Protective role of p70S6K in intestinal ischemia/reperfusion injury in mice.
Protective role of p70S6K in intestinal ischemia/reperfusion injury in mice.
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DOI：
10.1371/journal.pone.0041584
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kozar RA
中科院分区：
文献类型：
--
作者：
Ban K;Kozar RA
mTOR信号通路在调节细胞生长、增殖、存活和指导免疫应答中起着至关重要的作用。由于肠上皮细胞具有快速的细胞生长和分化，是重要的免疫调节器官，我们推测mTOR可能在肠缺血再灌注（I/R）诱导的损伤保护中发挥重要作用。为了更好地理解mTOR途径被肠I/R改变的分子机制，沿着研究了mTOR途径的主要效应物p70 S6 K以及雷帕霉素（mTOR的特异性抑制剂和临床上用于移植患者的免疫抑制剂）的作用。在体外实验中，使用肠上皮细胞系和缺氧/复氧证明，p70 S6 K的过表达促进细胞的生长和迁移，并减少细胞凋亡。通过雷帕霉素抑制p70 S6 K逆转了这些保护作用。在小鼠肠I/R模型中，p70 S6 K活性增加5分钟，并在再灌注6小时后保持升高。通过雷帕霉素抑制p70 S6 K使肠道损伤恶化，促进炎症，并增强肠道通透性。重要的是，雷帕霉素处理的动物具有显著增加的死亡率。这些新的结果证明了p70 S6 K在保护肠道免受I/R损伤中的关键作用，并表明在有肠道灌注不足风险的患者中使用mTOR抑制剂存在潜在危险。
The mTOR signaling pathway plays a crucial role in the regulation of cell growth, proliferation, survival and in directing immune responses. As the intestinal epithelium displays rapid cell growth and differentiation and is an important immune regulatory organ, we hypothesized that mTOR may play an important role in the protection against intestinal ischemia reperfusion (I/R)-induced injury. To better understand the molecular mechanisms by which the mTOR pathway is altered by intestinal I/R, p70S6K, the major effector of the mTOR pathway, was investigated along with the effects of rapamycin, a specific inhibitor of mTOR and an immunosuppressant agent used clinically in transplant patients. In vitro experiments using an intestinal epithelial cell line and hypoxia/reoxygenation demonstrated that overexpression of p70S6K promoted cell growth and migration, and decreased cell apoptosis. Inhibition of p70S6K by rapamycin reversed these protective effects. In a mouse model of gut I/R, an increase of p70S6K activity was found by 5 min and remained elevated after 6 h of reperfusion. Inhibition of p70S6K by rapamycin worsened gut injury, promoted inflammation, and enhanced intestinal permeability. Importantly, rapamycin treated animals had a significantly increased mortality. These novel results demonstrate a key role of p70S6K in protection against I/R injury in the intestine and suggest a potential danger in using mTOR inhibitors in patients at risk for gut hypoperfusion.
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