PuSH - Publikationsserver des Helmholtz Zentrums München

Houssaini, A. ; Kebe, K.* ; Breau, M.* ; Marcos, E.* ; Abid, S.* ; Bizard, E.* ; Huang, J.* ; Attwe, A.* ; Rideau, D.* ; Validire, P.* ; Maitre, B.* ; Amsellem, V.* ; Meiners, S. ; Adnot, S.*

Targeting the mtor signaling pathway to inhibit lung cell senescence in Chronic Obstructive Pulmonary Disease (COPD).

Acta Physiol. 217, 142-143 (2016)
DOI Verlagsversion bestellen
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Rationale: in COPD. We previously reported that senescent cells are increased in lungs from patients with COPD and express a robust senescence-associated secretory phenotype (SASP), which is proinflammatory. Here, we investigated whether lung cell senescence in COPD was related to overactivation of the mTOR (mechanistic target of rapamycin) signaling pathway and whether targeting this pathway inhibited cell senescence and/or suppressed the SASP in COPD. To assess the link between mTOR activation and cellular senescence in lung specimens and derived cultured Objectives: pulmonary-endothelial cells (P-ECs)and pulmonary artery smooth muscle cells (PA-SMCs) from patients with COPD and age- and sex-matched control smokers; to use a new mouse model that allows mTOR activation in targeted cells and determine whether this activation induces cell senescence. Strong activation of the mTOR-Akt signaling pathway was found in lungs from patients with COPD compared to Methods and Results: controls, with a marked PTEN decrease and activation of mTOR complex 1 (mTORC1) substrates S6K and 4EBP, and of mTORC2 substrates P-Akt and GSK3, together with an increase in p21 and p16 protein levels. Similar activation of the mTORC1 and mTORC2 substrates 473 were found in cultured PA-SMCs and P-ECs from patients with COPD compared to controls. Cultured P-ECs or PA-SMCs from patients with COPD exhibited an early onset of cell senescence as assessed by a decrease in the number of population doubling (PDLs) and an increase in beta-gal-positive cells. Treatment of the cells from patients with COPD with rapamycin (10 nM) normalized the number of PDLs to that seen in controls and decreased the number of beta-gal-positive cells. Treatment with rapamycin also increased PDLs in cells from controls but to a lesser extent than in those from patients with COPD. No such effects were seen after cell exposure to a selective S6-kinase inhibitor. Rapamycin reduced IL6 and other cytokine levels released by senescent cells. Cultured PA-SMCs from SM22-TSC1-/- mice, which exhibited strong mTORC1 activation in PA-SMCs, were characterized by an early onset of cell senescence compared to control mice, which was delayed by cell exposure to rapamycin. These results show that the increased propensity of lung cells to senescence in COPD is related to overactivation of the mTOR Conclusion: signaling pathway and can be suppressed by low doses of rapamycin.
Weitere Metriken?
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Meeting abstract
ISSN (print) / ISBN 1748-1708
e-ISSN 1748-1716
Zeitschrift Acta Physiologica
Quellenangaben Band: 217, Heft: , Seiten: 142-143 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Hoboken
Begutachtungsstatus Peer reviewed