title: Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury.
abstract: MTOR (mechanistic target of rapamycin [serine/threonine kinase]) plays a crucial role in many major cellular processes including metabolism, proliferation and macroautophagy/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 lung disorders, however, little is known about the role of MTOR and autophagy in pulmonary epithelium in the context of acute lung injury (ALI). In the present study, we observed that lipopolysaccharide (LPS) stimulation induced MTOR phosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-II, a hallmark of autophagy, in mouse lung epithelium and in human bronchial epithelial (HBE) cells. The activation of MTOR in HBE cells was mediated by TLR4 (toll-like receptor 4) signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, whereas inhibition of autophagy further augmented, LPS-induced expression of IL6 (interleukin 6) and IL8, through NFKB signaling in HBE cells. Mice with specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly attenuated airway inflammation, barrier disruption, and lung edema, and displayed prolonged survival in response to LPS exposure. Taken together, our results demonstrate that activation of MTOR in the epithelium promotes LPS-induced ALI, likely through downregulation of autophagy and the subsequent activation of NFKB. Thus, inhibition of MTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing ALI induced by certain bacteria.
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Hu
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Jian
authors.initials: J
authors.lastname: Lou
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Mao
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Tian-Wen
authors.initials: TW
authors.lastname: Lai
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Li-Yao
authors.initials: LY
authors.lastname: Liu
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Yu-Yan
authors.initials: YY
authors.lastname: Li
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Song-Min
authors.initials: SM
authors.lastname: Ying
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: a Department of Respiratory and Critical Care Medicine , Second Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou , China.|b State Key Lab of Respiratory Diseases , Guangzhou , China.
authors.forename: Hua-Hao
authors.initials: HH
authors.lastname: Shen
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001980:Bronchi / Q000473:pathology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: MTOR; acute lung injury; autophagy; epithelium; inflammation