Am. J. Respir. Cell Mol. Biol., Volume 22, Number 1, January, 2000 26-33

Disruption of the klotho Gene Causes Pulmonary Emphysema in Mice
Defect in Maintenance of Pulmonary Integrity during Postnatal Life

Tatsuo Suga, Masahiko Kurabayashi, Yoshichika Sando, Yoshio Ohyama, Toshitaka Maeno, Yuri Maeno, Hiroki Aizawa, Yutaka Matsumura, Tomoyuki Kuwaki, Makoto Kuro-o, Yo-ichi Nabeshima, and Ryozo Nagai

Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan; Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; Department of Physiology, School of Medicine, Chiba University, Chiba; Institute for Molecular and Cellular Biology, Osaka University, Osaka; and Core Research for Evolutional Science & Technology (CREST), Osaka, Japan

Homozygous mutant klotho (KL^/) mice exhibit multiple phenotypes resembling 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 emphysema in humans both histologically and functionally. Histology of the lung 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, showing enlargement of the air spaces accompanied by destruction of the alveolar 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. Pulmonary function tests revealed prolonged expiration time in KL^/ mice, which is comparable with the pathophysiology of pulmonary emphysema. The expression level of messenger RNA for type IV collagen, surfactant protein-A and mitochondrial -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 during postnatal life. The klotho mutant mouse is a useful laboratory animal model for examining the relationship between aging and pulmonary emphysema.

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