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)

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

Neutrophil proteinase 4 (NP4) is a major neutral proteinase of the human polymorphonuclear (PMN) leukocyte, which is present in amounts similar to leukocyte elastase. NP4(3) is a potent, non-specific proteinase, which may degrade structural and soluble proteins in the tissues and body fluids, and it has been implicated as an important pathogenetic factor in lung emphysema. We have studied the release of elastase and NP4(3) in an in vitro model of phagocytosis. alpha 1-proteinase inhibitor (alpha 1-PI) is the major plasma inhibitor of both leukocyte elastase and NP4(3), but alpha 1-PI bound leukocyte elastase more readily than NP4(3). The basic conditions were designed so that some proteolytic activity was present in the medium. Addition of increasing amounts of Secretory leukocyte protease inhibitor (SLPI) to the incubation mixtures resulted in binding of leukocyte elastase to this inhibitor and extinction of free proteolytic activity against both natural and synthetic substrates. The progressive binding of leukocyte elastase to SLPI instead of alpha 1-PI was paralleled by an increasing binding of NP4(3) to alpha 1-PI. SLPI is a potent inhibitor of leukocyte elastase and cathepsin G, and although it lacks inhibitory effect on NP4(3), it may obviously indirectly aid in the binding and inhibition of NP4(3) to alpha 1-PI, by taking care of at least part of the leukocyte elastase. As a specific NP4(3)-inhibitor is not readily available for therapeutic use, this effect may prove useful under in vivo conditions and enhance the protective effect of administered recombinant human SLPI.
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PMID:Release of neutrophil proteinase 4(3) and leukocyte elastase during phagocytosis and their interaction with proteinase inhibitors. 136 20

Proteinase-3 (PR-3) is a neutral serine proteinase present in the azurophil granules of human polymorphonuclear leukocytes. It degrades a variety of extracellular matrix proteins including elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters. It is identical to the target autoantigen (c-ANCA) associated with Wegener's granulomatosis and to myeloblastin, a serine proteinase first identified in HL-60 leukemia cells. In this study, the gene encoding PR-3 was cloned and sequenced. The gene spans approximately 6.5 kilobase pairs and consists of five exons and four introns. The genomic organization of PR-3 is similar to that of the other serine proteinases expressed in hemopoietic cells. Each residue of the catalytic triad of PR-3 is located on a separate exon, and the positions of the residues within the exons are similar to those in human leukocyte elastase and cathepsin G. The phase and placement of the introns in the PR-3 gene are also similar to those in human leukocyte elastase and cathepsin G. The 400-base pair (bp) 5'-flanking sequence of the PR-3 gene contains a TATA box at position 379. There is no CAAT box promoter element. The 3'-untranslated region is 200 bp, extending from a TGA stop codon to the site of polyadenylation 10 bp after the canonical AATAAA signal. Amplification of PR-3 from a human/hamster hybrid cell line localizes the gene to human chromosome 19. Evidence from Northern analysis suggests that PR-3 expression is primarily confined to the promyelocytic/myelocytic stage of bone marrow development.
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PMID:Structure, chromosomal assignment, and expression of the gene for proteinase-3. The Wegener's granulomatosis autoantigen. 140 Apr 30

A large series of variously substituted anthraquinones has been synthesized and assayed for inhibitory capacity against human leukocyte elastase (HLE) and cathepsin G (CatG), two serine proteinases implicated in diseases characterized by the abnormal degradation of connective tissue, such as pulmonary emphysema and rheumatoid arthritis. It was found that 2-alkyl-1,8-dihydroxyanthraquinone analogues are competitive inhibitors of HLE with IC50 values ranging from 4 to 10 microM, and also inhibit CatG with IC50 values ranging from 25 to 55 microM. Consequently, analogues containing the 2-alkyl-1-hydroxy-8-methoxyanthraquinone substitution pattern inhibit HLE to the same magnitude as for the compounds above, but show very little inhibition of CatG. Anthraquinones containing long, hydrophobic n-butyl carbonate moieties in the 1- and 8-positions in conjunction with a third hydrophobic substituent in the 2- or 3-position are highly selective for HLE, with Ki values in the range of 10(-7) M. All of the inhibitors described are completely reversible, with no evidence of acyl-enzyme formation detected.
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PMID:Novel anthraquinone inhibitors of human leukocyte elastase and cathepsin G. 157 86

Heparin and its derivatives inhibit human leucocyte proteinases i.e. elastase and cathepsin G, but do not inhibit porcine pancreatic elastase and Pseudomonas aeruginosa elastase. In vitro experiments, reported here, also indicate that elastin, one of the physiological substrates of human leucocyte elastase (HLE), could decrease by 30-fold the inhibitory potential of an hexadecasaccharide heparin fragment (dp 16) isolated from CY 222. Nevertheless, the inhibitory capacity of the heparin fragment still remains elevated with IC50 = 2.7 x 10(-7) M and still inhibits HLE in its free and adsorbed state to elastin. These overall data prompted us to evaluate the influence of CY 222 in HLE-induced emphysema. Emphysema was induced in mice eight weeks old, following a single instillation of 200 micrograms of HLE. CY 222 treated animals received 2.5 mg.kg-1 subcutaneously once daily, 6 days per week during 4 weeks prior to HLE instillation, and for eight weeks following HLE instillation. The heparin fragment treatment of the mice halved the mortality rate observed early following HLE instillation. After 8 weeks, surviving animals were examined for lung histological and morphometrical changes: mean linear intercept (MLI) and internal alveolar area (ISA). The CY 222 heparin fragments exerted a protective effect against HLE-induced emphysema by decreasing by 70% the MLI; these heparin fragments exerted no effect on emphysema induced by pancreatic elastase in hamsters or mice. Heparin derivatives represent a new class of physiological HLE low molecular weight inhibitors capable of preventing HLE-induced emphysema.
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PMID:Prevention of leucocyte elastase-induced emphysema in mice by heparin fragments. 178 73

Proteinase 3 (PR-3) is a human polymorphonuclear leukocyte (PMNL) serine proteinase that degrades elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters (Kao, R. C., Wehner, N. G., Skubitz, K. M., Gray, B. H., and Hoidal, J. R. (1988) J. Clin. Invest. 82, 1963-1973). We have determined the primary structure of several PR-3 peptides and have analyzed catalytic properties of the enzyme. The enzyme has considerable amino acid sequence homology with two other well characterized PMNL neutral serine proteinases, elastase and cathepsin G. Furthermore, the NH2-terminal amino acid sequence of PR-3 is identical to that of the target antigen of the anti-neutrophil cytoplasmic autoantibodies associated with Wegener's granulomatosis. PR-3 degrades a variety of matrix proteins including fibronectin, laminin, vitronectin, and collagen type IV. It shows no or minimal activity against interstitial collagens types I and III, respectively. The analysis of peptides generated by PR-3 digestion of insulin chains and the activity profile against a panel of chromogenic synthetic peptide substrates show that PR-3 prefers small aliphatic amino acids (alanine, serine, and valine) at the P1 site. The elastase-like specificity of PR-3 is consistent with its striking sequence homology to elastase at substrate binding sites. PR-3 is inhibited by alpha 1-proteinase inhibitor (ka = 8.1 x 10(6) M-1 S-1; delay time = 25 ms) and alpha 2-macroglobulin (ka = 1.1 x 10(7) M-1 S-1; delay time = 114 ms) but not by alpha 1-anti-chymotrypsin. In contrast to elastase and cathepsin G, PR-3 is not inhibited by secretory leukoprotease inhibitor and is weakly inhibited by eglin c. Thus, PR-3 is distinct from the other PMNL proteinases.
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PMID:Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase. Structural and functional properties. 203 50

Heterozygous alpha 1-antichymotrypsin (ACT) deficiency is inherited in an autosomal dominant mode independently of alpha 1-antitrypsin with a gene frequency (q) of 0.003. In a previous study, a high prevalence of enlarged residual volumes in subjects with the trait were noted. Neutrophil cathepsin G, the target proteinase of ACT, enhances the elastolytic action of elastase. Thus, hypothetically, subjects with the trait may have increased risk for developing pulmonary emphysema. To test whether heterozygous ACT deficiency predisposes to lung disease, plasma ACT concentrations were determined in a cohort of 1,872 middle-aged women. Women with subnormal levels were studied with respect to heredity, airway symptoms, and lung function. Twelve women (0.64% of the cohort) were classified as heterozygotes after family studies and were compared with control subjects, matched for age, weight, sex, and smoking status. There were no significant differences in airway symptoms between heterozygotes and control subjects. However, the prevalence of ex-smokers was significantly higher among heterozygotes than among the screened population as a whole (prevalence ratio, 2.18; 95% confidence interval, 1.004-4.72). There were no differences between the heterozygotes and the control subjects in the basal spirometry. However, after bronchodilation, five of the 12 heterozygotes manifested residual volumes greater than 2.5 standard deviations above normal mean compared with one of 24 control subjects (p = 0.012). The present investigation thus confirms our previous findings of an increased prevalence of enlarged residual volumes in heterozygous ACT deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary function in middle-aged women with heterozygous deficiency of the serine protease inhibitor alpha 1-antichymotrypsin. 232 51

Much of the tissue damage associated with emphysema and other inflammatory diseases has been attributed to the proteolytic activity of neutrophil elastase, a major component of the azurophil granule. Recently, two additional azurophil granule proteins with NH2-terminal sequence homology to elastase were isolated (Gabay, J. E., Scott, R. W., Campanelli, D., Griffith, J., Wilde, C., Marra, M. N., Seeger, M., and Nathan, C. F. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 5610-5614) and designated azurophil granule protein 7 (AGP7) and azurocidin. Azurocidin and AGP7 represent significant protein components of the azurophil granule, together comprising approximately 15% of the acid-extractable protein as judged by reverse-phase high performance liquid chromatography analysis. AGP7 migrates on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as four distinct glycoforms of molecular mass 28-34 kDa, whereas azurocidin exhibits three predominant bands with molecular mass of 28-30 kDa. Treatment of intact azurophil granules with [3H]diisopropyl fluorophosphate resulted in labeling of elastase, cathepsin G, and AGP7, whereas azurocidin was not labeled. Tryptic mapping of 3H-labeled AGP7 allowed us to identify and sequence the active-site polypeptide that has 70% identity to elastase over 20 residues. The active site peptide of azurocidin was also identified by sequence analysis of tryptic fragments and showed 65% identity to the active site of elastase. Surprisingly, the catalytic serine of azurocidin is replaced by glycine, explaining its inability to label with [3H]diisopropyl fluorophosphate. Thus, we have identified two azurophil proteins closely related to neutrophil elastase, one of which has apparently lost its proteolytic activity due to mutation of the catalytic serine.
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PMID:Characterization of two azurphil granule proteases with active-site homology to neutrophil elastase. 240 77

Elastase and cathepsin G are two of the major enzymes present in and secreted by human neutrophils. These proteinases can rapidly degrade connective tissue proteins. However, they also may be involved in other processes, including the activation or inactivation of protein hormones and the inactivation of plasma proteinase inhibitors. Neutrophil elastase has been implicated in the development of pulmonary emphysema, although a function for cathepsin G has not yet been elucidated. Both enzymes are normally tightly controlled by plasma proteinase inhibitors. However, this proteinase-proteinase inhibitor balance can be perturbed in favor of free enzyme by several methods, with resulting tissue damage. The use of inhibitors from several sources should be helpful in augmenting natural levels so that homeostasis can be maintained.
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PMID:Structure, function, and control of neutrophil proteinases. 245 77

Studies were designed to explore the possibility that human polymorphonuclear leukocyte granule constituents in addition to elastase (HLE) had the potential to cause emphysema. A two-step purification of three serine proteinases was developed. Granule extract proteins were initially separated by dye-ligand affinity chromatography. Fractions eluted were divided into four pools. Hamsters were given a single intratracheal instillation of saline +/- 0.1 mg protein of each pool. While pool 2 contained HLE and cathepsin G, the most dramatic bullous emphysema developed in animals treated with pool 4. The esterase from pool 4, designated proteinase 3 (PR-3) was purified, characterized in vitro, and tested for its ability to cause emphysema. PR-3 is a neutral serine proteinase with isoenzyme forms. Its ability to degrade elastin at pH 6.5 is slightly greater than that of HLE, but it is less active than HLE at pH 7.4 or 8.9. PR-3 has weak activity against azocasein. Its ability to degrade hemoglobin is intermediate to that of HLE and cathepsin G at pH 7.4. PR-3 has no activity against chromogenic substrates specific for HLE or cathepsin G. Its pI is substantially less than HLE or cathepsin G. It is also immunologically distinct from HLE. It induces emphysema in hamsters commensurate with that of HLE. We conclude that PR-3 may be important in the pathogenesis of human emphysema.
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PMID:Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters. 319 60


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