Neutrophil influx into the lungs of beige mice is followed by elastolytic damage and emphysema

The beige mouse is currently used as a model of elastase and cathepsin Cr d eficiency to demonstrate or exclude the role of these proteases in a variet y of pathologic conditions. We recently demonstrated that beige cathepsin G is tightly bound to neutrophil lysosomal membranes but is released in near normal quantities during exocytosis. Also, beige neutrophils contain a lat ent form of elastase that undergoes spontaneous activation when released un der in vitro or in vivo conditions. However, the pathogenic potential of th is enzyme in matrix degradation has not been ascertained previously. The po ssibility that in beige mice elastolytic proteases from neutrophils recruit ed into the lung have the capability to damage alveolar septa was investiga ted following an intratracheal instillation of N-formyl-L-methionyl-L-leucy l-L-phenylalanine(200 mu g) Neutrophil influx was followed by a decrease in lung elastin content (-18%) and by a significant increase of the mean line ar intercept (+30%) and of morphologic emphysema. The onset of pulmonary le sion was preceded by a marked increase of neutrophil elastase burden on the alveolar interstitium. The appearance of emphysema was prevented by admini stration of the serine protease inhibitor 4-(2-aminoetyl)-benzenesulfonyl f luoride hydrochloride (2.4 mu g/ml saline). These results demonstrate that the lung elastin degradation and emphysema can occur in beige lungs. The fa ct that the beige mouse does develop lung elastolytic changes after neutrop hil recruitment indicates that this mutant cannot be considered a model of neutrophil function deficiency and used as a model of elastase deficiency.