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JCI Insight. 2018 Feb 8;3(3). pii: 93203. doi: 10.1172/jci.insight.93203. eCollection 2018 Feb 8.

mTOR pathway activation drives lung cell senescence and emphysema.

Author information

1
INSERM U955, Département de Physiologie-Explorations Fonctionnelles, and DHU A-TVB Hôpital Henri Mondor, AP-HP, Créteil, France.
2
Comprehensive Pneumology Center (CPC), University Hospital, Ludwig-Maximilians University, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
3
Institut Mutualiste Montsouris, Département anatomopathologie, Paris, France.
4
Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052/CNRS 5286, Université de Lyon, Centre Léon Bérard, Lyon, France.
5
INSERM U845, Université Paris Descartes, 75015, Paris, France.

Abstract

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.

KEYWORDS:

Aging; COPD; Cellular senescence; Pulmonology

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