MTOR Suppresses Cigarette Smoke–Induced Epithelial Cell Death and Airway Inflammation in Chronic Obstructive Pulmonary Disease

Wang, Yong; Liu, Juan; Zhou, Jia; Huang, Huaqiong; Li, Zhou-Yang; Xu, Xu-Chen; Lai, Tianwen; Hu, Yue; Zhou, Hongbin; Chen, Hai-Pin; Ying, Songmin; Li, Wen; Shen, Huahao; Chen, Zhihua

doi:10.4049/jimmunol.1701681

Cited by 83 publications

(70 citation statements)

References 45 publications

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“…Mitani et al (24) 2016 Experimental Restored corticosteroid sensitivity by rapamycin. Wang et al (25) 2018 Experimental Suppression of cigarette smoke-induced cell death, airway inflammation and emphysema by mTOR, likely through modulation of autophagy, apoptosis and necroptosis. Duran et al (26) 2014 Clinical Current knowledge of drug-induced pneumonitis (mechanism, clinical impact and management) in cancer patients treated with mTOR inhibitors.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…Furthermore, a very elegant and recent study on isolated airway epithelium of human COPD and in mouse lung chronically exposed to cigarette smoke shows that activation of mTOR and/or inhibition of autophagy may be a new mechanism of cigarette smoke-induced COPD (25).…”

Section: Mtor Targeting In Lung Diseasesmentioning

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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“…By examining the process of apoptosis and trans-differentiation, we provide insights into the molecular basis of tissue remodeling in chronic lung disease. Importantly, the roles of autophagy and the use of Rapamycin have been considered in the context of COPD and Asthma, were tested in various models, but with variable effects (Kennedy and Pennypacker, 2016;Lam et al, 2013;Mitani et al, 2016;Mushaben et al, 2011;Wang et al, 2018). Cell type-specific effects of Rapamycin in the airways were discussed, but without reaching a consensus.…”

Section: Discussionmentioning

confidence: 99%

A changing signaling environment induces multiciliated cell trans-differentiation during developmental remodeling

Tasca

Helmstädter

Brislinger

et al. 2020

Preprint

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Multiciliated cells (MCCs) are extremely highly-differentiated, presenting >100 cilia and basal bodies. We analyzed how MCCs are lost from the airway-like Xenopus embryonic epidermis during developmental tissue remodeling. We found that some MCCs undergo apoptosis, but that the majority trans-differentiate into secretory cells. Trans-differentiation involves loss of ciliary gene expression, cilia retraction and lysosomal degradation. Apoptosis and trans-differentiation are both induced by a changing signaling environment through Notch, Jak/STAT, Thyroid hormone and mTOR signaling, and trans-differentiation can be inhibited by Rapamycin. This demonstrates that even cells with extreme differentiation features can undergo direct fate conversion. Our data further suggest that the reactivation of this developmental mechanism in adults can drive tissue remodeling in human chronic airway disease, a paradigm resembling cancer formation and progression.

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“…Exposure to cigarette smoke has been shown to increase AMPK activation in the lungs in a CSC concentration-dependent and timedependent manner [54]. A recent study also showed that the activation of mTOR suppressed airway inflammation and emphysema induced by cigarette smoke via the inhibition of autophagy and cell death [55]. Furlong et al showed that in the mouse ovary, cigarette smoke exposure activated autophagy by upregulating the AMPK/mTOR pathway [42].…”

Section: Discussionmentioning

confidence: 99%

β-Arrestin2 Inhibits Expression of Inflammatory Cytokines in BEAS-2B Lung Epithelial Cells Treated with Cigarette Smoke Condensate via Inhibition of Autophagy

et al. 2018

Cell Physiol Biochem

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Background/Aims: β-arrestin2 has been shown to have a role in human inflammatory disease. However, the role of β-arrestin2 in cigarette smoke-induced inflammation in the lung remains unknown. The aims of this study were to investigate the effects of β-arrestin2 on cigarette smoke condensate (CSC)-induced expression of inflammatory cytokines in the BEAS-2B human bronchial epithelial cell line in vitro, and the mechanisms involved. Methods: The MTT assay determined cell viability of cultured BEAS-2B cells. Autophagy was assessed by western blot, adenoviral mRFP-GFP-LC3 transfection, and immunofluorescence. The effects of β-arrestin2 shRNA knockdown were studied by western blot and real-time reverse transcription-polymerase chain reaction (RT-PCR). Western blot evaluated the AMPK/mTOR signaling pathway. Levels of inflammatory cytokines, interleukin (IL)-6, IL-8, and MCP-1 were measured in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). Results: CSC suppressed expression of β-arrestin2 in BEAS-2B cells, activated the AMPK/mTOR signaling pathway, increased cell autophagy and the expression of IL-6, IL-8, and MCP-1,pretreatment with the β-arrestin2 biased ligands, propranolol, and ICI118551 reversed these changes. Inhibition of autophagy reduced the expression of inflammatory cytokines following CSC. Conclusion: In the human bronchial epithelial cell line, BEAS-2B, β-arrestin2 reduced the expression of CSC-induced inflammatory cytokines by inhibiting autophagy, most likely via the AMPK/mTOR signaling pathway.

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MTOR Suppresses Cigarette Smoke–Induced Epithelial Cell Death and Airway Inflammation in Chronic Obstructive Pulmonary Disease

Cited by 83 publications

References 45 publications

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

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

A changing signaling environment induces multiciliated cell trans-differentiation during developmental remodeling

β-Arrestin2 Inhibits Expression of Inflammatory Cytokines in BEAS-2B Lung Epithelial Cells Treated with Cigarette Smoke Condensate via Inhibition of Autophagy

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