A genetically engineered mutant of alpha 1-antitrypsin protects connective tissue from neutrophil damage and may be useful in lung disease.
The effectiveness of a genetically engineered mutant of human alpha 1-antitrypsin (358 Met----Val) as an inhibitor of connective tissue breakdown was tested in a model of inflammation. The degradation of basement membrane collagen by stimulated neutrophils was efficiently inhibited by a tenfold lower concentration (0.2 mg/ml) of the mutant inhibitor than of the normal alpha 1-antitrypsin (2.4 mg/ml). Effective inhibition by normal alpha 1-antitrypsin occurred at much lower concentrations when azide or catalase was added, or when normal neutrophils were replaced by those from a donor with chronic granulomatous disease. These results confirm that neutrophils augment tissue proteolysis by the oxidative inactivation of the methionine at the reactive centre of alpha 1-antitrypsin. The replacement of this methionine by valine gives an effective inhibitor that is not inactivated by neutrophil oxidants. The availability of this genetically engineered mutant suggests the possibility of prophylaxis of lung dysplasias, notably emphysema, and of the shock syndromes associated with massive neutrophil activation.
D001485:Basement Membrane / Q000502:physiology*; D003238:Connective Tissue / Q000201:enzymology / Q000503:physiopathology*; D005818:Genetic Engineering; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000166:cytology; D008171:Lung Diseases / Q000503:physiopathology; D009154:Mutation; D009504:Neutrophils / Q000502:physiology*; D010196:Pancreatic Elastase / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000494:pharmacology*
D000515:alpha 1-Antitrypsin; D010196:Pancreatic Elastase; D006909:Hydroxyproline