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Dysregulation of mTOR and Autophagy in Pulmonary Epithelium Participates in LPS-Induced Acute Lung Injury
Critical Care SESSION TITLE: Mechanisms of Lung Injury SESSION TYPE: Original Investigation Slide PRESENTED ON: Saturday, April 16, 2016 at 04:00 PM - 05:00 PM
Dysregulation of mTOR and Autophagy in Pulmonary Epithelium Participates in LPS-Induced Acute Lung Injury 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; and Huahao Shen PhD* Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 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-kB (NF-kB)-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-kB-mediated inflammatory cytokines. CLINICAL IMPLICATIONS: Thus, inhibiting mTOR in pulmonary epithelial cells represents a novel therapeutic strategy for preventing LPS-induced ALI.
CRITICAL CARE
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 No Product/Research Disclosure Information DOI:
http://dx.doi.org/10.1016/j.chest.2016.02.190
Copyright ª 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
184A
[
149#4S CHEST APRIL 2016
]
Dysregulation of mTOR and Autophagy in Pulmonary Epithelium Participates in LPS-Induced Acute Lung Injury 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; and Huahao Shen PhD* Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China 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-kB (NF-kB)-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-kB-mediated inflammatory cytokines. CLINICAL IMPLICATIONS: Thus, inhibiting mTOR in pulmonary epithelial cells represents a novel therapeutic strategy for preventing LPS-induced ALI.
CRITICAL CARE
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 No Product/Research Disclosure Information DOI:
http://dx.doi.org/10.1016/j.chest.2016.02.190
Copyright ª 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
184A
[
149#4S CHEST APRIL 2016
]