INSERM U955, Département de Physiologie-Explorations Fonctionnelles, and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France.
Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
JCI Insight. 2018 Feb 8;3(3). doi: 10.1172/jci.insight.93203.
Chronic obstructive pulmonary disease (COPD) is a highly prevalent and devastating condition for which no curative treatment is available. Exaggerated lung cell senescence may be a major pathogenic factor. Here, we investigated the potential role for mTOR signaling in lung cell senescence and alterations in COPD using lung tissue and derived cultured cells from patients with COPD and from age- and sex-matched control smokers. Cell senescence in COPD was linked to mTOR activation, and mTOR inhibition by low-dose rapamycin prevented cell senescence and inhibited the proinflammatory senescence-associated secretory phenotype. To explore whether mTOR activation was a causal pathogenic factor, we developed transgenic mice exhibiting mTOR overactivity in lung vascular cells or alveolar epithelial cells. In this model, mTOR activation was sufficient to induce lung cell senescence and to mimic COPD lung alterations, with the rapid development of lung emphysema, pulmonary hypertension, and inflammation. These findings support a causal relationship between mTOR activation, lung cell senescence, and lung alterations in COPD, thereby identifying the mTOR pathway as a potentially new therapeutic target in COPD.
慢性阻塞性肺疾病（COPD）是一种高发且具有破坏性的疾病，目前尚无治愈方法。过度的肺细胞衰老可能是一个主要的致病因素。在这里，我们使用 COPD 患者和年龄、性别匹配的对照吸烟者的肺组织和衍生培养细胞，研究了 mTOR 信号在肺细胞衰老和 COPD 改变中的潜在作用。COPD 中的细胞衰老与 mTOR 激活有关，低剂量雷帕霉素抑制 mTOR 可防止细胞衰老并抑制促炎衰老相关分泌表型。为了探讨 mTOR 激活是否是一个因果致病因素，我们开发了在肺血管细胞或肺泡上皮细胞中过表达 mTOR 的转基因小鼠。在该模型中，mTOR 激活足以诱导肺细胞衰老，并模拟 COPD 肺改变，导致肺气肿、肺动脉高压和炎症的快速发展。这些发现支持 mTOR 激活、肺细胞衰老和 COPD 肺改变之间的因果关系，从而确定 mTOR 途径是 COPD 中一个潜在的新治疗靶点。
