Augmentation of lung antineutrophil elastase capacity with recombinant human alpha-1-antitrypsin.
To evaluate the potential use of recombinant DNA-produced alpha-1-antitrypsin (alpha-1-AT) to augment the lung antineutrophil elastase defenses in alpha-1-AT deficiency, we compared the kinetics of intravenously administered recombinant produced alpha-1-AT (r alpha-1-AT) and purified normal human plasma alpha-1-AT (p alpha-1-AT) in the blood and lung of rhesus monkeys. The r alpha-1-AT was produced in yeast transformed with an expressing plasmid containing a full-length human alpha-1-AT complementary deoxyribonucleic acid and purified to greater than 99% homogeneity. The r alpha-1-AT has a molecular weight of 45,000, no carbohydrates, and is identical in sequence to normal plasma alpha-1-AT except for an additional N-terminal acetylmethionine. Despite its lack of carbohydrates, the r alpha-1-AT inhibited human neutrophil elastase with an association rate constant similar to that of p alpha-1-AT. Rhesus monkeys were infused intravenously with 120 mg/kg of r alpha-1-AT (n = 13) or p alpha-1-AT (n = 12) and the serum, urine, and lung epithelial lining fluid (ELF) concentrations of these molecules quantified at various intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004848:Epithelium / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008168:Lung / Q000378:metabolism; D008253:Macaca mulatta; D008970:Molecular Weight; D011480:Protease Inhibitors / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000493:pharmacokinetics*
D001798:Blood Proteins; D011480:Protease Inhibitors; D000515:alpha 1-Antitrypsin