Premium
mTOR inhibition promotes LPS‐induced acute lung injury by inducing endothelial hyperpermeability
Author(s) -
Chen Xiaolin,
Fan Xing,
Sun Chongxiu
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb261
Subject(s) - pi3k/akt/mtor pathway , rho associated protein kinase , endothelial stem cell , phosphorylation , kinase , microbiology and biotechnology , mtorc2 , sirolimus , cancer research , pharmacology , chemistry , medicine , signal transduction , biology , in vitro , mtorc1 , biochemistry
Although mTOR inhibitors are widely used to treat various disorders in clinic, a considerable number of side effects have been described, including pneumonitis. The intrinsic mechanisms are not completely understood. This study aimed to elucidate the role of endothelial barrier dysfunction in the pathogenesis of mTOR inhibition‐induced lung injury. Measurement of TER (transendothelial electrical resistance) and transendothelial BSA flux indicated that inhibition of mTOR either through transfection with siRNA, or treatment with inhibitors rapamycin or torin 1, increased endothelial permeability, accompanied by F‐actin remodeling as visualized by immunofluorescent. Consistently, mice with specific knockout of Mtor in endothelial cells exhibited significantly aggravated lung injury, neutrophil infiltration and lung edema in response to LPS exposure. Studies with Rho‐associated kinase (ROCK) inhibitor (Y‐27632) and myosin light chain (MLC) kinase inhibitor (ML‐7) indicated that the hyperpermeability response was dependent on MLC phosphorylation, which is regulated by PKC activity. PKC contributed to mTOR inhibition‐induced MLC phosphorylation and endothelial hyperpermeability through P38/NF‐κB pathway to upregulate MLC kinase expression and ROCK/MYPT1 pathway to negatively control MLC phosphatase activity. Taken together, our results demonstrate that inhibition of mTOR promotes LPS‐induced acute lung injury, at least partly through inducing endothelial barrier dysfunction. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .