Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human leukocyte elastase (HLE) has been demonstrated on lung elastic fibers in areas of pulmonary emphysema. In vitro studies in our laboratory have shown that HLE-elastin complexes may be remarkably stable. We tested the possibility that elastin-bound HLE may retain catalytic activity in the presence of inhibitors that are effective against free HLE and found: (1) alpha-1-proteinase inhibitor (alpha 1PI), antileukoprotease (ALP), and eglin C inhibited free HLE on an approximately 1:1 molar basis, measured with either 3H-elastin or a synthetic peptide substrate; (2) the ability of each inhibitor to control catalytic activity of HLE when complexed with elastin was impaired (e.g., in a 24-h assay, a 70-fold molar excess of alpha 1PI gave only 93% inhibition of HLE); and (3) a chloromethyl ketone inhibitor of HLE gave qualitatively similar results, although at the low enzyme concentrations used it was a less effective inhibitor of free and elastin-bound enzyme than were the polypeptide inhibitors. Further, we found evidence for two distinct mechanisms of inhibition of elastin-bound HLE. alpha 1PI and eglin C prevented elastin solubilization largely by enhancing net dissociation of HLE from the complexes; enzyme remaining bound to the substrate retained essentially full activity. In contrast, ALP and the chloromethyl ketone prevented elastin solubilization by binding to the complexes and inhibiting the enzyme in situ. These results may have implications regarding progressive elastin solubilization in vivo and should stimulate further investigation of enzyme activity in heterogeneous systems in which one or more reactants are insoluble.
 ...
PMID:Inhibition of human leukocyte elastase bound to elastin: relative ineffectiveness and two mechanisms of inhibitory activity. 231 May 84

The present study was aimed at testing whether alpha 1-proteinase inhibitor-sufficient patients with lung emphysema or idiopathic spontaneous pneumothorax have an impaired antielastase protection at the lung alveolar level. We have collected bronchoalveolar lavage fluids (BALF) from 20 PIMM emphysematous patients (44 +/- 12 yr), 24 patients with pneumothorax but no radiologic evidence of emphysema (30 +/- 11 yr), 32 healthy subjects (27 +/- 6 yr), and 56 patients with sarcoidosis (30 +/- 11 yr). The BALF were assayed for immunoreactive albumin, alpha 1-proteinase inhibitor (alpha 1PI), leukocyte elastase-alpha 1PI complex (LE-alpha 1PI), and mucus proteinase inhibitor (MPI) as well as for porcine pancreatic elastase inhibitory capacity, a measure of active alpha 1PI. The healthy subjects and the patients with emphysema or pneumothorax had comparable levels of total and active alpha 1PI and total MPI. In contrast, the levels of LE-alpha 1PI complex were elevenfold higher in patients with emphysema than in normal subjects (p = 0.021) and tended to increase with the severity of the disease because they were negatively correlated with FEV1/FVC% (r = -0.55; 0.05 less than p less than 0.1). They did not vary with age in a population of patients with sarcoidosis (r = 0.03), suggesting that their eleven-fold increase in emphysematous patients is not related to the age of these subjects. Patients with pneumothorax had levels of LE-alpha 1PI complex that did not significantly differ from those of normal subjects (p = 0.24).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The antielastase screen of the lower respiratory tract of alpha 1-proteinase inhibitor-sufficient patients with emphysema or pneumothorax. 232 50

Isocoumarins are potent mechanism-based heterocyclic irreversible inhibitors for a variety of serine proteases. Most serine proteases are inhibited by the general serine protease inhibitor 3,4-dichloroisocoumarin, whereas isocoumarins containing hydrophobic 7-acylamino groups are potent inhibitors for human leukocyte elastase and those containing 7-alkylureidogroups are inhibitors for procine pancreatic elastase. Isocoumarins containing basic side chains that resemble arginine are potent inhibitors for trypsin-like enzymes. A number of 3-alkoxy-4-chloro-7-guanidinoisocoumarins are potent inhibitors of bovine thrombin, human factor Xa, human factor XIa, human factor XIIa, human plasma kallikrein, porcine pancreatic kallikrein, and bovine trypsin. Another cathionic derivative, 4-chloro-3-(2-isothiureidoethoxy) isocoumarin, is less reactive toward many of these enzymes but is an extremely potent inhibitor of human plasma kallikrein. Several guanidinoisocoumarins have been tested as anticoagulants in human plasma and are effective at prolonging the prothrombin time. The mechanism of inhibition by this class of heterocyclic inactivators involves formation of an acyl enzyme by reaction of the active site serine with the isocoumarin carbonyl group. Isocoumarins with 7-amino or 7-guanidino groups will then decompose further to quinone imine methide intermediates, which react further with an active site residue (probably His-57) to form stable inhibited enzyme derivatives. Isocoumarins should be useful in further investigations of the physiological function of serine proteases and may have future therapeutic utility for the treatment of emphysema and coagulation disorders.
 ...
PMID:Mechanism-based isocoumarin inhibitors for serine proteases: use of active site structure and substrate specificity in inhibitor design. 265 46

The tight-skin (Tsk) mouse has recently been proposed as a genetic model of emphysema. A morphometric study has shown that emphysema develops quickly, between 15 days and 1 month after birth. Previous biochemical and ultrastructural investigations of the lungs of 1- and 2-month-old Tsk mice revealed the presence of an ongoing elastolytic process. The goal of the present study was to investigate the role of mouse leukocyte elastase (MLE) in the development of emphysema in 1-month-old Tsk mice. Using electron microscopy and an immunogold labeling technique with rabbit anti-MLE IgG, MLE was localized within the lung neutrophils of control and Tsk mice. MLE was also found associated with elastin in the alveolar septa of Tsk but not of control mice. Little or no labeling was associated with other components (collagen, pneumocytes, and endothelium) of alveolar septa of Tsk mice. Lung elastin of control mice, or of control mice rendered emphysematous with porcine pancreatic elastase, showed negligible gold particle density when incubated with gold-conjugated rabbit IgG. Thus, under the present experimental conditions, an aspecific labeling of elastin is unlikely. This study indicates that MLE may be one of the factors responsible for the rapid development of emphysema in Tsk mice.
 ...
PMID:Immunoelectron-microscopic demonstration of elastase in emphysematous lungs of tight-skin mice. 276 16

The homozygote deficit of alpha 1 antitrypsin (alpha 1 PI-ZZ) in patients frequently results in a premature development of emphysema in the lung due to incomplete protection against proteases. An active inhibitor substitution appears to be useful. The presented study proves the biological effect of alpha 1 antitrypsin infused into 8 patients. The results were an activity increase of leukocyte elastase and trypsin inhibition in serum as well as doubling of alpha 1 antitrypsin in sputum. This therapeutical conception (with a dose of 60 mg/kg body weight/week) results in an efficient protection. Inhibitors specific for mucosa are not influenced. An improvement of lung function during 6 weeks of intravenous therapy was not achieved. The progressive destruction of lung parenchyma can be probably prevented, however.
 ...
PMID:Biochemical reaction of alpha 1 antitrypsin during the substitution therapy of patients with homozygote PI-ZZ deficit. 278 32

The alpha 1-protease inhibitor, or alpha-antitrypsin (AAT), a major plasma inhibitor of leukocyte elastase and bacterial proteases, is encoded at the PI locus on chromosome 14 (14q24.3-q32.1). A deficiency of AAT in individuals homozygous for the PI Z allele occurs in about 1 in 2,000-8,000 caucasians and is associated with an increased risk of early adult onset emphysema and liver disease in childhood. We have now used DNA polymorphisms associated with the AAT gene to investigate the origin of the PI Z allele. Using two genomic probes extending into the 5' and 3' flanking regions, respectively, we have identified eight polymorphic restriction sites. Extensive linkage disequilibrium occurs throughout the probed region with the PI Z allele, but not with normal PI M alleles. The Z allele occurs mainly with one haplotype, indicating a single, relatively recent, origin in caucasians.
 ...
PMID:DNA restriction fragments associated with alpha 1-antitrypsin indicate a single origin for deficiency allele PI Z. 298 9

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.
 ...
PMID:Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters. 319 60

Acute cigarette smoke causes polymorphonuclear leukocyte (neutrophil, PMN) recruitment to the lung followed by loss of elastase from the recruited cells. Dogs were exposed to cigarette smoke with different oxidant content, bronchoalveolar lavage (BAL) was performed, and the cell distribution in the recovered alveolar lining fluid was analyzed. Exposures were 1, 3, or 6 cigarettes on one or multiple days with a maximum dose of 42 cigarettes. The mean percent PMN present in control lavage was 2.01%, while the mean percent PMN recovered in BAL after a dose of 42 1R1 cigarettes was 13.05%. Recoverable PMN, after a single exposure to three 1R1 cigarettes, also increased from 1.7 to 10.4% by 15 h after cessation of smoke exposure. The cell response for multiple (2 and 7) day exposures was similar. The elastase content per BAL neutrophil decreased relative to peripheral blood PMN from the same animals. No free elastolytic activity was found in BAL, but PMN elastase antigen was present. Increased frequency of cigarette smoke exposure delayed the return to homeostatic cell conditions. The increased PMN accumulation observed may result in an increased proteolytic load in the pulmonary interstitium and contribute to the pathogenesis of emphysema.
 ...
PMID:Acute cigarette smoke exposure in dogs: the inflammatory response. 320 13

Hepatocytes are considered to be the predominant source of alpha 1-antitrypsin (AAT), the major antiprotease in human plasma. The development of emphysema in the hereditary PiZ AAT deficiency state suggests that inhibition of leukocyte elastase in the lung is a major function of this protein. In addition, patients with AAT deficiency are at increased risk for developing cholestasis in infancy and chronic liver disease as adults. The mechanism for hepatic cell injury, however, is not understood. Transgenic mice that express the normal human AAT gene demonstrate abundant AAT in hepatocytes and specific cell types of numerous nonhepatic tissues. Immunoperoxidase techniques have previously disclosed AAT in many of the cell types seen in transgenic mice; however, the issue of local synthesis vs. endocytosis in these cell types has remained unresolved. In this study, AAT mRNA was seen in a variety of tissues in the transgenic mouse. Immunoelectron microscopy of renal tubular and small intestinal epithelial cells in the transgenic mice demonstrated AAT within the cisternae of the rough endoplasmic reticulum, as in hepatocytes. These findings support the possibility of local synthesis in the various cell types. The results suggest that in addition to maintaining tissue integrity in the lung, the protease/antiprotease balance may have physiological functions in other organs as well.
 ...
PMID:Multiple tissues express alpha 1-antitrypsin in transgenic mice and man. 326 Jun 5

Pulmonary emphysema is currently thought to be due to an elastase-antielastase imbalance with resultant destruction of alveolar structures. The present study was aimed at testing whether alpha 1-proteinase inhibitor (alpha 1 PI) is the major component of the antielastase screen of the lower respiratory tract of healthy subjects. Bronchoalveolar lavage was performed in 8 nonsmokers (27.8 +/- 3.8 years) and 9 smokers (25 +/- 0.96 years). The lavage fluids were tested for leukocyte and pancreatic elastase inhibitory capacity (LEIC and PEIC) and immunoreactive alpha 1 PI and bronchial inhibitor (brI) content. The mean +/- s.e.m. levels of LEIC, PEIC, alpha 1 PI and brI were 0.16 +/- 0.039, 0.042 +/- 0.006, 0.09 +/- 0.007 and 0.013 +/- 0.002 mol/mol albumin, respectively. Thus, on the average, the molar concentration of brI was about 14% that of alpha 1 PI. The difference between LEIC and alpha 1 PI did not reach statistical significance (P = 0.0503). The PEIC was however significantly lower than the alpha 1 PI levels (P less than 0.05), indicating that the lavage fluids contained both active and inactive alpha 1 PI. Nonsmokers and smokers did not differ in their LEIC, PEIC, alpha 1 PI and brI levels. When the data were examined on an individual basis, the subjects could be divided into 2 groups: group I (n = 9; 3 nonsmokers, 6 smokers) whose LEIC/alpha 1 PI molar ratios were higher than unity and group II (n = 8; 5 nonsmokers, 3 smokers) whose LEIC/alpha 1 PI molar ratios were equal or lower than unity. Group I subjects had significantly higher LEIC values (0.26 +/- 0.05 mol elastase inhibited/mol albumin) than group II individuals (0.055 +/- 0.006; P less than 0.001) but the two groups had similar levels of immunoreactive alpha 1 PI (0.09 and 0.08 mol alpha 1 PI/mol albumin for group I and II, respectively), functionally active alpha 1 PI (percentage of active alpha 1 PI: 53% and 37% for group I and II, respectively) and immunoreactive brI (0.016 and 0.010 mol brI/mol albumin for group I and II, respectively). These results suggested that the lavage fluids from group I contained significant amounts of undefined leukocyte elastase inhibitor(s). Gel filtration of a lavage fluid from group I showed that the undefined elastase inhibitor(s) co-eluted with brI. Most of the lavage fluids were still able to inhibit leukocyte elastase following removal of alpha 1 PI by perchloric acid precipitation.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:The elastase inhibitory capacity and the alpha 1-proteinase inhibitor and bronchial inhibitor content of bronchoalveolar lavage fluids from healthy subjects. 331 Oct 75


<< Previous 1 2 3 4 5 6 7 8 9 Next >>