PI3K-Akt pathway suppresses coagulation and inflammation in endotoxemic mice
PI3K-Akt pathway suppresses coagulation and inflammation in endotoxemic mice
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DOI：
10.1161/01.atv.0000143096.15099.ce
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发表时间：
2004-10-01
影响因子：
8.7
通讯作者：
Mackman, N
中科院分区：
文献类型：
--
作者：
Schabbauer, G;Tencati, M;Mackman, N
目的：内毒素血症中，脂多糖（LPS）可诱导全身炎症反应和血管内凝血.单核细胞通过表达多种促炎细胞因子（如肿瘤坏死因子-α（TNF-α）和促凝血分子组织因子（TF））来协调对LPS的先天性免疫应答。在这项研究中，我们分析了磷酸肌醇3-激酶（PI 3 K）-Akt通路的作用，在凝血激活和先天性免疫反应的小鼠模型内毒素emotion.Methods和结果- Wortmannin和LY 294002被用来抑制PI 3 K-Akt通路。我们发现渥曼青霉素抑制LPS诱导的血细胞Akt磷酸化。PI 3 K-Akt通路的抑制显著增加血细胞中TF mRNA的表达、血浆中TF抗原和凝血酶-抗凝血酶III水平以及内毒素血症小鼠肝脏中的纤维蛋白沉积。PI 3 K-Akt通路的抑制也强烈增强LPS诱导的细胞因子表达和血浆中可溶性E-选择素的水平，表明单核细胞和内皮细胞的活化增强。Wortmannin治疗还增加了内毒素血症小鼠肝脏和肾脏中巨噬细胞的数量。最后，渥曼青霉素和LY 294002显着降低了内毒素血症mice.Conclusions的生存时间-这些数据表明，PI 3 K-Akt通路抑制LPS诱导的炎症和凝血内毒素血症小鼠。
Objective - In endotoxemia, lipopolysaccharide (LPS) induces a systemic inflammatory response and intravascular coagulation. Monocytes orchestrate the innate immune response to LPS by expressing a variety of pro-inflammatory cytokines, such as tumor necrosis factor-alpha(TNF-alpha), and the procoagulant molecule, tissue factor (TF). In this study, we analyzed the role of the phosphoinositide 3-kinase (PI3K)-Akt pathway in the activation of coagulation and the innate immune response in a mouse model of endotoxemia.Methods and Results - Wortmannin and LY294002 were used to inhibit the PI3K-Akt pathway. We found that wortmannin inhibited LPS-induced Akt phosphorylation in blood cells. Inhibition of the PI3K-Akt pathway significantly increased TF mRNA expression in blood cells, TF antigen, and thrombin - antithrombin III levels in the plasma, and fibrin deposition in the liver of endotoxemic mice. Inhibition of the PI3K-Akt pathway also strongly enhanced LPS-induced cytokine expression and the levels of soluble E-selectin in the plasma, suggesting enhanced activation of both monocytes and endothelial cells. Wortmannin treatment also increased the number of macrophages in the liver and kidney of endotoxemic mice. Finally, wortmannin and LY294002 dramatically reduced the survival time of endotoxemic mice.Conclusions - These data suggest that the PI3K-Akt pathway suppresses LPS-induced inflammation and coagulation in endotoxemic mice.