Tsuji Takao, Aoshiba Kazutetsu, Nagai Atsushi
First Department of Medicine, Tokyo Women's Medical University 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
Am J Respir Crit Care Med. 2006 Oct 15;174(8):886-93. doi: 10.1164/rccm.200509-1374OC. Epub 2006 Aug 3.
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.
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.
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.
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.
慢性阻塞性肺疾病（COPD）的患病率与年龄相关，提示COPD发病机制与衰老之间存在密切关系。在本研究中，我们调查了肺气肿肺组织中肺泡上皮细胞和内皮细胞的衰老是否加速。
从肺气肿患者、无症状吸烟者和无症状非吸烟者获取肺组织样本。通过定量荧光原位杂交评估端粒缩短来评估细胞衰老，并通过免疫组织化学评估衰老相关细胞周期蛋白依赖性激酶抑制剂的表达，对石蜡包埋的肺组织切片进行评估。组织切片还进行增殖细胞核抗原（PCNA）、表面活性蛋白A和CD31的免疫染色。
肺气肿患者中p16INK4a和p21CIP1/WAF1/Sdi1阳性的II型细胞百分比显著高于无症状吸烟者和非吸烟者。他们中p16INK4a阳性的内皮细胞百分比也显著高于无症状吸烟者和非吸烟者，且p21CIP1/WAF1/Sdi1阳性的内皮细胞百分比高于无症状非吸烟者。肺气肿患者的肺泡II型细胞和内皮细胞中的端粒长度显著短于无症状非吸烟者。p16INK4a表达水平与PCNA表达水平呈负相关。肺泡细胞衰老水平与气流受限呈正相关。
这些结果表明，肺气肿患者的肺泡上皮细胞和内皮细胞衰老加速。细胞衰老可能解释了促进肺气肿肺组织中肺泡细胞丢失的异常细胞更新。
