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Published ahead of print on August 3, 2006, doi:10.1164/rccm.200509-1374OC
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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 886-893, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200509-1374OC

Original Article

Alveolar Cell Senescence in Patients with Pulmonary Emphysema

Takao Tsuji, Kazutetsu Aoshiba and Atsushi Nagai

First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Atsushi Nagai, M.D., First Department of Medicine, Tokyo Women's Medical University 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: anagai{at}chi.twmu.ac.jp

Rationale and Objectives: The prevalence of chronic obstructive pulmonary disease (COPD) is age-dependent, suggesting an intimate relationship between the pathogenesis of COPD and aging. In this study we investigated whether the senescence of alveolar epithelial and endothelial cells is accelerated in emphysematous lungs.

Methods: Samples of lung tissue were obtained from patients with emphysema, asymptomatic smokers, and asymptomatic nonsmokers. Paraffin-embedded lung tissue sections were evaluated for cellular senescence by quantitative fluorescence in situ hybridization to assess telomere shortening, and by immunohistochemistry to assess the expression of senescence-associated cyclin-dependent kinase inhibitors. Tissue sections were also immunostained for proliferating cell nuclear antigen (PCNA), surfactant protein A, and CD31.

Main Results: The patients with emphysema had significantly higher percentages of type II cells positive for p16INK4a and p21CIP1/WAF1/Sdi1 than the asymptomatic smokers and nonsmokers. They had also significantly higher percentages of endothelial cells positive for p16INK4a than the asymptomatic smokers and nonsmokers, and higher percentages of endothelial cells positive for p21CIP1/WAF1/Sdi1 than the asymptomatic nonsmokers. Telomere length in alveolar type II cells and endothelial cells was significantly shorter in the patients with emphysema than in the asymptomatic nonsmokers. The level of p16INK4a expression was negatively correlated with the level of PCNA expression. The level of alveolar cell senescence was positively correlated with airflow limitation.

Conclusions: These results suggest that the senescence of alveolar epithelial and endothelial cells is accelerated in patients with emphysema. Cellular senescence may explain the abnormal cell turnover that promotes the loss of alveolar cells in emphysematous lungs.

Key Words: cyclin-dependent kinase inhibitors • senescence • telomere




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