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)

Antitrypsin is the predominant protease inhibitor in human plasma. Despite its name, its prime function is an inhibitor of neutrophil elastase. It is the archetype of a family of protease inhibitors (serpins) characteristically with a MW 50,000 and a highly ordered tertiary structure. Its role is as a protector of vulnerable tissues against digestion by leukocyte enzymes, and plasma deficiency predisposes to premature emphysema. Northern Europeans are uniquely susceptible to deficiency due to the frequency of two mutants (Z & S) both having substitutions at glutamic acids that form key salt bridges in the molecule. In the reactive center of antitrypsin is a labile methionine which allows leucocytes to switch off inhibitory activity but this contributes to the accelerated lung degeneration in cigarette smokers. Although plasma replacement therapy is one option for treatment a first approach is to avoid smoking and other environmental irritants.
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PMID:The molecular structure and pathology of alpha 1-antitrypsin. 211 61

Tissue inhibitor of metalloproteinases (TIMP) is the major inhibitor of collagenase, gelatinase, proteoglycanase, stromelysin, and metalloelastases. An imbalance between proteases and inhibitors has been implicated in numerous disease processes including tumor invasion, rheumatoid arthritis, emphysema, and aortic aneurysm disease. The purpose of this investigation was to develop a polyclonal antibody to recombinant TIMP and establish an immunoassay to measure immunoreactive protein in normal and diseased tissues. A polyclonal antibody was produced in rabbit against recombinant human TIMP which was characterized and used to establish a radioimmunoassay. The assay was used to measure immunoreactive protein in fibroblast conditioned medium, human serum, and aortic extracts. There was more immunoreactive TIMP in matrix associated urea extracts than soluble salt extracts from human aorta, suggesting that TIMP is matrix associated. The sensitivity of the assay enables the specific measurement of this inhibitor in serum, fibroblast culture medium, and tissue extracts.
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PMID:Tissue inhibitor of metalloproteases (TIMP) is matrix associated in aortic tissue: report of a radioimmunoassay. 232 85

The tight-skin (Tsk) mouse has recently been proposed as a genetic model of emphysema. In the present study, the development of emphysema was investigated in these mice with histological, biochemical, and ultrastructural methods at 4 days and at 1 and 2 months of life. At 4 days after birth, histological examination of the lungs revealed only a mild enlargement of the primary sacculi. Neither biochemical nor ultrastructural changes were seen however at this time. At 1 month of age, the histological examination showed marked emphysema-like changes, characterized by enlargment of air spaces accompanied by destruction of alveolar walls. Biochemical analysis showed a marked decrease in insoluble elastin content and a significant increase in salt-extractable collagen. Ultrastructural investigation revealed edema fluid in the interstitium and broken and disorganized elastic fibers. All these findings strikingly resemble the changes which occur in the lungs early after an instillation of elastase. In the 2-month-old Tsk mice the histological lesion progressed in severity. The ultrastructural findings were similar to those observed at 1 month, and the biochemical changes showed no signs of recovery. Thus, in these mice, the emphysematous lesion develops very rapidly between 4 days and 1 month of life and shows the characteristics of an elastolytic process which is still ongoing at 2 months of age.
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PMID:A biochemical and morphological investigation of the early development of genetic emphysema in tight-skin mice. 272 56

Homozygous inheritance of the Z-type mutant form of the alpha 1-antitrypsin (alpha 1AT) gene results in the most common form of alpha 1AT deficiency, a human hereditary disease associated with a high risk for the development of emphysema and an increased incidence of neonatal hepatitis. The alpha 1AT-synthesizing cells of individuals with the Z gene have normal alpha 1AT messenger RNA levels, but alpha 1AT secretion is markedly reduced secondary to accumulation of newly synthesized alpha 1AT in the rough endoplasmic reticulum. Crystallographic analysis of alpha 1AT predicts that in normal alpha 1AT, a negatively charged Glu342 is adjacent to positively charged Lys290. Thus the Glu342----Lys342 Z mutation caused the loss of a normal salt bridge, resulting in the intracellular aggregation of the Z molecule. The prediction was made that a second mutation in the alpha 1AT genet that changed the positively charged Lys290 to a negatively charged Glu290 would correct the secretion defect. When the second mutation was added to the Z-type complementary DNA, the resulting gene directed the synthesis and secretion of amounts of alpha 1AT similar to that directed by the normal alpha 1AT complementary DNA in an in vitro eukaryotic expression system. This suggests the possibility that a human hereditary disease can be corrected by inserting an additional mutation in the same gene.
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PMID:Repair of the secretion defect in the Z form of alpha 1-antitrypsin by addition of a second mutation. 290 2

The most common causes of hypoxic cor pulmonale are chronic bronchitis and emphysema. Although the clinical situation in some patients is characterized early by hypoxemia, oedema is rare in patients with an arterial pO2 above 60 mm Hg. The presence of oedema can be regarded as an unfavorable prognostic indicator. For many years, peripheral oedema had been considered an expression of congestive cardiac failure; it may be assumed, however, that neither right nor left ventricular failure is prerequisite to the development of oedema. Oedema formation can be attributed to excessive retention of salt and water or a redistribution of body water into the extracellular compartment. Hypercapnia and acidosis affect direct stimulation of renal hydrogen ion secretion. The resulting electrochemical imbalance is compensated by reabsorption of sodium. Hypercapnia and, in acute phases possibly, hypoxia lead to a fall in renal blood flow mediated by alpha-adrenergic stimulation through activation of the renin-angiotensin-aldosterone system. An increase in plasma ADH may also contribute to development of oedema. The development of cor pulmonale or respiratory insufficiency can be enhanced by nocturnal hypoventilation and hypoxia during sleep as well as by sleep apnoea. Nocturnal hypoxia, smoking and reduced oxygen tension in the relevant kidney cells responsible for erythropoietin release promote the occurrence of secondary polycythaemia. For treatment of acute exacerbations in cor pulmonale associated with infections bronchitis antibiotics such as amoxycillin and cotrimoxacol are drugs of first choice. While the use of digoxin is of doubtful value, the cautious administration of diuretics may bring symptomatic relief. In addition to physiotherapy, beta-2-selective bronchodilators and nebulized bronchodilator therapy can be useful; theophyllines dilate airways and increase cardiac output but they can cause arrhythmias and a deterioration of arterial blood gases in hypoxic patients. If the patient has been treated chronically with corticosteroids, the dosage will have to be incremented; if asthma is suspected, corticosteroid treatment is essential. Controlled oxygen therapy is the most important single therapy aimed at relief of severe arterial hypoxaemia. Oxygen should be titrated initially (for the first one or two days) to achieve an arterial tension of at least 48 mm Hg. Thereafter, the oxygen flow should be increased to yield an arterial tension in excess of 60 mm Hg during continued treatment for two to three weeks.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoxic cor pulmonale: a review. 294 54

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

Leukocyte elastase has been implicated in the etiology of pulmonary emphysema. Recently, two genetic models of emphysema have been described, in mouse, which may enhance our understanding of the pathogenesis of emphysema. We therefore sought to purify mouse leukocyte elastase in order to characterize its biochemical properties. Leukocyte enzyme has been purified by a two-step procedure involving salt extraction of granular fraction, followed by preparative isoelectric focusing on Sephadex G-75 Superfine. The enzyme hydrolyses elastin and synthetic substrates for elastase, even if to a different extent. Inhibition studies indicates that the enzyme is a serine proteinase. Mouse elastase has a single isoelectric point of 8.65 and it behaves on sodium dodecyl sulphate polyacrylamide gel electrophoresis as a major band (molecular weight 29,000) and two minor bands (molecular weight 27,000 and 25,800, respectively.
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PMID:Isolation and partial characterization of a proteinase with elastolytic activity from mouse blood leukocytes. 335 74

Furoyl saccharin, a novel heterocyclic acylating agent which has been previously found to possess a potent inhibitory capacity in vitro for elastase and other serine proteases, has been investigated in vivo in two acute animal models of emphysema. In hamsters, intratracheal (i.tr.) administration of 0.1 mg porcine pancreatic elastase resulted seven days later, in a 42% increase of the mean linear intercept (Lm). Addition of 0.3 mg to 0.3 mg furoyl saccharin to elastase exhibited a partial, not dose-related, but statistically significant inhibition of the increase of LM. Addition of 1 mg furoyl saccharin (equivalent to a dose of 12.5 mg/kg) completely abolished the increase in Lm. In the rabbit i.tr. instillation of 3.7 mg porcine pancreatic elastase induced within seven days, a 48% increase of the Lm, a 27% decrease of the internal surface area (ISA) of the lungs and a 33% decrease of the ISA corrected to an arbitrary total lung volume of 70 ml (ISA70). Furoyl saccharin given i.tr. 15 min prior to elastase at the doses 3, 10 and 20 mg prevented significantly in a dose-related manner, the changes in Lm, ISA and ISA70. The highest furoyl saccharin dose (equivalent to a dose of 10.8 mg/kg) completely protected against the emphysematous lesion. Additionally furoyl saccharin (20 mg i.tr.) prevented in the rabbit model the depletion in lung insoluble elastin and the increase in salt soluble collagen induced by the elastase administration. These results show that furoyl saccharin also in vivo has a marked antielastase activity.
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PMID:Effect of the novel synthetic protease inhibitor furoyl saccharin on elastase-induced emphysema in rabbits and hamsters. 363 28

Experiments were carried out on anesthetized rats which had to aspirate actively watery fluids of different osmolarities (range: freshwater--2.9% NaCl solution) by a tracheotomy tube. The cytologic and histological alterations which are to be found are mainly of osmotic origin. In aspiration of hypotonic solutions macroscopy shows the well-known emphysema aquosum. Corresponding to the structure of the respiratory system, the histological alterations show areolar limitations. The influx of fluids causes a wide range of reactions from the development of an alveolar-interstitial edema in combination with intracellular and intercellular vesiculation, karyolysis with swollen homogenized nuclei of the subendothelial, septal, and epithelial cells to a necrosis of all the cellular elements. A pronounced microangiopathy with edema of the vascular walls, a hydrops of the myocytes containing large vacuoles and perivascular edema with dilated lymphatic channels are likewise to be found. The alveolar macrophages are considerably increased. Sporadic ruptures of the alveolar walls and microhemorrhages occur. In salt water drowning alterations of the shape of both the erythrocytes (thorn-apple form) and the alveolar epithelium in combination with a striking of the pneumocytes and villous transformation prevail. Besides, these are capillary hyperemia and sludge. In a careful specimen analysis a differentiation of the findings between vital reactions and postmortem fluid impact is possible.
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PMID:[Lung histology in experimental drowning]. 683 69

We measured the mean capillary tuft area by a custom-built semi-automatic technique in postmortem sections from the kidneys of 16 patients with "blue and bloated" chronic bronchitis and emphysema and in seven patients of similar age who were free of respiratory and renal disease at death. Nine bronchitic patients had received domiciliary oxygen treatment while seven had not. The mean glomerular tuft area in these treated bronchitic patients (14 200 microns2) was not significantly different from that of the untreated patients (16 900 microns2) but the tuft area in the bronchitic subjects was significantly larger than that of the non-bronchitic controls (12 100 microns2, p less than 0 . 02). There was no reduction in glomerular cellularity to suggest passive venous distension, and glomerular size was not correlated with clinical or pathological indices of cor pulmonale (including red cell mass). The arterial oxygen tension (Po2), however, was correlated with glomerular size (r = 0 . 68, p less than 0 . 01) if allowance was made for the higher Po2 of the patients receiving oxygen. The percentage of glomeruli with an identifiable juxtaglomerular apparatus also increased with increasing glomerular size. These structural changes in the kidneys of patients with severe chronic bronchitis and emphysema may reflect changes in renal salt and water handling that are potentially reversible by oxygen treatment.
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PMID:The renal glomerulus in hypoxic cor pulmonale. 717 90


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