MTOR Pathway Activation Drives Lung-Cell Senescence and Emphysema in Chronic Obstructive Pulmonary Disease

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 contribute substantially to the pathogenesis of COPD. Here, we explored the potential role for the mTOR signaling pathway in cell senescence and lung alterations in COPD, using lung specimens 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 pro-inflammatory senescence-associated secretory phenotype. To assess whether mTOR activation was causal in lung pathology, we generated mice with constitutive or conditional deletion of the tuberous sclerosis complex heterodimer TSC1 (a negative regulator of mTOR complex 1), in smooth muscle cells (SMCs), endothelial cells (ECs), or alveolar epithelial cells (AECs). In this model, mTOR activation was sufficient to induce early-onset replicative cell senescence in cultured pulmonary artery SMCs from mice with TSC1 deletion. Mice with conditional TSC1 deletion in ECs or AECs developed lung emphysema, pulmonary hypertension, and inflammation in the absence of any other stimuli and concomitantly with the accumulation of senescent lung cells. Rapamycin prevented all these effects. These results support causal links between mTOR activation, cell senescence, and lung alterations in COPD, thereby identifying the mTOR pathway as a new therapeutic target for COPD. Keywords: mTOR, senescence, COPD