Targeting the mTOR signaling pathway to inhibit lung cell senescence in COPD

EUROPEAN RESPIRATORY JOURNAL(2016)

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摘要
Cell senescence, defined as a stable cell-cycle arrest combined with stereotyped phenotypic changes, might play a causal role 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. Strong activation of the mTOR-Akt signaling pathway was found in lungs from patients with COPD compared to controls, with a marked PTEN decrease and activation of mTOR complex 1 (mTORC1) substrates, and of mTORC2 substrates, together with an increase in p21 and p16 protein levels. Similar activation of the mTORC1 and mTORC2 substrates 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).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. 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.These results show that the increased propensity of lung cells to senescence in COPD is related to overactivation of the mTOR signaling pathway and can be suppressed by low doses of rapamycin.
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关键词
COPD - mechanism,Proteomics,Cell biology
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