mTOR pathway activation drives lung cell senescence and emphysema

Houssaïni, Amal; Bréau, Marielle; Kebe, Kanny; Abid, Shariq; Marcos, Élisabeth; Lipskaia, Larissa; Rideau, Dominique; Parpaleix, Aurélien; Huang, Jin; Amsellem, Valérie; Vienney, Nora; Validire, Pierre; Maître, Bernard; Attwe, Aya; Lukas, Christina; Vindrieux, David; Boczkowski, Jorge; Dérumeaux, Geneviève; Pende, Mario; Bernard, David; Meiners, Silke; Adnot, Serge

doi:10.1172/jci.insight.93203

Cited by 149 publications

(120 citation statements)

References 57 publications

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“…mTOR activation by PI3K has many effects, including inhibition of FOXO transcription factors, which regulate antioxidants and longevity. mTORC1 is activated in COPD peripheral lung and peripheral blood mononuclear cells (PBMC), demonstrated by increased phosphorylated S6 kinase, and is effectively inhibited by rapamycin (44,45). Gene expression profiling also reveals increased mTOR pathway activation in aged COPD lungs compared to age-matched controls (46).…”

Section: Pi3k-mtor Signalingmentioning

confidence: 99%

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Barnes

Baker

Donnelly

2019

Am J Respir Crit Care Med

297

199

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Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16 INK4a respectively, leading to activation of p21 CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence. Loss of key anti-aging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN, thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a, which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6 and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing SASP and reversing cell cycle arrest in epithelial cells from peripheral airways of COPD patients. MiR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 MAP kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis.

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Section: Pi3k-mtor Signalingmentioning

confidence: 99%

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Barnes

Baker

Donnelly

2019

Am J Respir Crit Care Med

297

199

View full text Add to dashboard Cite

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“…Upregulated pathways in Sin3a-LOF AT2 cells included oxidative phosphorylation, mitochondrial dysfunction, sirtuin signaling, EIF2 signaling, and mTOR signaling. Interestingly, these pathways are all linked to cellular senescence (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53).…”

Section: A Novel Mouse Model Of Conditional At2 Stem Cell Senescencementioning

confidence: 99%

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Yao

Guan

Carraro

et al. 2019

Preprint

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Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfb activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfb activation, block fibrogenesis.

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“…In fact, data on transgenic mice with mTOR over-activity in lung vascular cells show rapid cell senescence with development of emphysema, pulmonary hypertension and inflammation. These results suggest that mTOR inhibition could be a potential therapeutic approach in COPD (23). Moreover, a study in humans shows that rapamycin restores corticosteroid sensitivity on isolated mononuclear cells from COPD patients suggesting its possible use in this disease (24).…”

Section: Mtor Targeting In Lung Diseasesmentioning

confidence: 85%

“…Malouf et al (21) 2011 Clinical Association of everolimus with faster 3-year disease progression in surgically confirmed IPF. Houssaini et al (23) 2018 Experimental Causal relationship between mTOR activation, lung cell senescence and lung alterations in COPD. Mitani et al (24) 2016 Experimental Restored corticosteroid sensitivity by rapamycin.…”

Section: Resultsmentioning

confidence: 99%

Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?

Pasini

Flati

Comini

et al. 2019

COPD: Journal of Chronic Obstructive Pulmonary Disease

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The mammalian target of rapamycin (mTOR) signalling pathway regulates fundamental metabolic processes such as inflammation, autophagy and apoptosis, all of which influence cell fate. Recent experimental data suggest that mTOR signalling is involved in many diseases, including lung diseases, but with contrasting data. Overexpression of mTOR and its signalling proteins have been linked to lung cell senescence and development of emphysema, pulmonary hypertension and inflammation. On the other hand, mTOR inhibitors, as rapamycin and/or its derivatives, restore corticosteroid sensitivity in peripheral blood mononuclear cells from chronic obstructive pulmonary disease (COPD) patients, and overexpression of mTOR suppresses cigarette smoke-induced inflammation and emphysema, suggesting that induction of mTOR expression/activity might be useful to treat COPD. This apparent discrepancy is due to complex and heterogenic enzymatic pathway of mTOR. Translation of pre-clinical positive data on the use of mTOR inhibitors to COPD therapy needs a more in-depth knowledge of mTOR signalling. ARTICLE HISTORY

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mTOR pathway activation drives lung cell senescence and emphysema

Cited by 149 publications

References 57 publications

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?

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