UMLS:C0034067 - FACTA Search

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)

Alpha 1-antitrypsin (alpha 1AT) deficiency resulting from homozygous inheritance of the Z-type alpha 1AT gene is associated with serum alpha 1AT levels of less than 50 mg/dl and the development of emphysema in the third to fourth decades. Despite the overwhelming evidence that the emphysema of PiZZ individuals develops because of a "deficiency" of alpha 1AT and hence an insufficient antineutrophil elastase defense of the lung, epidemiologic evidence has shown that levels of alpha 1AT of only 80 mg/dl protect the lung from an increased risk of emphysema. With this background, we hypothesized that homozygous inheritance of the Z-type may confer an added risk beyond a simple deficiency of alpha 1AT by virtue of an inability of the Z-type alpha 1AT molecule to inhibit neutrophil elastase as effectively as the common M1-type molecule. To evaluate this hypothesis, the functional status of alpha 1AT from PiZZ individuals (n = 10) was compared with that of alpha 1AT from PiM1M1 individuals (n = 7) for its ability to inhibit neutrophil elastase (percent inhibition) as well as its association rate constant for neutrophil elastase (K association). Plasma alpha 1AT concentration, measured by radial immunodiffusion, was 34 +/- 1 mg/dl in PiZZ patients vs. 237 +/- 14 mg/dl for PiM1M1 plasma, a sevenfold difference. When titrated against neutrophil elastase, the present inhibition of PiZZ plasma was significantly less than Pi M1M1 plasma (ZZ 78 +/- 1% vs. M1M1 95 +/- 1%, P less than 0.001) as was purified Z type alpha 1AT (ZZ, 63 +/- 2% vs. M1M1 86 +/- 2%, P less than 0.001). Sodium dodecyl sulfate (SDS) gel comparisons of the complexes formed with M1-type alpha 1AT and Z-type alpha 1AT with elastase demonstrated the Z alpha 1AT-elastase complexes were less stable than the M1 alpha 1AT-elastase complexes, thus releasing some of the enzyme to continue to function as a protease. Consistent with these observations, the K association of purified Z-type alpha 1AT for neutrophil elastase was lower than that of M1-type alpha 1AT (ZZ 4.5 +/- 0.3 X 10(6) M-1s-1 vs. M1M1 9.7 +/- 0.4 X 10(6) M-1s-1, P less than 0.001), suggesting that for the population of alpha 1AT molecules, the active Z-type molecules take more than twice as long as the active M1-type alpha 1AT to inhibit neutrophil elastase. Consequently, not only is there less alpha1AT in PiZZ individuals, but the population of Z-type alpha1AT molecules is less competent as an inhibitor of neutrophil elastase than M1-type alpha1AT molecules. This combination of defects suggests that PiZZ individuals have far less functional antielastase protection than suggested by the reduced concentrations of alpha1AT alone, further explaining their profound risk for development of emphysema.
...
PMID:Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase. 350 Jan 83

Genetic deficiency of alpha 1-antitrypsin in man is a predisposing factor to emphysema and a disorder potentially correctable by somatic gene therapy. A full-length human alpha 1-antitrypsin cDNA was cloned into a retroviral vector and introduced into cells which package the recombinant gene in a retroviral capsule. Cells infected with the recombinant retrovirus express human alpha 1-antitrypsin mRNA and protein. The recombinant protein is glycosylated, secreted and exhibits anti-protease activity against human neutrophil elastase.
...
PMID:Retroviral mediated transfer and expression of human alpha 1-antitrypsin in cultured cells. 350 2

The current working hypothesis concerning the pathogenesis of human pulmonary emphysema proposes that neutrophils migrate through the alveolar interstitium and degranulate, releasing proteolytic enzymes into the interstitium. These enzymes, in particular elastase, can bind to and degrade interstitial elastin. This report describes an immunohistochemical, ultrastructural technique that utilizes polyclonal antibodies to localize neutrophil elastase in human lungs. Using both the immunoperoxidase and the immunogold methods on thin, embedded sections of surgically resected human emphysematous lung tissue, elastase was localized in neutrophils in the lung interstitium and extracellularly in association with interstitial elastic fibers in human lungs that showed local emphysema of varying severity. Quantitative morphometric data were obtained from the lungs of eight patients undergoing lobectomy for removal of pulmonary carcinomas. Patients had preoperative forced expiratory volume (FEV1)% levels ranging from 55 to 77. There was a correlation between a quantitative measure of the local distribution of neutrophil elastase in contact with alveolar interstitial elastin and the local presence of emphysematous change as determined by mean linear intercept of the various histologic sections. These data support the validity of the "protease-protease inhibitor balance hypothesis" as an explanation of the pathogenesis of human pulmonary emphysema.
...
PMID:Immunolocalization of elastase in human emphysematous lungs. 352 10

Eglin-c is a naturally occurring polypeptide of 70 amino acids with a molecular mass of 8,100 daltons. It is a strong inhibitor of human neutrophil elastase (HNE) and cathepsin-G, and, when given intratracheally to hamsters 1 h before human neutrophil elastase, it can prevent or ameliorate the emphysema produced by HNE. The present experiments were designed to determine the duration of the effectiveness of eglin-c, prepared by DNA technology from Escherichia coli, in preventing the emphysema and secretory cell metaplasia induced by HNE. Eglin-c (2,000 micrograms in 0.5 ml saline) was effective in ameliorating emphysema, as determined histologically and physiologically, when it was given intratracheally to hamsters 1, 2, 4, and 8 h before the intratracheal instillation of 300 micrograms of HNE. Eglin-c ameliorated bronchial secretory cell metaplasia when given 1 h before HNE but not when the time intervals were 2 h or longer. The clearance of [3H]eglin-c from the lungs was assessed. Four h after intratracheal instillation of 446 micrograms of [3H]eglin-c, 33% of the tritium was found in the lung tissue and bronchoalveolar lavage fluid; 83% of the radioactivity in the lavage fluid supernatant was associated with functionally active eglin-c. No evidence of bronchopulmonary toxicity was seen in hamsters given 4 intratracheal instillations of 2,000 micrograms of eglin-c at 1-wk intervals.
...
PMID:Effect of varying the time interval between intratracheal administration of eglin-c and human neutrophil elastase on prevention of emphysema and secretory cell metaplasia in hamsters. With observations on the fate of eglin-c and the effect of repeated instillations. 353 70

An inherited deficiency of alpha 1-antitrypsin with blood concentrations less than 80 mg/dl is associated with the accelerated development of emphysema. Current concepts of the pathogenesis of emphysema suggest that an imbalance between neutrophil elastase and alpha 1-antitrypsin in the lung allows neutrophil elastase to work unimpeded to destroy the alveolar structures. Because the common form of the inherited deficiency (homozygous Z) results from impaired hepatic release of alpha 1-antitrypsin, one therapeutic approach to increase plasma and hence lung alpha 1-antitrypsin concentrations is to enhance hepatic release or production of alpha 1-antitrypsin. In a preliminary trial with 6 alpha 1-antitrypsin-deficient subjects, we have previously shown that in 1 month, the impeded androgen danazol can augment serum alpha 1-antitrypsin concentrations by 37%. To evaluate the use of impeded androgens in alpha 1-antitrypsin deficiency on a broader scale, we have treated: 43 homozygous Z patients with danazol 200 mg given orally 3 times a day for 30 days; 6 homozygous Z patients with a similar danazol dose but given for 6 to 18 months; and 7 homozygous Z patients with stanazolol, another synthetic androgen, 2 mg given orally 3 times a day for 30 days. Of the 43 patients treated with danazol for 1 month, 23 (53%) responded with a serum alpha 1-antitrypsin concentration greater than or equal to 20% higher than baseline, an average increase of 52% over the pretreatment concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Evaluation of danazol therapy for patients with PiZZ alpha-1-antitrypsin deficiency. 353 71

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.
...
PMID:Antiprotease targeting: altered specificity of alpha 1-antitrypsin by amino acid replacement at the reactive centre. 354 50

Plasma elastase is considered to indicate neutrophil elastase that has been released in vivo and has complexed with plasma inhibitors. Because smoking may play a pathogenetic role in emphysema by inducing elastase release in the lung, which may be reflected in the plasma elastase level, we evaluated the effect of smoking on plasma elastase in healthy men by using an enzyme-linked immunosorbent assay. No significant difference was found in plasma elastase levels between 30 smokers and 29 nonsmokers (103 +/- 23 [SD] ng/ml vs. 97 +/- 23 ng/ml). We found no significant change in plasma elastase level in eight heavy smokers when we compared morning with afternoon plasma samples taken about 7 hours later, while the subjects continued to smoke ad libitum in the interval. However, we found a significant rise in plasma elastase level in 12 healthy smokers who were tested after 8 hours of abstinence from smoking and then immediately and 1/2, 1, and 2 hours after intense smoking (eight cigarettes smoked over a period of 2 hours). Neutrophil count increased from a baseline of 3.8 +/- 0.7 X 10(3)/mm3 to 8.0 +/- 2.5 X 10(3)/mm3 at 1 hour, and 8.8 +/- 3.1 X 10(3)/mm3 at 2 hours. Plasma elastase level increased significantly (P less than 0.02) from a baseline of 111 +/- 30 ng/ml to 141 +/- 24 ng/ml at 1 hour after completion of smoking, but was not significantly different from baseline 2 hours after smoking (130 +/- 34 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Effect of smoking on plasma neutrophil elastase levels. 363 17

A neonatal rat aorta smooth muscle cell culture system with a unique elastin-rich extracellular matrix was used as a model substrate for elastases. To study the susceptibility to solubilization of insoluble elastin, cultures were incubated in the presence of human neutrophil elastase (HNE) or porcine pancreatic elastase (PPE) and in the absence of serum for periods up to 45 min. Both the incubation media and cell layers were then assessed for elastin and collagen markers, total protein, and lactate dehydrogenase (LDH). Although HNE and PPE exhibited comparable activity against elastin purified from the cell layer, HNE exhibited a 6.7- to 25-fold reduction in its elastin solubilizing activity using intact cell layers as compared with the purified elastin, whereas PPE exhibited only a 1.5- to 2.5-fold reduction. This effect could not satisfactorily be explained as preferential inhibition of HNE activity in the culture system, because the amount of protein solubilized by HNE was 59% that of PPE. The mean elastin content of PPE-solubilized protein was 110% that of the elastin content of the corresponding cell layer; the value for HNE-solubilized protein was only 16%. Thus, the amount of elastin per microgram of solubilized protein for HNE was 15% that for PPE. Possible explanations for the greatly diminished elastolytic activity of HNE in the culture system include the preference of HNE for other substrates in the cell layer, the inability of HNE to penetrate sufficiently into the cell layer, and the presence of sulfated glycosaminoglycans in the vicinity of the elastin that act in an inhibitory fashion. Although there was extensive proteolytic damage to the extracellular matrix, LDH and DNA measurements indicated that little loss of cells or cell viability occurred. The observed differences in elastolytic activity of HNE and PPE in the culture system parallel the relative emphysema-inducing potency of the elastases in the hamster model of elastase-induced emphysema.
...
PMID:Elastin in a neonatal rat smooth muscle cell culture has greatly decreased susceptibility to proteolysis by human neutrophil elastase. An in vitro model of elastolytic injury. 366 86

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)
...
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

The protease-antiprotease theory of pulmonary emphysema holds that alveolar structures may be destroyed by neutrophil elastase but are normally protected from destruction by elastase inhibitors. Bronchoalveolar lavage allows to collect three types of antielastases: alpha 1-proteinase inhibitor (alpha 1 PI), bronchial mucus inhibitor and "unidentified inhibitors". Alpha 1 PI acts as an irreversible inhibitor of serine-proteinases. It reacts much faster with neutrophil elastase than with other enzymes and is therefore considered as a physiological inhibitor of this leukoproteinase. Oxidation of Met into methionine sulfoxide leads to a dramatic reduction of the inhibitory capacity of alpha 1 PI. This oxidative inactivation may be brought about by oxidants excreted by phagocytes and cigarette smoke condensate. A back-up control is provided by methionine sulfoxide reductase, an enzyme present in phagocytes and capable of reducing oxidized alpha 1 PI. The bronchial inhibitor is an acid-stable protein secreted by the mucus cells of the respiratory tract. It is a reversible tight-binding inhibitor which reacts with neutrophil elastase. Although it occurs in low amounts in the lower respiratory tract it may play an active physiological role because of its low molecular weight which allows its easy diffusion within the interstitial tissue.
...
PMID:The antielastase screen of the lower respiratory tract. 387 35

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>