Alveolar cell senescence in patients with pulmonary emphysema.
OBJECTIVE
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.


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.
Tsuji
Takao
T
First Department of Medicine, Tokyo Women's Medical University 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Aoshiba
Kazutetsu
K
Nagai
Atsushi
A
D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D004247:DNA / Q000235:genetics; D005260:Female; D015870:Gene Expression; D019942:Genes, p16 / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology*; D011656:Pulmonary Emphysema / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D037662:Pulmonary Surfactant-Associated Protein A / Q000378:metabolism; D016615:Telomere / Q000473:pathology; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D037662:Pulmonary Surfactant-Associated Protein A; D004247:DNA; D020827:rap1 GTP-Binding Proteins