Telomere Dysfunction Causes Sustained Inflammation in Chronic Obstructive Pulmonary Disease
Telomere Dysfunction Causes Sustained Inflammation in Chronic Obstructive Pulmonary Disease
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DOI：
10.1164/rccm.201105-0802oc
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发表时间：
2011-12-15
影响因子：
24.7
通讯作者：
Adnot, Serge
中科院分区：
文献类型：
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作者：
Amsellem, Valerie;Gary-Bobo, Guillaume;Adnot, Serge
基本原理：慢性阻塞性肺疾病（COPD）与慢性炎症的发病机制不明。目的：探讨是否端粒功能障碍和衰老的肺血管内皮细胞（P-ECs）诱导炎症在COPD。方法：前瞻性比较COPD患者和年龄和性别匹配的对照吸烟者。调查小鼠空端粒酶逆转录酶（Tert）或端粒酶RNA组分（Terc）genes. Measures和主要结果：原位肺标本研究显示，COPD患者p16和p21染色的衰老P-EC的百分比高于对照组。与对照组相比，COPD患者培养的P-EC表现出早期复制性衰老，细胞群体倍增减少，β-半乳糖苷酶阳性细胞百分比较高，端粒酶活性降低，端粒较短，早期细胞传代时p16和p21 mRNA水平较高。衰老的P-EC释放细胞因子和介质：IL-6，IL-8，单核细胞趋化蛋白（MCP）-1，Hu-GRO和可溶性细胞间粘附分子（sICAM）-1的水平升高，与对照组相比，在早期细胞传代中，P-EC的培养基中，与衰老的P-EC增加和端粒缩短成比例。MCP-1和sICAM-1的上调导致单核细胞粘附和迁移增加。与对照受试者相比，在患者肺中测量的MCP-1、IL-8、Hu-GRO α和ICAM-1水平升高与P-EC衰老标准和端粒长度相关。在Tert（-/-）和/或Terc（-/-）小鼠肺中，相应的细胞因子（MCP-1、IL-8、Hu-GRO α和ICAM-1）的水平也发生了改变，尽管没有外部刺激并且与端粒功能障碍成比例。
Rationale: Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation of unknown pathogenesis.Objectives: To investigate whether telomere dysfunction and senescence of pulmonary vascular endothelial cells (P-ECs) induce inflammation in COPD.Methods: 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.Measurements and Main Results: 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 beta-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-GRO alpha, 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-GRO alpha, and ICAM-1) were also altered, despite the absence of external stimuli and in proportion to telomere dysfunction.Conclusions: Telomere dysfunction and premature P-EC senescence are major processes perpetuating lung inflammation in COPD.