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)

When neutrophils invade inflamed areas of the body to remove either dead or foreign components they inadvertently release potent enzymes which can, if not properly controlled, cause severe damage to healthy tissue. This can lead to a myriad of diseases including emphysema, rheumatoid arthritis, and glomuerlopnephritis, all of which are really problems of abnormal connective tissue turnover due to uncontrolled protelysis by neutrophil elastase and cathepsin G. An important step in elucidating the functions of both elastase and cathepsin G has been made by virtue of the fact that the amino acid sequence of each has been determined. Furthermore, the crystal structure of one, neutrophil elastase, is now understood. With this knowledge in mind and with the potential for a similar understanding of the mechanism of action of cathepsin G, it should soon be possible to produce synthetic inhibitors of each enzyme which can act as adjunct inhibitors to those naturally circulating in the blood or present in other tissues. As a result there is great hope for reducing the severity of injury produced by these enzymes and, therefore, in decreasing the risk for development of the debilitating diseases associated with abnormal proteolysis by neutrophil proteinases.
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PMID:Neutrophil elastase and cathepsin G: structure, function, and biological control. 326 7

Leucocyte proteinases, e.g. leucocyte elastase and cathepsin G, are inhibited by heparin. The activities of pig pancreatic and Pseudomonas aeruginosa elastases are unaffected by this polysaccharide. Heparin derivatives of known Mr and degree of sulphation were isolated. The inhibition of leucocyte elastase by these oligosaccharides can be classified as tight-binding hyperbolic non-competitive. Ki values ranged from 40 nM to 100 microM and were found to be inversely correlated with the chain length of the oligosaccharides. Desulphated compounds lacked inhibitory potential towards leucocyte elastase. Over-O-sulphated di- and tetra-saccharides are more potent inhibitors than their over-N-sulphated counterparts. It is proposed that the therapeutic use of heparin and its derivatives could be extended to disease states such as emphysema and rheumatoid arthritis, where the role of leucocyte elastase has been clearly established.
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PMID:Inhibition of leucocyte elastase by heparin and its derivatives. 341 72

Eglin c is a small protein inhibitor of human leucocyte elastase and cathepsin G which has potential as a therapeutic agent for the treatment of disease states associated with inflammation. In particular, Eglin c has been proven effective in experimental animal models of emphysema and shock. While initial studies indicate that Eglin c is virtually non-toxic and does not produce deleterious effects to the cardiovascular system, central nervous system or basic metabolism (unpublished results), an allergenic potential of the protein has not yet been ruled out.
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PMID:A brief review of the biochemistry and pharmacology of Eglin c, an elastase inhibitor. 353 58

Alpha-1 antitrypsin (alpha 1AT) is an efficient inhibitor of the human neutrophil proteases, elastase and cathepsin G. The reactive centre P1 residue (Met358) of alpha 1AT is important in defining the specificity of inhibition; furthermore, oxidation of this residue results in a loss of inhibitor activity. There is evidence that oxidative inactivation of alpha 1AT may be involved in the pathogenesis of pulmonary emphysema associated with cigarette smoking. We have studied the effect of a series of amino acid replacements at the active centre on the inhibition properties of alpha 1AT. The mutant proteins were produced in E. coli following in vitro mutagenesis of the alpha 1AT cDNA. Alpha-1-AT (Ile358), (Ala358) and (Val358) were efficient inhibitors of both neutrophil and pancreatic elastase, but not cathepsin G. Alpha-1-AT (Ala356, Val358) and alpha 1AT (Phe358) were specific for pancreatic elastase and cathepsin G respectively. Alpha-1-AT (Leu358) inhibited both neutrophil elastase and cathepsin G. These data show that, for effective inhibition, a potential cleavage site for the protease must be displayed at the alpha 1AT active centre. In each case, replacement of Met358 led to resistance to oxidative inactivation. Since alpha 1AT (Leu358) inhibits both neutrophil proteases and is resistant to oxidation, this variant may be of increased potential for the therapy of destructive lung disorders.
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PMID:Antiprotease targeting: altered specificity of alpha 1-antitrypsin by amino acid replacement at the reactive centre. 354 50

To determine whether purified human neutrophil cathepsin G (Cat-G) can act by itself or in concert with purified human neutrophil elastase (HNE) in the induction of emphysema and bronchial secretory cell metaplasia (SCM), we gave golden Syrian hamsters 100 micrograms of HNE alone or in combination with either 100 or 200 micrograms of Cat-G. Other groups of animals received intratracheal doses of up to 600 micrograms of Cat-G alone. The severity of emphysema was determined from measurements of lung volumes, compliance, forced expiratory flow, and the mean linear intercept. The severity of SCM in the main airways was graded on sections stained by the alcian blue and periodic acid-Schiff reaction. The Cat-G was a weak inducer of SCM; significant SCM was produced by 400 and 600 micrograms but not by 100 or 200 micrograms or 200 micrograms of Cat-G. The Cat-G (100 and 200 micrograms) did not potentiate the SCM induced by 100 micrograms of HNE. The Cat-G alone did not produce emphysema, and neither 100 nor 200 micrograms of Cat-G potentiated the mild emphysema induced by 100 micrograms of HNE. These results were not consonant with a report that Cat-G and HNE were synergistic in solubilizing human lung elastin. We therefore measured the ability of Cat-G and HNE to solubilize several radiolabeled elastins. The combination of Cat-G and HNE did not solubilize significantly more hamster lung elastin (23%) than the sum of their individual activities.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of combined human neutrophil cathepsin G and elastase on induction of secretory cell metaplasia and emphysema in hamsters, with in vitro observations on elastolysis by these enzymes. 384 80

Eglin c is an elastase/cathepsin G inhibitor from leech Hirudo medicinalis. The gene for this 70 aminoacid peptide was synthesized chemically, cloned and expressed by E. coli. Here we report biochemical and pharmacological studies. The rate of complex formation between Eglin c and human leukocyte elastase (HLE) or human cathepsin G (H. Cat. G) was determined and compared to those of a number of other proteinase/proteinase-inhibitor interactions (alpha 1 PI and alpha 2M). The association rate constants of Eglin c with the leukocyte enzymes are of the same order of magnitude as those with the naturally occurring inhibitors alpha 1 PI and alpha 2M. The association rate constant of Eglin c (extracted from leech) and Eglin c (biotechnology product) with HLE was found to be identical. The equilibrium constants Ki of the Eglin c/HLE and the Eglin c/H. Cat. G interactions are in the order of 10(-10) M. In an experiment with the hamster emphysema model, 0.5 mg or 2 mg of Eglin c applied intratracheally one hour before an HLE-insult completely protected the animals against emphysema and no signs of toxicity due to Eglin c were observed.
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PMID:Eglin c, a pharmacologically active elastase inhibitor. 386 12

Tissue proteolytic enzymes are currently believed to be critical to the pathogenesis of panacinar emphysema. Polymorphonuclear leukocytes (Polys) have several enzymes including elastase and cathepsin G in their azurophil granules. They have collagenase in their specific granules. We have found that this collagenase is doubly latent. It has the lysosomal type of latency that depends on the impermeability of the unit membrane that surrounds each specific granule. In addition it has a latency that is converted to activity by proteolytic enzymes. The cathepsin G of the azurophil granule is a potent activator of this latent collagenase once the collagenase is released from its membrane dependent latency. Thus latency of enzymes, the nature of the latency and accessibility of the latent enzymes to activating mechanisms must all be taken into account in any analysis of their contribution to pathogenesis of local lung disease. Equally important is that fact that polys are not a prominent cellular component of normal lung. Polys must be attracted to the lung by chemotactic peptides. These peptides must be released by the interaction of inflammatory stimuli, such as smoke particles, with complement components or they must be provided by other sources. The hypothesis that lung damage in panacinar emphysema is mediated by polys and their proteases is attractive and suggestive evidence supporting this is available. However, more evidence that takes into full account the cell biology of the proteases any poly turnover in the lung are needed to extend the hypothesis and to form a rational basis for therapeutic and prophylactic measures.
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PMID:Neutral proteases of human polymorphonuclear granulocytes: putative mediators of pulmonary damage. 625 Aug 11

The association rate constants for the interaction of alpha-1-proteinase inhibitor, oxidized alpha-1-proteinase inhibitor, and alpha-1-antichymotrypsin with several mammalian serine proteinases have been determined. The results indicate that leukocyte elastase reacts more rapidly with alpha-1-proteinase inhibitor than any other proteinase tested, while leukocyte cathepsin G shows the strongest association with alpha-1-antichymotrypsin. Oxidation of the critical methionine residue of alpha-1-proteinase inhibitor reduces the association with leukocyte elastase by a factor of more than 2000 and also lowers the association with all of the other enzymes tested with the exception of chymotrypsin. Significantly, oxidation completely abolishes any interaction of alpha-1-proteinase inhibitor with porcine elastase, human plasmin or human thrombin. These data support previous results (Johnson, D., and Travis, J. (1979) J. Biol. Chem. 254, 4022-4026) which indicated that oxidation of human alpha-1-proteinase inhibitor in vivo could reduce the effectiveness of this inhibitor in controlling proteolysis. In the lung, in particular, oxidizing agents of both chemical and biological sources could, indirectly, augment elastolysis in this tissue, resulting in the development of pulmonary emphysema.
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PMID:Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. 698 30

The granule-associated elastase homologues neutrophil elastase (NE), proteinase 3 (PR3), and azurocidin (AZU) are involved in immune defense reactions of neutrophils and monocytes. Proteinase 3 and NE contribute to the destruction and elimination of microorganisms, cleave elastin and other proteins of connective tissues, and generate chemotactic activities by forming alpha 1-proteinase inhibitor (alpha 1-PI) complexes. Azurocidin is cytotoxic to certain microorganisms and chemotactic to monocytes. All three proteins are produced and packaged into azurophil granules in large quantities during neutrophil development. The genes encoding AZU, PR3, and NE are closely clustered in this sequence within 50 kb of genomic DNA and have the same transcriptional orientation. All three genes show the same exon-intron organization as neutrophil cathepsin G, mast cell chymase 1, and the lymphocyte serine proteases, granzymes A, B, and H. The AZU-PR3-NE gene cluster was mapped to the telomeric region on the short arm of human chromosome 19 (19p13.3), whereas cathepsin G, lymphocyte granzymes B and H, and mast cell chymase 1 are organized as a separate gene cluster on chromosome 14q11.2. Neutrophil-derived serine proteases are widely regarded as pathogenic factors in degenerative and inflammatory diseases with abnormal tissue catabolism. Autoantibodies against PR3 are an obligate feature in the pathogenesis of Wegener's granulomatosis, a systemic autoimmune vasculitis. In addition, PR3 appears to regulate growth and terminal differentiation of the myelomonocyte lineage. Future investigations will clarify whether allelic variations in the AZU-PR3-NE locus predispose patients to increased degradation of elastic fibers, as in pulmonary emphysema, and to the formation of autoantibodies against PR3 in patients with Wegener's granulomatosis.
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PMID:Structure of the azurocidin, proteinase 3, and neutrophil elastase genes. Implications for inflammation and vasculitis. 795 51

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


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