Disruption of the klotho gene causes pulmonary emphysema in mice - Defect in maintenance of pulmonary integrity during postnatal life

Homozygous mutant klotho (KL-/-) mice exhibit multiple phenotypes resemblin g human aging, In the present study, we focused on examining the pathology of the lungs of klotho mice and found that it closely resembled pulmonary e mphysema in humans both histologically and functionally. Histology of the l ung of KL-/- mice was indistinguishable from those of wild-type littermates up to 2 wk of age. The first histologic changes appeared at 4 wk of age, s howing enlargement of the air spaces accompanied by destruction of the alve olar walls, and progressed gradually with age. In addition to these changes , we observed calcium deposits in type I collagen fibers in alveolar septa and degeneration of type II pneumocytes in 8- to 10-wk-old KL-/- mice. Pulm onary function tests revealed prolonged expiration time in KL-/- mice, whic h is comparable with the pathophysiology of pulmonary emphysema. The expres sion level of messenger RNA for type IV collagen, surfactant protein-A and mitochondrial ger RNA for type IV collagen, surfactant protein-A and mitoch ondrial beta-adenosine triphosphatase was significantly increased in KL-/- mice, which may represent a compensatory response to alveolar destruction. Additionally, the heterozygous mutant klotho mice also developed pulmonary emphysema late in life, around 120 wk of age. These findings indicate that klotho gene expression is essential to maintaining pulmonary integrity duri ng postnatal life. The klotho mutant mouse is a useful laboratory animal mo del for examining the relationship between aging and pulmonary emphysema.