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)

Individuals with serum alpha1-antitrypsin levels below 80 mg/dl are clearly at risk for the development of accelerated panacinar emphysema. One possible approach to the therapy of this disorder would be to raise serum levels of this major antiprotease to establish protease-antiprotease homeostasis within the lung parenchyma. Because danazol, an impeded androgen, elevates levels of C1 inhibitor in patients deficient of that serum antiprotease, we hypothesized that this agent might also increase alpha1-antitrypsin levels in patients with alpha1-antitrypsin deficiency. To evaluate this concept, seven patients with severe emphysema associated with alpha1-antitrypsin deficiency (six PiZ and 1 M(Duarte)Z) and one asymptomatic individual (PiSZ) received 600 mg of danazol daily for 30 d. Five of the six PiZ patients responded to danazol therapy with significant increases in serum alpha1-antitrypsin levels (mean increase of 37%; P < 0.03). The two individuals who were heterozygous for the Z protein increased their serum levels by 85% (PiM(Duarte)Z) and 87% (PiSZ), respectively. These increases in serum alpha1-antitrypsin antigen were accompanied by commensurate increases in serum trypsin inhibition. Crossed immunoelectrophoresis showed no alterations of the microheterogeneity of the alpha1-antitrypsin or the presence of protease-antiprotease complexes in serum during danazol therapy. These data demonstrate that serum alpha1-antitrypsin levels can be augmented by danazol therapy in PiZ individuals as well as those heterozygotes with severe deficiency of alpha1-antitrypsin. The clinical relevance of these increases in serum alpha1-antitrypsin remains speculative, but these findings suggest that danazol may provide a means of improving the protease-antiprotease balance in these individuals and thus impede the progression of their lung disease.
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PMID:Danazol-induced augmentation of serum alpha 1-antitrypsin levels in individuals with marked deficiency of this antiprotease. 696 89

Emphysema is often associated with the Z type mutation of alpha 1-antitrypsin, which causes aggregation of the molecule in the liver and consequent plasma deficiency. The aggregation appears to be due to loop-sheet polymerization, although why the mutant protein polymerizes in vivo is unclear. Here we show that, unlike wild type antitrypsin, which folds in minutes, the folding of Z type alpha 1-antitrypsin is extremely slow. Once folded, however, the native Z protein shows substantial stability towards urea and incubation at 37 degrees C. The folding defect in Z antitrypsin leads to accumulation of an intermediate and it is the intermediate rather than the native protein which has a high tendency to aggregate.
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PMID:The Z type variation of human alpha 1-antitrypsin causes a protein folding defect. 766 92

Alpha-1-antitrypsin deficiency is a relatively common but under-recognized genetic disease in which individuals homozygous for the mutant Z disease-associated allele are at risk for the development of liver disease and emphysema. The protein product of the mutant Z gene is synthesized in hepatocytes but accumulates intracellularly rather than being appropriately secreted. The downstream effects of the intracellular accumulation of the mutant Z protein include the formation of unique protein polymers, activation of autophagy, mitochondrial injury, endoplasmic reticulum stress, and caspase activation, which subsequently progress in a cascade, causing chronic hepatocellular injury. The variable clinical presentations among affected individuals suggest an important contribution of genetic and environmental disease modifiers, which are only now being identified. The heterozygous carrier state for the mutant Z gene, found in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modifier gene for other liver diseases.
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PMID:Alpha-1-antitrypsin deficiency: diagnosis, pathophysiology, and management. 1651 30

Alpha (1)-antitrypsin deficiency is a common genetic disease in which individuals homozygous for the mutant Z allele are at risk for the development of liver disease and emphysema. The mutant Z protein product is synthesized in hepatocytes but then accumulates intracellularly rather then being appropriately secreted. The effects of the intracellular accumulation of the mutant Z protein in the liver include the formation of protein polymers, activation of autophagy, mitochondrial injury, and caspase activation, which progress in a cascade causing hepatocellular injury. Liver disease can occur at any age, although the majority of children are free of significant liver dysfunction. The variable clinical presentations suggest an important contribution of genetic and environmental disease modifiers. The heterozygous carrier state for the mutant Z gene, present in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modifier gene for other liver diseases.
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PMID:Alpha1-antitrypsin deficiency in childhood. 1768 74

Alpha-1 antitrypsin Deficiency (AATD) is a common, but under recognized metabolic genetic disease. Although many mutations in the alpha-1 antitrypsin (AAT) gene are described, the Z variant is the allele overwhelmingly associated with liver disease. PI*ZZ homozygotes occur in approximately 1 in 2,000-5,000 births in North American and European populations. The AAT protein is synthesized in large quantities by the liver, and then secreted into serum. Its physiologic function is to inhibit neutrophil proteases in order to protect host tissues from non-specific injury during periods of inflammation. The mutant Z gene of AAT directs the synthesis of a mutant protein which folds abnormally during biogenesis in the endoplasmic reticulum of hepatocytes and is retained intracellularly, rather than efficiently secreted. Intracellular proteolysis pathways, including the proteasome and autophagy, are activated as a response to the intracellular burden of misfolded protein. The lack of circulating anti-protease activity leaves the lung vulnerable to injury and the development of emphysema. The intracellular accumulation of AAT mutant Z protein within hepatocytes can cause liver injury, cirrhosis and hepatocellular carcinoma by triggering a cascade of chronic hepatocellular apoptosis, regeneration, and end organ injury. There is no specific treatment for PI*ZZ associated liver disease, other than standard liver supportive care and liver transplantation. There is a high degree of variability in the clinical manifestations among PI*ZZ homozygous patients, suggesting a strong influence of as yet poorly characterized, genetic and environmental disease modifiers. Studies of the processes of intracellular injury have led to a new era of rational therapeutic development.
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PMID:Liver disease in alpha-1 antitrypsin deficiency: current understanding and future therapy. 2352 37