Activation Of Mammalian Target Of Rapamycin (mTOR) In A Murine Model Of Lipopolysaccharide (LPS)-induced Acute Lung Injury (ALI)

Background:A growing body of evidence indicates that the mammalian target of rapamycin (mTOR) pathway, a key cellular signaling pathway associated with cellular functions, has distinct effects also in the in inflammatory process. However, the role of the mTOR pathway in lippolysaccharide (LPS) induced acute lung injury (ALI) is far of being elucidated. Objective:In this study, selective mTOR inhibitor rapamycin (Rapa) was used to test whether mTOR activation is critical in a murine model of LPS-induced ALI.Methods:To examine the issue, mice were received LPS (20mg/kg) by intratracheal administration. Rapamycin-pretreated (8mg/kg body weight for consecutive five days) mice were compared to mice injected with vehicle alone. Lung tissues and bronchoalveolar lavage (BAL) were obtained 8 hours after LPS instillation. Levels of local inflammatory cytokines, cell numbers in BAL fluid, pulmonary edema, histopathology change, and ALI survival (40mg/kg LPS was used) were evaluated.Results:The phosphorylation of S6, a major downstream target of mTOR, increased significantly in murine lung tissue after LPS stimulation compared to control, which was blocked by rapamycin. Administration of rapamycin diminished the levels of TNF-α(LPS vs LPS+Rapa:1672.74±193.73 vs 539.17±140.47 pg/ml,P<0.01)and IL-6 (LPS vs LPS+Rapa:7790.88±1170.54 vs 1968.57±474.62, pg/ml, P<0.01) in BAL fluid, and abrogated IL-1βup-regulation (LPS vs LPS+Rapa:6394.20±904.59 vs 3196.08±487.46, pg/mg protein, P<0.01) but reinforced MMP-9 up-regulation (LPS vs LPS+Rapa:17.98±3.17 vs 37.86±19,00, pg/mg protein, P<0.05) induced by LPS in lung tissue. However, rapamycin had little effects on the development and severity of lung injury after intratracheal LPS administration, as determined by pulmonary edema, inflammatory cell influx, and histopathology changes of ALI as well as the thickness of alveolar septum. And most important, there was no difference in lethality of LPS-mediated ALI between the rapamycin and vehicle pretreated mice.Conclusion:These results indicate that inhibition of mTOR activation has a limited effect in ALI process. Our data indicated that rapamycin appears not be a candidate drug in treating ALI if it is used alone. Grant support:This work was supported by 973 Program of China (2009CB522106).