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mTOR pathway activation drives lung cell senescence and emphysema
Amal Houssaini, … , Silke Meiners, Serge Adnot
Amal Houssaini, … , Silke Meiners, Serge Adnot
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e93203. https://doi.org/10.1172/jci.insight.93203.
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Research Article Aging Pulmonology

mTOR pathway activation drives lung cell senescence and emphysema

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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.

Authors

Amal Houssaini, Marielle Breau, Kanny Kebe, Shariq Abid, Elisabeth Marcos, Larissa Lipskaia, Dominique Rideau, Aurelien Parpaleix, Jin Huang, Valerie Amsellem, Nora Vienney, Pierre Validire, Bernard Maitre, Aya Attwe, Christina Lukas, David Vindrieux, Jorge Boczkowski, Genevieve Derumeaux, Mario Pende, David Bernard, Silke Meiners, Serge Adnot

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Figure 4

Effect of rapamycin treatment on synthesis of pro-inflammatory cytokines.

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Effect of rapamycin treatment on synthesis of pro-inflammatory cytokines...
Effect of rapamycin treatment on the levels of proinflammatory cytokines (IL-6, IL-8, and CCL2) measured in conditioned media of PA-SMCs (A) from 7 patients with COPD and 8 controls, and P-ECs (B) from 8 patients with COPD and 8 controls. Values are mean ± SEM. *P < 0.05, compared with values from controls, #P < 0.05, ##P < 0.01 compared with vehicle-treated cells, by 2-way ANOVA. (C) Levels of cytokines released by PA-SMCs treated with a retroviral vector expressing the NF-κB inhibitor IκΒαM, compared with the levels released by cells treated with the control vector. The graphs show levels of IL-6, IL-8, and CCL2 in PA-SMC–conditioned media, cumulative PDL, and percentage of β-Gal–positive cells. **P < 0.01 compared with values in cells infected with the control vector, by 2-tailed unpaired t test. These measurements were performed in cells deprived of serum for 24 hours (P-ECs) or for 48 hours (PA-SMCs).

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