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发表刊物：
American Journal of Respiratory Cell and Molecular Biology
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刊物所在地：
USA
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关键字：
cell contraction,endothelial permeability,inflammation
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摘要：
Compromised endothelial-cell (EC) barrier function is a hallmark of inflammatory diseases. mTOR inhibitors, widely applied as clinical therapies, cause pneumonitis through mechanisms that are not yet fully understood. This study aimed to elucidate the EC mechanisms underlying the pathogenesis of pneumonitis caused by mTOR inhibition (mTORi). Mice with EC-specific deletion of mTOR complex components (Mtor, Rptor or Rictor) were administered LPS to induce pulmonary injury. Cultured ECs were treated with pharmacologic inhibitors, siRNA, or overexpression plasmids. EC barrier function was evaluated in vivo with Evans blue assay and in vitro by measurement of transendothelial electrical resistance and albumin flux. mTORi increased basal and TNFα-induced EC permeability, which was caused by myosin light chain (MLC) phosphorylation-dependent cell contraction. Inactivation of mTOR kinase activity by mTORi triggered PKCδ/p38/NF-κB signaling that significantly upregulated TNFα-induced MLCK (MLC kinase) expression, whereas Raptor promoted the phosphorylation of PKCα/MYPT1 independently of its interaction with mTOR, leading to suppression of MLCP (MLC phosphatase) activity. EC-specific deficiency in mTOR, Raptor or Rictor aggravated lung inflammation in LPS-treated mice. These findings reveal that mTORi induces PKC-dependent endothelial MLC phosphorylation, contraction, and hyperpermeability that promote pneumonitis.
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第一作者：
Xiaolin Chen
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通讯作者：
ChongXiu Sun
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全部作者：
Anthony G. Passerini,QianLu Yang,DaiMin Zhang,YouQiang Su,Qiannan Li,Yiying Wang,Xing Fan,Chengxiu Hu
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论文类型：
Research Article
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论文编号：
10.1165/rcmb.2020-0390OC
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卷号：
65
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期号：
6
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页面范围：
646-657
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ISSN号：
1044-1549
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是否译文：
否
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发表时间：
2021-07
