mTOR inhibition promotes pneumonitis through inducing endothelial contraction and hyperpermeability.

Journal:American Journal of Respiratory Cell and Molecular Biology

Place of Publication:USA

Key Words:cell contraction,endothelial permeability,inflammation

Abstract: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.

All the Authors:Chengxiu Hu,Xing Fan,Yiying Wang,Qiannan Li,YouQiang Su,DaiMin Zhang,QianLu Yang,Anthony G. Passerini

First Author:Xiaolin Chen

Indexed by:Research Article

Correspondence Author:ChongXiu Sun

Document Code:10.1165/rcmb.2020-0390OC

Volume:65

Issue:6

Page Number:646-657

ISSN No.:1044-1549

Translation or Not:no

Date of Publication:2021-07-09

Date of Publication:2021-07-09