title: Inactivation of mammalian target of rapamycin (mTOR) by rapamycin in a murine model of lipopolysaccharide-induced acute lung injury.
abstract: BACKGROUND
  The mammalian target of rapamycin (mTOR) pathway, a key cellular signaling pathway associated with various cellular functions, has distinct roles in the inflammatory process. In this study, the mTOR inhibitor rapamycin (Rapa) was used to test whether inhibition of mTOR activation attenuates lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a murine model.
  
  
  METHODS
  Mice pretreated with Rapa or vehicle were given LPS intratracheally. Local cell numbers and inflammatory cytokines present in the bronchoalveolar lavage fluid (BAL), wet-to-dry weight ratio, histopathology of the lungs, and survival were evaluated.
  
  
  RESULTS
  The phosphorylation of S6, a major downstream target of mTOR, had a 3-fold increase in lung tissue after LPS stimulation, but the increase was blocked by Rapa. Rapa reduced the levels of TNF-α (LPS vs. LPS + Rapa, (1672.74 ± 193.73) vs. (539.17 ± 140.48) pg/ml, respectively; P < 0.01) and IL-6 (LPS vs. LPS + Rapa: (7790.88 ± 1170.54) vs. (1968.57 ± 474.62) pg/ml, respectively; P < 0.01) in the BAL fluid. However, Rapa had limited effects on the overall severity of ALI, as determined by the wet-to-dry weight ratio of the lungs, number of neutrophils in the BAL fluid, and changes in histopathology. In addition, Rapa failed to reduce mortality in the LPS-induced ALI model.
  
  
  CONCLUSIONS
  We confirmed that mTOR was activated during LPS-induced ALI and strongly inhibited by Rapa. Although Rapa reduced the levels of the mediators of inflammation, the overall severity and survival of the ALI murine model were unchanged.
authors: Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
authors: Lan
authors: L
authors: Wang
authors: Yao-Song
authors: YS
authors: Gui
authors: Xin-Lun
authors: XL
authors: Tian
authors: Bai-Qiang
authors: BQ
authors: Cai
authors: De-Tian
authors: DT
authors: Wang
authors: Dong
authors: D
authors: Zhang
authors: He
authors: H
authors: Zhao
authors: Kai-Feng
authors: KF
authors: Xu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy*; D000818:Animals; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects*
chemical_list: D008070:Lipopolysaccharides; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus