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)

alpha 1-antitrypsin, a 52 kDa antiprotease, provides the major defense to the lower respiratory tract against the ravages of neutrophil elastase, a powerful serine protease. A variety of mutations in the coding exons of the alpha 1-antitrypsin gene result in 'alpha 1-antitrypsin deficiency', leading to emphysema at an early age. A subset of mutations cause liver disease and a rare mutation is associated with a bleeding diathesis. Preventive treatment for the emphysema associated with alpha 1-antitrypsin deficiency is available in the form of intermittent infusions with alpha 1-antitrypsin, and strategies have been developed to reverse the deficiency state with gene therapy.
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PMID:The alpha 1-antitrypsin gene and its deficiency states. 269 85

Alpha-1-antitrypsin (A1AT) deficiency is an autosomal hereditary disorder associated with a major reduction in serum A1AT levels. Clinically, A1AT deficiency is associated with emphysema in adults and, less commonly, liver disease in neonates. A1AT is a 52-kDa, 394-amino acid, single-chain glycoprotein normally present in serum at 150 to 350 mg/dl. The A1AT gene, composed of seven exons dispersed over 12 kb of chromosomal segment 14q31-32.3, is expressed in hepatocytes and mononuclear phagocytes. The A1AT protein, a member of the class of protease inhibitor proteins known as serpins (serine protease inhibitors), is a globular molecule composed of nine alpha-helices and three beta-pleated sheets. The major function of A1AT is to inhibit neutrophil elastase; A1AT does so through an active site centered around Met358 contained within an external stressed loop on the surface of the molecule. A1AT is a highly pleomorphic protein with greater than 75 variants determined at the protein and/or gene level. These variants can be categorized into four groups according to their serum A1AT level and function: normal, deficient, dysfunctional, and absent. There are two important salt bridges within the A1AT molecule (Glu342-Lys290; Glu263-Lys387); a mutation in the A1AT gene causing disruption of either salt bridge causes distinct molecular pathology resulting in reduced serum A1AT levels. Clinically relevant variants can be distinguished by a combination of isoelectric focusing of serum, restriction fragment length analysis of genomic DNA, oligonucleotide probes, and direct sequencing of the variant A1AT genes.
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PMID:Molecular basis of alpha-1-antitrypsin deficiency. 328 85

Emphysema is an increase in size of the air spaces distal to the terminal bronchioles, and can thus only be diagnosed pathologically, but new quantitative CT methods hold promise, diagnosing, quantitating and locating the lesions in man, in life, non-invasively. The protease/antiprotease theory of the pathogenesis of emphysema proposes that cigarette smoke attracts alveolar macrophages to distal terminal bronchioles, these in turn releasing neutrophil chemotactic factors which attract circulating polymorphonuclear leucocytes, to release potent proteolytic enzymes (serine protease) in addition to the alveolar macrophage protease. These enzymes, which can cleave all the macromolecules of the lung interstitium, are antagonized (at least the serine elastase) in health by alpha 1-antitrypsin, a normal constituent of lung lining fluid. However, this can be oxidized by oxidants in cigarette smoke, and oxidants released by polymorphonuclear leucocytes in microbial killing. The role of these actions, and of antioxidants (both natural and therapeutic) and antielastases are reviewed, as well as the activities of lung defence cells in this process. Despite this explosion of recent knowledge, we are still unable to answer the all important question "Why don't all smokers develop emphysema?", and further research is needed into variability in these multiple factors involved in this important new theory of the pathogenesis of this, possibly the commonest of all respiratory disorders of a chronic disabling nature.
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PMID:The pathogenesis of emphysema. 351 67

Serum enzyme activity in 81 patients with various medical and dermatologic problems was determined with succinyl-(L-alanyl)3-p-nitroanilide as substrate. Values exceeding the limit of mean +/- 3 SD in healthy controls were detected in 16 patients. The highest activity, greater than 80 times the mean in the controls, was found in a 20-year-old patient with severe pulmonary emphysema and cutis laxa. The enzyme activity in the patient's serum was enhanced by Ca2+ and was inhibited by metal chelators but not by serine protease inhibitors. The pH optimum of the enzyme was 7.6. The enzyme was partially purified by gel filtration chromatography. Enzyme activity eluted in two major peaks with apparent molecular weights of greater than 10(7) daltons (peak I) and approximately 2.5 X 10(5) daltons (peak II). When compared with the elution patterns in the patient's mother and a healthy control, the elevated enzyme activity in the patient's serum was associated with peak I. The partially purified enzyme in peak I was not complexed with alpha 2-macroglobulin. The peak I enzyme was capable of degrading tropoelastin and a synthetic dinitrophenyl peptide at a glycyl-isoleucyl sequence, but not native or denatured collagen.
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PMID:Characterization and partial purification of a neutral protease from the serum of a patient with autosomal recessive pulmonary emphysema and cutis laxa. 388 13

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

Elastic fibers are progressively lysed during maturation and aging and in an accelerated fashion in several aging diseases such as diabetes, arteriosclerosis, emphysema and several skin diseases. Several enzymes (elastase-type proteases) were isolated in recent years in our laboratory which appear to be involved in these processes. A cell membrane bound serine protease was isolated from arterial smooth muscle cells and was shown to increase with in vitro aging of the cells. A metallo-protease was isolated from skin fibroblasts and was shown to be capable of attacking the constituents of elastic fibers, mainly the microfibrillar glycoproteins and also the desmosine cross linked elastin in vivo. This partially purified fibroblast enzyme was shown to attack these elastic fibers when injected into the dermis. A new selective staining procedure was used to visualise and quantitate, by computerized image analysis, the skin elastic fibers in normal and pathological human or animal skin biopsies. This method, combined with the injection of elastase in rabbit skins, alone or together with inhibitors, enables the ex vivo/in vivo study of elastase action (and of its inhibition).
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PMID:Interaction between elastin and elastases and its role in the aging of the arterial wall, skin and other connective tissues. A review. 639 11

Human leukocyte elastase (HLE) is a serine protease produced by neutrophils that has been implicated in diseases such as emphysema and cystic fibrosis. An HLE inhibitor may have therapeutic value in these diseases. An active site model of HLE bound to a tripeptidic trifluoromethyl ketone (TFMK) inhibitor, 2, was created from X-ray structures of HLE and porcine pancreatic elastase. Analysis of the model indicated a preferred binding conformation for the tripeptide and potentially important interactions between it and the enzyme. This information was used to aid in the design of a series of novel, pyridone-containing, non-peptidic HLE inhibitors such as 2-[3-[[(benzyloxy)carbonyl]amino]-2-oxo- 1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)ace tam ide (5b) (Ki = 280 +/- 78 nM). Inspection of the active site model suggested that a benzyl substituent at the 5-position of the pyridone ring might improve potency by forming a lipophilic interaction with the enzyme S2 pocket. Synthesis and biological evaluation of a series of 5-benzylpyridone TFMKs provided evidence for this proposition. Further analysis of the model indicated that substitution on the 3-amino group of the pyridone ring with a hydrogen bond acceptor could potentially lead to interactions with the NH atoms of glycine-218 and/or -219. The oxalate derivative 2-[5-benzyl- 3-(carboxycarbonyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifl uor o-1- isopropyl-2-oxopropyl)acetamide (5v) was synthesized and found to have a Ki of 48 +/- 9 nM. Unfortunately, none of the compounds tested was active in an in vivo model of HLE-induced lung injury when dosed orally.
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PMID:Non-peptidic inhibitors of human leukocyte elastase. 1. The design and synthesis of pyridone-containing inhibitors. 793 32

Human neutrophil elastase is a 29 kDa, 220-residue single chain glycoprotein which functions as a powerful serine protease. Because NE is capable of destroying a broad range of substrates including cross-linked elastin and the major forms of collagen as well as the cell walls of gram-negative bacilli, it possesses the two-edged sword property that is required for normal tissue turnover and host defense, yet potentially harmful in its ability to destroy normal tissues simultaneously. In this regard, NE plays a central role in the pathogenesis of pulmonary emphysema by destroying the alveolar walls of the lung in the conditions that antiproteases in the lung such as alpha 1-antitrypsin (alpha 1-AT) are inactivated-e.g., cigarette smoking, or alpha 1-AT deficiency caused by mutations of the alpha 1-AT gene-resulting in excess burden of NE in the lung. The gene encoding the NE protein has 5 exons and is located at chromosome 19p13.3. Expression of the NE gene is tightly controlled mainly at the transcriptional level, and limited to the early stage of myeloid cell differentiation in bone marrow cells, mostly in promyelocytes. The knowledge on the modulation of lineage- and differentiation-specific NE gene expression could offer the possible therapeutic strategy to the diseases such as pulmonary emphysema.
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PMID:[Structure and expression of the human neutrophil elastase gene--regulatory mechanism and its relevance to the respiratory diseases]. 883 87

Trifluoroacetylpeptide anilides are powerful reversible inhibitors of human neutrophil elastase (HNE), a serine protease implicated in the pathogenesis of pulmonary emphysema. The in vitro effectiveness of three inhibitors, CF3CO-Phe-Ala-NH-p-C6H4-CF3 (1), CF3CO-Val-Ala-NH-p-C6H4-CF3 (2) and CF3CO-Lys-Ala-NH-p-C6H4-CH(CH3)2 (3) was analyzed. The protection of lung tissue sections of rats from the degradation induced by HNE has been evaluated quantitatively by automated image analysis. Inhibitor 1 (22 microM), 2 (50 microM) or 3 (35 and 70 microM) significantly reduced the HNE-induced degradation of the elastin network by 75, 42, 54 and 44%, respectively. Inhibitor 3 was tested intratracheally on an experimental model of pulmonary emphysema. Rats that received the elastase inhibitor 1 h before instillation of HNE were significantly protected by 40% from experimental emphysema. Reduced protections were observed with the treatment by the inhibitor 1 or 4 h after challenge with the enzyme.
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PMID:Protection of rat lung from elastase-induced elastic fiber degradation in vitro and from emphysema in vivo by a trifluoroacetylpeptide anilide inhibitor. 888 99

The pathogenesis of emphysema is considered to be an imbalance of protease and antiprotease activity in the lower respiratory tract leading to uninhibited degradation of lung interstitium by elastolytic enzymes. An increased amount of the serine protease neutrophil elastase (NE) is though to play a major role in this degradation. Because the expression of NE is limited to neutrophil precursors in the bone marrow, we hypothesized that nicotine, which is readily absorbed from lung and distributed to tissue, including bone marrow, would increase expression of the NE gene and protein. HL-60 cells, a myeloblast/promyelocyte cell line, were cultured in the presence or absence of 0.06 and 0.8 microM nicotine for 5 d. Both concentrations of nicotine caused a 2.4- to 3.3-fold increase, respectively, in NE gene expression over unstimulated cells, and NE protein increased 4.8- to 3.4-fold over unstimulated cells, respectively, similar to our positive control DMSO. Nicotine did not induce upregulation of the NE gene by initiating cell differentiation. Both low and high nicotine concentrations upregulate the NE gene in HL-60 cells leading to increased NE protein concentration per cell suggesting a pathophysiologic mechanism for emphysema.
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PMID:Nicotine enhances expression of the neutrophil elastase gene and protein in a human myeloblast/promyelocyte cell line. 891 74


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