Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
Chin Med J (Engl). 2011 Oct;124(19):3112-7.
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.
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.
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.
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.
哺乳动物雷帕霉素靶蛋白（mTOR）通路是一种与多种细胞功能相关的关键细胞信号通路，在炎症过程中具有不同的作用。在本研究中，使用 mTOR 抑制剂雷帕霉素（Rapa）来测试抑制 mTOR 激活是否能减轻脂多糖（LPS）诱导的小鼠急性肺损伤（ALI）模型中的肺损伤。
用 Rapa 或载体预处理的小鼠经气管内给予 LPS。评估支气管肺泡灌洗液（BAL）中的局部细胞数量和炎症细胞因子、湿重/干重比、肺组织病理学和存活率。
LPS 刺激后肺组织中 mTOR 的主要下游靶标 S6 的磷酸化增加了 3 倍，但被 Rapa 阻断。Rapa 降低了 BAL 液中 TNF-α（LPS 与 LPS+Rapa，分别为（1672.74±193.73）和（539.17±140.48）pg/ml；P<0.01）和 IL-6（LPS 与 LPS+Rapa：分别为（7790.88±1170.54）和（1968.57±474.62）pg/ml；P<0.01）的水平。然而，Rapa 对肺的湿重/干重比、BAL 液中的中性粒细胞数量和组织病理学变化等 ALI 的总体严重程度的影响有限。此外，Rapa 未能降低 LPS 诱导的 ALI 模型中的死亡率。
我们证实 mTOR 在 LPS 诱导的 ALI 中被激活，并被 Rapa 强烈抑制。尽管 Rapa 降低了炎症介质的水平，但 ALI 小鼠模型的总体严重程度和存活率没有改变。
