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Published ahead of print on August 3, 2006, doi:10.1164/rccm.200509-1374OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 8, October 2006, 886-893

A more recent version of this article appeared on October 15, 2006
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Submitted on September 4, 2005
Accepted on August 3, 2006

Alveolar Cell Senescence in Pulmonary Emphysema Patients

Takao Tsuji1, Kazutetsu Aoshiba1*, and Atsushi Nagai1

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

* To whom correspondence should be addressed. E-mail: kaoshiba{at}chi.twmu.ac.jp.

Rationale and Objectives: The prevalence of 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 emphysema patients, 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 emphysema patients 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 emphysema patients 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 emphysema patients. Cellular senescence may explain the abnormal cell turnover that promotes the loss of alveolar cells in emphysematous lungs.
Key words: senescence, cyclin-dependent kinase inhibitors, telomere




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