The beige mouse: role of neutrophil elastase in the development of pulmonary emphysema

Mutant beige mice and normal C57 black mice were given endotoxin intratracheally (IT) once a week for 10 weeks. The objective was to establish whether repeated recruitment of neutrophils to the lung, at levels that induced lung injury to normal mice, would be ineffective in producing lung lesions in neutrophil elastase-deficient beige mice. Endotoxin (25 mg) given IT causes a rapid influx of neutrophils into the lungs of both the C57 black and beige mice, reaching a maximum after 18 h and remaining elevated for at least another 30 h. After 10 weeks of endotoxin instillation the normal C57 black mouse lungs showed evidence of lung injury. There were histological signs of alveolar wall damage, and the mean linear intercepts (Lm) were increased 30% in the endotoxin-treated group. The specific compliance of the lungs from the endotoxin-treated mice was slightly increased. Beige mice, on the other hand, showed no histological or morphological evidence that the neutrophil influx produced lung injury. There was, however, a notable difference in the histological appearance of the control beige lungs compared to control C57 blacks. Beige lungs appeared normal at birth but apparently do not undergo normal alveolarization during neonatal development. Adult lungs have fewer alveoli with smooth terminal air ducts lacking the normal complement of alveolar struts. There was not indication of copper deficiency or problems in elastin synthesis or structure in the beige mice. The results of these studies support a preeminent role for elastase in neutrophil-induced lung lesions.