Institut National de la Santé et de la Recherche Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.
Am J Respir Crit Care Med. 2011 Dec 15;184(12):1358-66. doi: 10.1164/rccm.201105-0802OC. Epub 2011 Sep 1.
Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of unknown pathogenesis.
To investigate whether telomere dysfunction and senescence of pulmonary vascular endothelial cells (P-ECs) induce inflammation in COPD.
Prospective comparison of patients with COPD and age- and sex-matched control smokers. Investigation of mice null for telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes.
In situ lung specimen studies showed a higher percentage of senescent P-ECs stained for p16 and p21 in patients with COPD than in control subjects. Cultured P-ECs from patients with COPD exhibited early replicative senescence, with decreased cell-population doublings, a higher percentage of β-galactosidase-positive cells, reduced telomerase activity, shorter telomeres, and higher p16 and p21 mRNA levels at an early cell passage compared with control subjects. Senescent P-ECs released cytokines and mediators: the levels of IL-6, IL-8, monocyte chemotactic protein (MCP)-1, Hu-GRO, and soluble intercellular adhesion molecule (sICAM)-1 were elevated in the media of P-ECs from patients compared with control subjects at an early cell passage, in proportion to the senescent P-EC increase and telomere shortening. Up-regulation of MCP-1 and sICAM-1 led to increased monocyte adherence and migration. The elevated MCP-1, IL-8, Hu-GROα, and ICAM-1 levels measured in lungs from patients compared with control subjects correlated with P-EC senescence criteria and telomere length. In Tert(-/-) and/or Terc(-/-) mouse lungs, levels of the corresponding cytokines (MCP-1, IL-8, Hu-GROα, and ICAM-1) were also altered, despite the absence of external stimuli and in proportion to telomere dysfunction.
Telomere dysfunction and premature P-EC senescence are major processes perpetuating lung inflammation in COPD.
慢性阻塞性肺疾病（COPD）与发病机制不明的慢性炎症有关。
研究端粒功能障碍和肺血管内皮细胞（P-EC）衰老是否会引发 COPD 中的炎症。
对 COPD 患者和年龄、性别匹配的对照吸烟者进行前瞻性比较。研究缺乏端粒酶逆转录酶（Tert）或端粒酶 RNA 成分（Terc）基因的小鼠。
原位肺标本研究显示，COPD 患者的衰老 P-EC 中，p16 和 p21 染色的比例高于对照组。与对照组相比，COPD 患者的培养 P-EC 表现出早期复制衰老，细胞倍增减少，β-半乳糖苷酶阳性细胞比例更高，端粒酶活性降低，端粒较短，早期细胞传代时 p16 和 p21 mRNA 水平更高。衰老的 P-EC 释放细胞因子和介质：与对照组相比，早期细胞传代时，P-EC 培养基中白细胞介素 6（IL-6）、白细胞介素 8（IL-8）、单核细胞趋化蛋白 1（MCP-1）、Hu-GRO 和可溶性细胞间黏附分子 1（sICAM-1）的水平升高，与衰老 P-EC 增加和端粒缩短成正比。MCP-1 和 sICAM-1 的上调导致单核细胞黏附和迁移增加。与对照组相比，COPD 患者肺组织中测得的升高的 MCP-1、IL-8、Hu-GROα 和 ICAM-1 水平与 P-EC 衰老标准和端粒长度相关。在 Tert（-/-）和/或 Terc（-/-）小鼠的肺部，尽管没有外部刺激，但相应细胞因子（MCP-1、IL-8、Hu-GROα 和 ICAM-1）的水平也发生了改变，这与端粒功能障碍成比例。
端粒功能障碍和过早的 P-EC 衰老，是 COPD 中肺部炎症持续存在的主要过程。
