the aerosol route. 211 65

The immunolocalization of human neutrophil elastase (HNE) in the alveolar interstitium of 6 patients with emphysema was investigated by immunochemical electron microscopy. The results showed that HNE is localized in the azurophil granules of neutrophils, and extracellularly on the elastic fibers of alveolar interstitium and basement membranes of epithelium and endothelium. The damage of elastic fibers and basement membranes could be observed. The HNE level of the alveolar interstitium was obviously elevated and closely related to the severity of emphysematous lesions as shown by measuring the mean linear intercept (MLI) in 4 emphysematous lungs with chronic bronchitis (r = 0.84). This suggests that HNE might play an important role in the pathogenesis of emphysema. Although enlarged airspace and increased MLI data were observed in 2 patients, one with asthma and the other, an elderly patient, without lung diseases, the HNE level of alveolar interstitium is much less than that of the other 4 chronic obstructive pulmonary disease patients. This implies that the mechanism of the the airspace enlargement occurring in the 2 patients may be different from that of others. These findings support the hypothesis of elastase-antielastase imbalance on the pathogenesis of pulmonary emphysema.
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PMID:Damaging role of neutrophil elastase in the elastic fiber and basement membrane in human emphysematous lung. 211 77


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