The pallid mouse. A model of genetic alpha 1-antitrypsin deficiency.

Abstract

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.

EXPERIMENTAL DESIGN:

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.

• Authors: P A Martorana, T Brand, C Gardi, P van Even, M M de Santi, P Calzoni, P Marcolongo, G Lungarella
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 68 Issue 2 Pg. 233-41 (Feb 1993) ISSN: 0023-6837 [Print] United States
• PMID: 8441253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• alpha 1-Antitrypsin
• Elastin
• Pancreatic Elastase

Topics

• Animals
• Base Sequence
• Disease Models, Animal
• Elastin (analysis)
• Lung (chemistry, pathology, ultrastructure)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Microscopy, Electron
• Microscopy, Immunoelectron
• Molecular Sequence Data
• Pancreatic Elastase (analysis, antagonists & inhibitors, immunology)
• Pulmonary Alveoli (ultrastructure)
• Pulmonary Emphysema (etiology, pathology)
• alpha 1-Antitrypsin (genetics)
• alpha 1-Antitrypsin Deficiency