MTOR dependent-induction of lung cell senescence leads to lung fibrosis or emphysema - 20/03/24

Cellular senescence – defined as a stable cell-cycle arrest combined with stereotyped phenotypic changes – plays a causal role in a variety of aged-associated lung diseases. Previous work by our groups and others has shown that cellular senescence contributes to the pathobiology of both lung emphysema and lung fibrosis. However, it remains a conundrum on how these different pathological entities share a common pathogenic mechanism, i.e. lung senescent cell accumulation. The mTOR (mechanistic target of rapamycin) pathway has been validated as o,ne of a cell-senescence inducer. We reasoned here that activation of mTORC1 could either promote lung emphysema or fibrosis depending on the specific lung cell types undergoing senescence.

We generated mice with conditional deletion of the tuberous sclerosis complex heterodimer TSC1 (a negative mTORC1 regulator) in selected lung cells including fibroblast and SMCs (SM22-TSC1–/–mice), endothelial cells (P-ECs; PDGF-TSC1–/–mice), and alveolar epithelial cells (AECs; SPC-TSC1–/–mice) Mice with conditional and cell-specific TSC1 deletion were generated using the cre-lox strategy.

Compared with controls, SM22-TSC1–/–mice developed lung fibrosis as assessed by the Ashcroft score but without lung emphysema as assessed by the absence of changes in the mean linear intercept. In contrast, PDGF-TSC1–/–mice developed lung emphysema with no significant associated lung fibrosis whereas SPC-TSC1–/–mice developed both lung emphysema and lung fibrosis, although to a lower extent than SM22TSC1 mice. This occurred together with an increase of the lung protein levels of the senescence markers p16 and p21as well as of the DNA damage marker gH₂AX in the three mice strains, with p16 being higher in SM22-TSC1–/–mice than in the two other mutant mice. By the phenotypes of the mutant mice, the fibrosis markers Col1A, PAI1, and vimentin Col3, were increased in both SM22 and SPC-TSC1–/–mice whereas Col3 and pSmad3 were increased only in SM22-TSC1–/–mice. As expected TSC1 deletion in targeted cells leads to higher lung levels of p-AktSer-473, p-GSK-3, p-S6K, and p–4E-BP1 after 3 months. To question whether mice with TSC1 deletion in selected cells developed lung alterations due to the induction of cell senescence, we treated the three mutant mouse strains with the senolytic compound ABT263 (50mg/kg/day) 3 times a week during the 3 weeks following tamoxifen treatment. Treatment with ABT263 efficiently reduced the phenotypic alterations in the three mouse strains.

Lung mTOR activation may lead to either lung fibrosis or emphysema via senescence of selected lung cells.