Science and Research

mTOR pathway activation drives lung cell senescence and emphysema

Chronic obstructive pulmonary disease (COPD) is a highly prevalent and devastating condition for which no curative treatment is available. Exaggerated lung cell senescence may be a major pathogenic factor. Here, we investigated the potential role for mTOR signaling in lung cell senescence and alterations in COPD using lung tissue 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 proinflammatory senescence-associated secretory phenotype. To explore whether mTOR activation was a causal pathogenic factor, we developed transgenic mice exhibiting mTOR overactivity in lung vascular cells or alveolar epithelial cells. In this model, mTOR activation was sufficient to induce lung cell senescence and to mimic COPD lung alterations, with the rapid development of lung emphysema, pulmonary hypertension, and inflammation. These findings support a causal relationship between mTOR activation, lung cell senescence, and lung alterations in COPD, thereby identifying the mTOR pathway as a potentially new therapeutic target in COPD.

  • Houssaini, A.
  • Breau, M.
  • Kebe, K.
  • Abid, S.
  • Marcos, E.
  • Lipskaia, L.
  • Rideau, D.
  • Parpaleix, A.
  • Huang, J.
  • Amsellem, V.
  • Vienney, N.
  • Validire, P.
  • Maitre, B.
  • Attwe, A.
  • Lukas, C.
  • Vindrieux, D.
  • Boczkowski, J.
  • Derumeaux, G.
  • Pende, M.
  • Bernard, D.
  • Meiners, S.
  • Adnot, S.

Keywords

  • Aged
  • Animals
  • Case-Control Studies
  • Cells, Cultured
  • Cellular Senescence/drug effects
  • Female
  • Humans
  • Lung/cytology/drug effects/*pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Primary Cell Culture
  • Pulmonary Disease, Chronic Obstructive/*pathology
  • Pulmonary Emphysema/genetics/*pathology
  • Sirolimus/pharmacology
  • TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
  • Tobacco Smoking/pathology
  • Tuberous Sclerosis Complex 1 Protein/deficiency/genetics
  • *Aging
  • *copd
  • *Cellular senescence
  • *Pulmonology
Publication details
DOI: 10.1172/jci.insight.93203
Journal: JCI Insight
Number: 3
Work Type: Original
Location: CPC-M
Disease Area: COPD
Partner / Member: HMGU, LMU
Access-Number: 29415880
See publication on PubMed

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