Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging

Kennedy, Brian K.; Pennypacker, Juniper K.

doi:10.1513/annalsats.201609-680aw

Cited by 17 publications

(16 citation statements)

References 34 publications

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“…Collectively, these data provide new insights into the protective role of MTOR in COPD pathogenesis through the suppression of cell death and inflammation in the lung. Moreover, the current study also provides possible mechanistic explanations for the adverse pulmonary effects of MTOR inhibitors in clinical use (20,21).…”

Section: Discussionmentioning

confidence: 78%

“…Moreover, despite the functions of autophagy in regulation of CS-induced apoptosis, cilia loss, and mucus production, the role and mechanisms of autophagy in CS-induced chronic airway inflammation are not well investigated. Interestingly, patients with breast cancer, renal cell carcinoma or other diseases, treated with MOTR inhibitors tend to develop dyspnea, cough or interstitial lung disease (20,21), but the underlying mechanisms remain unclear.…”

mentioning

confidence: 99%

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

Wang

Liu

Zhou

et al. 2018

The Journal of Immunology

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Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2-MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-κB pathway. Mice with a specific knockdown of in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema-likely through modulation of autophagy, apoptosis, and necroptosis-and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD.

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Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

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

Wang

Liu

Zhou

et al. 2018

The Journal of Immunology

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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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“… 29 As pharmacologic inhibitors of mTOR, such as everolimus and sirolimus, can directly inhibit T-lymphocyte proliferation, there is ample evidence that mTOR inhibitors are effective for the treatment of pulmonary and renal LAM. 30 – 34 Li et al reported that IGFBP2 could bind insulin, IGF1, and IGF2 in the circulation to modulate cell survival, migration, and invasion of neoplasms. Targeting IGFBP2 may serve as a potential therapeutic strategy for women with LAM and other female gender-specific neoplasms.…”

Section: Discussionmentioning

confidence: 99%

Lymphangioleiomyomatosis: a case report and review of diagnosis and treatment

Liu¹,

Guo²,

Zhao³

et al. 2018

OTT

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Lymphangioleiomyomatosis (LAM) is a rare disease that generally affects young women and involves the abnormal proliferation of smooth muscle-like cells (LAM cells) in the lungs (pulmonary LAM) and extrapulmonary sites (extrapulmonary LAM). This disease is rare in males. It is hard to distinguish between lung cancer and pulmonary LAM, especially during early stages. Herein, we present a case of a 66-year-old man with a small nodule in the right upper lobe that was first diagnosed as a lung malignancy using a chest CT scan. After a wedge dissection, a pathologist performed a histologic and immunohistochemical examination, and a diagnosis of pulmonary LAM was made. We further performed a 518-gene panel analysis using next-generation sequencing, and only three genes, BARD1, BLM, and BRCA2, were found to have mutations. We also provide a summary of the diagnosis and treatment of this disease.

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Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging

Abstract: The mammalian target of rapamycin

Cited by 17 publications

References 34 publications

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

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

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

Lymphangioleiomyomatosis: a case report and review of diagnosis and treatment

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