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)

This article reviews some properties of human leucocyte elastase. This 30 kDa glycoprotein formed of 218 amino acid residues, is a serine proteinase which cleaves proteins at Val-X, Ala-X, Leu-X or Met-X bonds. Leucocyte elastase solubilizes fibrous elastin and also degrades other extracellular matrix proteins. It hydrolyses and inactivates a number of plasma proteins. Synthetic substrates are more convenient than elastin to measure elastase activity. A large number of natural and synthetic inhibitors of leucocyte elastase have been described. The former include alpha 1-proteinase inhibitor or alpha 1-antitrypsin, inter-alpha-inhibitor, alpha 2-macroglobulin, bronchial and cervical mucous inhibitor and a number of animal and plant proteins. Numerous synthetic inhibitors with therapeutic potentials have been designed. The efficiency of an inhibitor depends, among others, upon its rate of association with the enzyme and upon the stability of the enzyme-inhibitor complex. Elastase probably plays a physiological function in neutrophil migration, phagocytosis and tissue remodeling. It apparently plays a pathological role in pulmonary emphysema, rheumatoid arthritis, infections and inflammation. The pathogenic role of leucocyte elastase is best understood in emphysema.
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PMID:[Human leukocyte elastase]. 306 2

The peptide boronic acid, MeOSuc-Ala-Ala-Pro-boroVal-pinacol (AAPbV), is an effective inhibitor of both pancreatic and leukocyte elastase. Initial work showed that AAPbV diminishes the effect of emphysema induced by pancreatic elastase. This initial work has been expanded to show that AAPbV provides a high degree of protection against elastase-induced increases in lung volume and mean linear intercept when given intratracheally at 200 mg/kg either 15 min before, simultaneous with, or 15 min after instilling elastase. Intraperitoneal administration, although less effective, is dose dependent and dependent on the time of treatment. We conclude that a reversible protease inhibitor can be used to prevent aberrant proteolysis in vivo.
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PMID:Effects of dosage and timing of administration of a peptide boronic acid inhibitor on lung mechanics and morphometrics in elastase-induced emphysema in hamsters. 363 80

A highly effective, reversible elastase inhibitor, MeOSuc-Ala-Ala-Pro-boroVal-OH, was tested for its ability to prevent emphysema induced by intratracheally administered elastase in hamsters. Anesthetized hamsters were given elastase intratracheally with or without the inhibitor or were given elastase intratracheally and the inhibitor intraperitoneally. Two weeks after administration, lungs were removed, and static air pressure volume curves were performed followed by intratracheal fixation and morphometric determination of mean linear intercepts. The results indicate significant preservation of structure and function whether the inhibitor is given intratracheally or intraperitoneally and suggest that this inhibitor may be useful in controlling diseases arising from aberrant proteolysis by elastolytic enzymes.
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PMID:A new peptide boronic acid inhibitor of elastase-induced lung injury in hamsters. 363 81

The chloromethylketone derivative of the tetrapeptide, alanyl alanyl prolyl alanine significantly diminishes the extent of experimental elastase-induced emphysema in hamsters. A total of 19 mg of alanyl alanyl prolyl alanine chloromethylketone was administered intraperitoneally in divided doses before and immediately after intratracheal instillation of a standard dose (4 units) of porcine pancreatic elastase. Morphologic evaluation and measurement of mean linear intercept, internal surface area, and lung volume performed 7, 45, and 120 days after exposure to elastase indicated a marked decrease in the extent of emphysema in the group treated with alanyl alanyl prolyl alanine chloromethylketone compared with the control group. Lung elastin content determined biochemically confirmed the preservation of elastin in the hamsters treated with alanyl alanyl prolyl alanine chloromethylketone. At postmortem examination by light microscopy, no pathologic abnormalities were observed in the organs of hamsters treated with alanyl alanyl prolyl alanine chloromethylketone. These data indicate that alanyl alanyl prolyl alanine chloromethylketone in the doses administered (1) had significant anti-elastase activity in vivo; (2) markedly decreased the extent of elastase-induced emphysema; and (3) produced no adverse toxic effect during the period covered by this study protocol.
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PMID:The effect of the specific elastase inhibitor, alanyl alanyl prolyl alanine chloromethylketone, on elastase-induced emphysema. 689 38

The effectiveness of N-acetyl-L-alanyl-L-alanyl-L-prolyl-L-alanine chloromethylketone (AAPACK) in preventing the development of experimental emphysema in hamsters, when administered 60 min after exposure to elastase, was studied. When 19 mg of AAPACK was injected intraperitoneally in divided doses commencing 60 min after the intratracheal instillation of pancreatic elastase, the development of emphysema was not prevented using morphologic, morphometric, and physiologic means of evaluation. Thirty-eight per cent of hamsters given AAPACK became ill and lost weight. At autopsy, these hamsters had a renal tubular nephropathy and focal interstitial disease. The glomeruli were spared. Five of these hamsters with renal tubular lesions had azotemia. Focal necrosis was observed in the heart of 3 and in the liver of 5 animals with renal lesions. These studies indicated that AAPACK, in the protocol followed where elastase precedes administration of the inhibitor, (1) does not prevent the development of elastase-induced emphysema, and (2) does produce a unique renal tubular nephropathy.
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PMID:Effects of oligopeptide chloromethylketone administered after elastase: renal toxicity and lack of prevention of experimental emphysema. 691 47

In order better to understand the pathophysiology of the equine form of emphysema, two elastinolytic enzymes from horse neutrophils, referred to as proteinases 2A and 2B, have been extensively characterized and compared with the human neutrophil proteinases, proteinase-3 and elastase. Specificity studies using both the oxidized insulin B-chain and synthetic peptides revealed that cleavage of peptide bonds with P1 alanine or valine residues was preferred. Further characterization of the two horse elastases by N-terminal sequence and reactive-site analyses indicated that proteinases 2A and 2B have considerable sequence similarity to each other, to proteinase-3 from human neutrophils (proteinase 2A), to human neutrophil elastase (proteinase 2B) and to a lesser extent to pig pancreatic elastase. Horse and human elastases differed somewhat in their interaction with some natural protein proteinase inhibitors. For example, in contrast with its action on human neutrophil elastase, aprotinin did not inhibit either of the horse proteinases. However, the Val15, alpha-aminobutyric acid-15 (Abu15), alpha-aminovaleric acid-15 (Nva15) and Ala15 reactive-site variants of aprotinin were good inhibitors of proteinase 2B (Ki < 10(-9) M) but only weak inhibitors of proteinase 2A (Ki > 10(-7) M). In summary, despite these differences, the horse neutrophil elastases were found to resemble closely their human counterparts, thus implicating them in the pathological degradation of connective tissue in chronic lung diseases in the equine species.
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PMID:Structural and functional characterization of elastases from horse neutrophils. 751 52

Secretory leukocyte protease inhibitor (SLPI) is a 12 kD nonglycosylated serine antiproteinase secreted by cells of mucosal surfaces. In human lung, SLPI is present in the respiratory epithelium. It is the major barrier to tissue destruction mediated by the polymorphonuclear leukocyte (PMN) serine proteinases, elastase and cathepsin G, within the upper respiratory tract. We have recently described a third PMN serine proteinase, proteinase-3, that like elastase causes lung matrix destruction and experimental emphysema. The current studies examine interactions between SLPI and proteinase-3. The results show that: (1) SLPI and its reactive-site variants have no or minimal inhibitory activity against proteinase-3; (2) native SLPI does not complex with proteinase-3; (3) proteinase-3 selectively degrades both native and oxidized SLPI; (4) the cleavage of SLPI by proteinase-3 occurs at the peptide bond COOH-terminal to Ala-16 in the NH2-terminal domain of SLPI.
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PMID:Interaction of secretory leukocyte protease inhibitor with proteinase-3. 810 Jul 9

Alpha 1-antichymotrypsin (alpha 1-ACT) is a serine proteinase inhibitor (serpin) with cathepsin G, mast cell chymase and chymotrypsin as target enzymes. We present the case of a middle-aged man with low plasma levels of alpha 1-ACT, asthma with progression to emphysema, and chronic HCV positive liver disease with selective accumulation of alpha 1-ACT in hepatocytes. This secretory defect is analogous to that seen in Pi Z alpha 1-antitrypsin deficiency. The molecular basis of alpha 1-ACT deficiency in this patient has been characterized by direct sequencing of the alpha 1-ACT genes from the patient and his father. A C-->G transversion in exon III causing a 229Pro-->Ala substitution is proposed to cause a conformational change resulting in abnormal transport through the RER. This mutation was found in one of 20 additional tested patients with chronic obstructive lung disease, but in no control. Two additional polymorphisms of the gene have been identified in unrelated healthy individuals with normal plasma alpha 1-ACT levels. The alpha 1-ACT deficiency state may predispose to obstructive lung disease and influence the course of liver disease. Identification of a specific mutation allows identification of heterozygotes for this deficiency allowing future evaluation of its clinical significance.
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PMID:The molecular basis of alpha 1-antichymotrypsin deficiency in a heterozygote with liver and lung disease. 822 25

Trifluoroacetylpeptide anilides are powerful reversible inhibitors of human neutrophil elastase (HNE), a serine protease implicated in the pathogenesis of pulmonary emphysema. The in vitro effectiveness of three inhibitors, CF3CO-Phe-Ala-NH-p-C6H4-CF3 (1), CF3CO-Val-Ala-NH-p-C6H4-CF3 (2) and CF3CO-Lys-Ala-NH-p-C6H4-CH(CH3)2 (3) was analyzed. The protection of lung tissue sections of rats from the degradation induced by HNE has been evaluated quantitatively by automated image analysis. Inhibitor 1 (22 microM), 2 (50 microM) or 3 (35 and 70 microM) significantly reduced the HNE-induced degradation of the elastin network by 75, 42, 54 and 44%, respectively. Inhibitor 3 was tested intratracheally on an experimental model of pulmonary emphysema. Rats that received the elastase inhibitor 1 h before instillation of HNE were significantly protected by 40% from experimental emphysema. Reduced protections were observed with the treatment by the inhibitor 1 or 4 h after challenge with the enzyme.
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PMID:Protection of rat lung from elastase-induced elastic fiber degradation in vitro and from emphysema in vivo by a trifluoroacetylpeptide anilide inhibitor. 888 99

Human neutrophil elastase (HNE, IEC 3. 4. 21. 37) is a causative factor of inflammatory diseases, including emphysema and rheumatoid arthritis. Enzymatic characterization is important for the development of new drugs involved in the regulation of this enzyme. In this study, we investigated the enzymatic and biochemical properties of five different elastolytic enzymes, with a molecular mass between 24 kDa and 72 kDa. Three elastases, molecular masses of 27, 29, 31 kDa, might be elastase isozymes that have the same NH2-terminal amino acid sequences of Ile-Val-Gly-Gly-Arg-Arg-Ala. The 24-kDa enzyme, which showed the identical NH2-terminal amino acid sequences to elastase, was a degraded fragment of native elastase. The elastolytic activity was conserved at the 6/7 domain of the NH2-terminal region. The inhibitory characteristics of PMSF, DipF were the same as those of native elastases. The 72-kDa molecule, which showed elastolytic activity, might be a trimer formed between native elastases (31 kDa and 29 kDa) and a cathepsin G-like enzyme, which did not show elastolytic activity but enhanced the elastolytic activity of neutrophil elastase. Although this cathepsin G-like enzyme showed weak cathepsin G activity, it has distinguishable NH2-terminal sequences of Ile-Val-Gly-Gly-Ser-Arg-Ala- from those of elastase or cathepsin G. The potentiation of elastolytic activity could be a result of the trimerization of native elastase with a cathepsin G-like enzyme, and was then weakly inhibited by serine protease inhibitors, such as PMSF, DipF. Therefore, we suggest the cathepsin G-like enzyme to be a novel enzyme, which has an important role in the development of inflammation.
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PMID:Enzymatic and molecular biochemical characterizations of human neutrophil elastases and a cathepsin G-like enzyme. 1110 Nov 39


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