mTOR pathway activation drives lung cell senescence and emphysema
| Autor: | Elisabeth Marcos, David Bernard, Larissa Lipskaia, Nora Vienney, Bernard Maitre, David Vindrieux, Shariq Abid, Kanny Kebe, Marielle Breau, Jorge Boczkowski, Valérie Amsellem, Pierre Validire, Amal Houssaini, Jin Huang, Aurélien Parpaleix, Silke Meiners, Mario Pende, Christina Lukas, Dominique Rideau, Geneviève Derumeaux, Aya Attwe, Serge Adnot |
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| Přispěvatelé: | Faculté de Médecine, Université Paris Est, Institut National de la Santé et de la Recherche Biomédicale (INSERM), U955, Equipe 4, Créteil 94000, France |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Senescence Male [SDV]Life Sciences [q-bio] Cell Primary Cell Culture Inflammation Mice Transgenic Aging Copd Cellular Senescence Pulmonology Tuberous Sclerosis Complex 1 Protein Proinflammatory cytokine 03 medical and health sciences Mice Pulmonary Disease Chronic Obstructive 0302 clinical medicine medicine Tobacco Smoking Animals Humans Lung emphysema Lung ComputingMilieux_MISCELLANEOUS PI3K/AKT/mTOR pathway Cells Cultured Aged Sirolimus COPD business.industry TOR Serine-Threonine Kinases General Medicine respiratory system Middle Aged medicine.disease 3. Good health respiratory tract diseases Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Pulmonary Emphysema 030220 oncology & carcinogenesis Case-Control Studies Cancer research Female medicine.symptom business Research Article |
| Zdroj: | JCI Insight JCI Insight, American Society for Clinical Investigation, 2018, 3 (3), ⟨10.1172/jci.insight.93203⟩ JCI insight 3:93203 (2018) |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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