Telomere dysfunction and exaggerated lung cell senescence now appear as major pathological processes leading to lung alterations in COPD. Pulmonary vascular endothelial cells (P-ECs) and smooth muscle cells (PA-SMCs) derived from lungs of patients with COPD exhibit increased susceptibility to replicative senescence compared to controls. However, the mechanisms underlying lung cell senescence in COPD remain poorly understood. Recent studies suggest that cell senescence and aging occur in response to overactivation of the mammalian target of rapamycin (mTOR) signaling pathway.
To investigate whether lung cell senescence is related to overactivation of the mTOR signaling pathway in COPD, we studied lung specimens and derived cultured PA-SMCs and P-ECs from patients with COPD and age- and sex-matched control smokers.
Marked 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 S6K and 4EBP and of mTORC2 substrates P-Akt473 and GSK3, together with an increase in p21 protein levels. In-situ analysis of lung specimens revealed prominent P-Akt473, P-S6K, and P-GSK3 staining in PA-SMCs and P-ECs from patients with COPD compared to controls, most notably the cells exhibiting staining for p16 and p21. In cultured PA-SMCs from patients and controls that were subjected to repeated passages, the onset of replicative cell senescence was associated with similar alterations, including decreased PTEN and activation of mTORC1 and mTORC2 substrates. Cell exposure to low-dose rapamycin, which selectively inhibits mTORC1 but not mTORC2, delayed the early onset of senescence, increasing the cell-population doublings and decreasing the percentage of beta-galactosidase-positive cells; and suppressed the senescence-associated secretory phenotype associated with COPD. Cell exposure to sulforaphane, which stimulates nff2, or bortezomib, which inhibits the proteasome, did not alter or potentiated the cell senescence process.
These results show that the increased propensity of lung vascular cells to senescence in COPD is related to overactivation of the mTOR/Akt signaling pathway and can be suppressed by rapamycin treatment.
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Publié par Elsevier Masson SAS.