The pallid mouse. A model of genetic alpha 1-antitrypsin deficiency.
BACKGROUND
The current hypothesis of pulmonary emphysema is based on an alteration of the protease-antiprotease balance within the lower respiratory tract. This hypothesis derives largely from studies in emphysema patients with genetic deficiency in serum alpha 1-antitrypsin. In animals, naturally occurring deficiency in serum elastase inhibitory capacity associated with early development of emphysema has been reported in the tight-skin mouse. We describe here a mouse model of genetic deficiency of alpha 1-antitrypsin in which emphysema occurs late in life.


METHODS
A genetic deficiency in serum alpha 1-antitrypsin was investigated in pallid mice, a strain with spontaneous occurring emphysema. Additionally, the possible pathogenetic role of an elastase-anti-elastase imbalance in pallid mice was investigated using molecular biologic, biochemical, histologic, ultrastructural, and immunoelectron microscopic methods.


RESULTS
Pallid mice have markedly low levels of serum alpha 1-antitrypsin associated with a severe deficiency in serum elastase inhibitory capacity. However, they have normal alpha 1-antitrypsin mRNA levels in the liver. At ultrastructural examination, disruption of alveolar septa is first seen at 8 months of age. At histologic examination, some patchy areas of air-space enlargement with destruction of alveolar septa are seen from 12 months of age onward. These histologic changes are paralleled by a decrease in lung elastin content. The development of the pulmonary lesions is preceded by an alveolar elastolytic burden detected by an immunogold technique.


CONCLUSIONS
All these data suggest that the lung changes in pallid mice are the result of an elastolytic process due to a severe inborn deficiency of serum alpha 1-antitrypsin. This animal model reproduces important features of the human condition and may provide new insights into the pathogenesis of emphysema.
Martorana
P A
PA
Cassella AG, Pharmaforschung, Frankfurt/M., Germany.
Brand
T
T
Gardi
C
C
van Even
P
P
de Santi
M M
MM
Calzoni
P
P
Marcolongo
P
P
Lungarella
G
G
D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D004549:Elastin / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000276:immunology; D011650:Pulmonary Alveoli / Q000648:ultrastructure; D011656:Pulmonary Emphysema / Q000209:etiology* / Q000473:pathology; D000515:alpha 1-Antitrypsin / Q000235:genetics; D019896:alpha 1-Antitrypsin Deficiency
D000515:alpha 1-Antitrypsin; D004549:Elastin; D010196:Pancreatic Elastase