Critical Care: Mechanisms of Lung Injury |

Dysregulation of mTOR and Autophagy in Pulmonary Epithelium Participates in LPS-Induced Acute Lung Injury FREE TO VIEW

Yue Hu, PhD; Yuanyuan Mao, MS; Jian Lou, PhD; Tianwen Lai, PhD; Chen Zhu, PhD; Liyao Liu, MS; Chao Zhang, PhD; Juan Liu, MS; Songmin Ying, PhD; Wen Li, PhD; Zhihua Chen, PhD; Huahao Shen, PhD
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Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

Copyright 2016, American College of Chest Physicians. All Rights Reserved.

Chest. 2016;149(4_S):A184. doi:10.1016/j.chest.2016.02.190
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SESSION TITLE: Mechanisms of Lung Injury

SESSION TYPE: Original Investigation Slide

PRESENTED ON: Saturday, April 16, 2016 at 04:00 PM - 05:00 PM

PURPOSE: Mechanistic target of rapamycin (mTOR) plays a crucial role in many major cellular processes including cellular metabolism, proliferation and autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both mTOR and autophagy have been suggested to be involved in the regulation of acute lung injury (ALI). Epithelium, being a key component of respiratory tract defence, plays a key role in both the pathogenesis and resolution of ALI. However, little is known about the role of mTOR and autophagy in pulmonary epithelium in the context of ALI.

METHODS: To examine the expression of mTOR-autophagy signaling pathways and associated inflammatory cytokines, pulmonary epithelial cells (HBE) were exposed to lipopolysaccharide (LPS) in vitro. Alveoli and airway epithelium-specific mTOR knockout mice (SP-C-rtTA/(tetO)7-Cre/mTORflox/flox and CC10-rtTA/(tetO)7-Cre/mTORflox/flox) were given LPS intratracheally, and 24h later the mice were sacrificed to analyzing lung barrier integrity and the extent of inflammation.

RESULTS: We observed that LPS stimulation induced mTOR phosphorylation and pro-inflammatory cytokines in vivo. Using HBE cell lines, we also found up-regulated mTOR phosphorylation, suppressed autophagy, and activated nuclear factor-κB (NF-κB)-mediated inflammatory cytokines following LPS exposure. Mice with impaired mTOR airway or alveolar epithelial cells exhibited markedly attenuated pro-inflammatory cytokines, barrier disruption and lung edema in response to LPS infection.

CONCLUSIONS: Taken together, our results demonstrated that activation of mTOR in the epithelium promotes LPS-induced ALI, likely through autophagy down-regulation and its subsequent induction of NF-κB-mediated inflammatory cytokines.

CLINICAL IMPLICATIONS: Thus, inhibiting mTOR in pulmonary epithelial cells represents a novel therapeutic strategy for preventing LPS-induced ALI.

DISCLOSURE: The following authors have nothing to disclose: Yue Hu, Yuanyuan Mao, Jian Lou, Tianwen Lai, Chen Zhu, Liyao Liu, Chao Zhang, Juan Liu, Songmin Ying, Wen Li, Zhihua Chen, Huahao Shen

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