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)

To evaluate the concept that lung elastin degradation is accelerated in homozygous alpha-1-antitrypsin (AAT) deficient persons, we prepared acid hydrolysates of urine and used a radioimmunoassay for desmosine to measure urine concentrations of this elastin-specific cross-link in such persons and in control subjects. Excretion of desmosine in 17 homozygous AAT-deficient (PiZZ) patients with emphysema was compared with that in 27 patients with interstitial lung diseases (16 sarcoid, 5 idiopathic pulmonary fibrosis, 6 other interstitial lung diseases) and 26 healthy subjects. Both smokers and nonsmokers were present in all groups. Urinary desmosine concentration (microgram/100 mg creatinine) was 2.35 +/- 0.93 in the PiZZ patients, 2.49 +/- 1.01 in those with interstitial lung disease, and 2.05 +/- 0.54 in the healthy control subjects (p greater than 0.1, all comparisons). Because abnormal pulmonary elastolysis may be largely completed before symptoms of emphysema develop in AAT-deficient persons, we also tested 6 asymptomatic adults with homozygous AAT deficiency (PiZZ) and 5 PiZZ children. Urine desmosine (microgram/100 mg creatinine) was not significantly elevated in either group compared with that in the age-matched control subjects, although children (PiZZ and age-matched controls) showed higher excretions than did adults (6 asymptomatic PiZZ adults, 2.60 +/- 0.91; 5 PiZZ children, 3.27 +/- 0.62; 10 control children, 3.61 +/- 0.62). These data suggest that pathologic lung elastolysis in the PiZZ subject may constitute too small a fraction of total-body elastin turnover to be detected by this method.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Urinary excretion of desmosine (elastin cross-links) in subjects with PiZZ alpha-1-antitrypsin deficiency, a phenotype associated with hereditary predisposition to pulmonary emphysema. 387 94

Chronic obstructive pulmonary disease (COPD), a major cause of morbidity and death in the smoking population, develops insidiously over many years, and significant impairment of lung function usually occurs before the disease is diagnosed. Because lung elastin degradation appears to be a prerequisite for the development of the disease, immunologic detection of elastin-derived peptides in the blood might be an effective approach to the early detection and monitoring of the disease. We here report an improved enzyme-linked immunosorbent assay for elastin peptides using a peroxidase-antiperoxidase complex as the reporter group. The assay is sensitive to 2 ng/ml elastin peptides. We show that for optimal, reproducible results the assay should be carried out at 16 degrees C rather than at room temperature and that determinations should be made on plasma containing protease inhibitors rather than on serum. The levels of elastin-derived peptides appeared to remain relatively constant when multiple samples were taken during a 5- to 10-wk period from individual subjects. In addition, patients with COPD had elevated elastin peptide levels (127 +/- 47 ng/ml) compared with levels in normal nonsmokers (58 +/- 17 ng/ml), whereas normal smokers had values intermediate between the 2 groups (mean peptide levels of 76 +/- 42 ng/ml). A small group of normal smokers (20%) had elevated elastin peptide levels similar to those in the emphysema group and may represent that group of smokers who are at risk of developing obstructive lung disease.
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PMID:Utilization of a peroxidase antiperoxidase complex in an enzyme-linked immunosorbent assay of elastin-derived peptides in human plasma. 389 Jun 38

Many studies have been carried out in the past 10 yr dealing with the possible role of elastase in the pathogenesis of pulmonary emphysema. These include newer observations in animal models revealing augmentation of elastase-induced lesions by lathyrogens or by exposure to cigarette smoke. In general, the animal model experiments have focussed attention on repair-processes in the lung and shown that such processes may exert a major influence on the outcome of the initial proteolytic insult. Human studies exploring correlations between elastase levels in neutrophils or serum and development of disease have provided conflicting data; however, measurement of enzymes in pulmonary secretions have yielded more suggestive results. Assessments of lung elastase inhibitors in humans continue to support the importance of alpha-1-proteinase inhibitor in the protection of the lower respiratory tract, but newer information on locally produced, low molecular weight elastase inhibitors indicates that these, too, may play a significant role. Attempts have been made to link cigarette smoking to the development of emphysema at the chemical and cellular levels. These studies have focussed on: (1) the recruitment of elastase-producing leukocytes to smokers' lungs, (2) inactivation of lung elastase-inhibitors by tobacco products or by metabolites released from tobacco-stimulated lung cells, and (3) interference with elastin neosynthesis (repair) in the smoker. Additional information is also available concerning the biochemical properties of neutrophil and macrophage elastases, although it is still unclear which of these enzymes plays the predominant role in chronic lung injury associated with smoking. Perhaps the greatest advance in the emphysema field in recent years involves new discoveries concerning the structure and function of the alpha-1-proteinase (elastase) inhibitor. Applications of recombinant DNA technology and genetic engineering have made it possible to design modified inhibitors with striking new properties. These agents may enjoy significant clinical application in the not too distant future.
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PMID:Elastases and emphysema. Current assessment of the protease-antiprotease hypothesis. 389 82

Unrestrained proteolysis in the lung is believed to initiate emphysema, a disease common among tobacco smokers. However, few studies have found extracellular protease activity in human lung lavage. In this investigation, elastase and serine protease activities were measured in bronchoalveolar lavage supernatants (BAL) from patients undergoing routine investigations. Significantly more elastolytic activity (against insoluble [3H]-elastin) was recovered in the lavage of smokers than that of non-smokers. However, no significant difference was found when the levels of serine proteolytic activity (against N-succinyl-L-trialanyl-p-nitroanilide) were compared. The elastolytic component of the protease activity rose from 5% in non-smokers' BAL to over 30% in that of smokers, suggesting that elastase activity is selectively enhanced by smoking. In lavages from most smokers, 80% or more of the elastase activity was serine-dependent, whereas lavages from non-smokers contained variable proportions of serine elastase. Both alpha 1-proteinase inhibitor (alpha 1-PI) and a low molecular weight antiprotease, bronchial mucus proteinase inhibitor (BMPI) were detectable in the lavage samples, the latter contributing up to 76% of the total antiprotease quantified in the lavage. Functional antiprotease was detected in 85% of the lavages. Since there were no differences in either antiprotease levels or functional inhibitory capacities between lavages from smokers and controls, it is concluded that the imbalance in the protease/antiprotease profile of the smokers' lung results from an enhancement of proteases, specifically of elastolytic activity, rather than a reduction in inhibitory capacity.
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PMID:Extracellular elastolytic activity in human lung lavage: a comparative study between smokers and non-smokers. 390 6

The severity of pulmonary emphysema can be affected by exposure to cigarette smoke in several ways. Inactivation of alpha-1-antitrypsin and recruitment of leukocytes to lung airways shifts the protease-antiprotease balance towards increased elastolytic activity. The present study demonstrates an additional effect of cigarette smoke inhalation and retardation of the repair process and of the neosynthesis of cross-linked elastin. Hamsters with elastase-induced emphysema, exposed to cigarette smoke for 1 wk immediately after elastase administration, showed a 40% reduction of 14C-lysine incorporation into the elastin-specific cross-links, desmosine, and isodesmosine. Concomitantly, there was a decrease in the level of lung lysyl oxidase to that observed in uninjured control animals, in sharp contrast to the sevenfold increase in lysyl oxidase activity in hamsters with elastase-induced emphysema recovering under atmospheric conditions. These findings suggest that impairment of the production of lysyl oxidase and the resynthesis of cross-linked elastin by smoke inhalation exacerbates alveolar destruction.
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PMID:Cigarette smoke impairs elastin resynthesis in lungs of hamsters with elastase-induced emphysema. 392 58

Amino acid analysis of human fetal lung elastin was undertaken in 49 instances of live-born neonates, ranging from 380 g to full term, and in 3 abortuses of 12-14 wk gestation. The data suggest that formation of the cross-linking agents, desmosine and isodesmosine, occurs early, between 14 and 22 wk. The ratio of neutral to charged amino acids remains low until the 36th wk when it attains adult levels. The composition of elastin was independent of sex and duration of survival. In three neonatal pulmonary diseases (respiratory distress syndrome, atelectasis, and hemorrhage) ratios were significantly lower than those found in nondiseased lungs. This may be a reflection of immaturity or may be a predisposing factor in neonatal lung disease. The latter hypothesis is attractive and receives indirect support from the association of a more polar elastin with other diseases, including adult emphysema and atheromatous aortic change.Our finding of relatively high polarity in elastin from human fetal lung is consistent with previous observations in a variety of fetal organs of other species.
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PMID:Lung tissue elastin composition in newborn infants with the respiratory distress syndrome and other diseases. 483 91

When pancreastic elastase is introduced into the lungs of hamsters to produce emphysema, there is an initial rapid destruction of elastin followed by a subsequent resynthesis. In order to investigate its pathologic significance, we attempted to interfere with this resynthesis by feeding inhibitors of elastin cross-linking. The feeding of the lathyrogens beta-aminoproprionitrile (beta APN) or penicillamine resulted in a marked worsening of the elastase-induced emphysema, as measured by the average distance between alveolar walls and the internal alveolar surface area, when compared with the effect of elastase in animals fed a normal diet. The lathyrogens produced no effect on lung morphology without elastase injections. In elastase-injected animals, the principlal biochemical effect of beta APN was a decrease in the aldehyde content of the elastin without a measurable decrease in desmosine cross-links. These results indicated that the formation of normal connective tissue proteins during the replair of elastolytic injury helps to limit the degree of anatomic deformity that is produced.
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PMID:The effect of lathyrogens on the evolution of elastase-induced emphysema. 610 44

Four families of macromolecules make up the pulmonary fibrous connective tissue which one finds in all connective tissue: collagen elastin, the proteoglycans and the structural glycoproteins. The regulation of the synthesis of these macromolecules and their arrangement and interaction within the intracellular space are conditions necessary for the development and maintenance of a normal pulmonary fibrous connective tissue. The quantitative relationship of these macromolecules changes with age; it is also profoundly modified in chronic obstructive lung disease. An understanding of the pathogenesis of the modifications, requires the study of the regulatory mechanisms involved in the synthesis and degradation of the macromolecules of the pulmonary connective tissue. In recent years we have made some progress in the domain of the regulation of the synthesis and degradation of collagen, but we still know very little about elastin. Over the past few years our laboratory has isolated several cellular elastases which probably intervene in these processes. Elastoplastic proteases have been isolated from platelets, leucocytes, macrophages, fibroblasts and smooth muscle cells. Human serum and purified lipoproteins also possess an elastolytic activity which is easily measured in clinic. Which of these enzymes is responsible for the lysis of the elastic laminae seen in emphysema has not yet been established. It seems possible that one important factors in certain pathological states is the faulty protection given by modified serum inhibitors. Our recent studies with Mrs Ch. LAMFUMA and Mrs MOCZAR suggest an important role for the structural glycoproteins in the pulmonary connective tissue. It is possible that qualitative an or quantitative modifications in these glycoproteins could also play an important role in pathology.
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PMID:[Pulmonary fibrous ground substance. Macromolecules of the intercellular matrix]. 611 Dec 65

A mild form of emphysema was produced in pigs raised on a copper-deficient, zinc-supplemented diet. The copper-requiring enzyme, lysyl oxidase, catalyzes the cross-linking of tropoelastin into mature elastin. Zinc further inhibits the activity of lysyl oxidase. Lungs from animals raised on copper-deficient, zinc-supplemented diets of demonstrate perforations in alveolar walls and diminished amounts of elastin bronchi and pulmonary arteries. Mean linear intercepts are greater and alveolar internal surface areas are less than those in control animals, fulfilling the generally accepted definition of emphysema. Physiologic confirmation is provided by a leftward shift of the saline volume-pressure curves when compared with those in control animals. Ultrastructurally, the alveolar walls are effaced and pores of Kohn are enlarged. There are areas in which elastin is absent leaving remnant microfibrils, and there are other changes consistent with active elastin synthesis. Biochemical data demonstrate no difference in elastin content as micrograms/ml of fat-free dry weight but do demonstrate increased collagen content in experimental animal lungs compared with that in control lungs. Ultrastructural similarities to enzyme-induced models of emphysema suggest the presence of elastin degradation in our model. We speculate that although the copper-deficient, zinc-supplemented state may stimulate protein synthesis in general, elastin is being degraded by endogenous means, but collagen is not.
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PMID:A copper-deficient, zinc-supplemented diet produces emphysema in pigs. 612 18

Human alveolar macrophages (AM) bind and internalize neutrophil elastase (NE) in vitro by receptor-mediated endocytosis. Blood monocytes are progenitors of AM, and if they possess receptors for NE, they could bind and internalize NE in the pulmonary interstitium and may effect elastin degradation, which likely accompanies the development of emphysema. To determine whether monocytes contain receptors for NE, radioiodinated NE (I-NE) binding was assessed, and the results were compared with binding of I-NE to AM obtained concurrently from the same donors. The binding of I-NE to monocytes cultured in vitro for 8 days was also assessed. Specific binding of I-NE to monocytes and AM reached 80% of maximum in 30 min; similar quantities bound to AM and monocytes after a 2-h incubation with I-NE, and a smaller quantity bound to cultured monocytes. The estimated association constant for specific binding was 6 X 10(6)M-1 and 4 X 10(6)M-1 for AM and monocytes, respectively. The fate of I-NE in monocytes and AM at 24 h after uptake was assessed and compared using molecular sieve chromatography. Approximately 50% of the I-NE initially bound to either monocytes or AM remained cell-associated at the end of culture; 62 to 65% of this material eluted at 29,000 daltons and solubilized particulate elastin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A comparison of the binding and fate of internalized neutrophil elastase in human monocytes and alveolar macrophages. 631 57


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