MACROPHAGE MIGRATION INHIBITORY FACTOR-INDUCED AUTOPHAGY CONTRIBUTES TO THROMBIN-TRIGGERED ENDOTHELIAL HYPERPERMEABILITY IN SEPSIS
MACROPHAGE MIGRATION INHIBITORY FACTOR-INDUCED AUTOPHAGY CONTRIBUTES TO THROMBIN-TRIGGERED ENDOTHELIAL HYPERPERMEABILITY IN SEPSIS
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DOI：
10.1097/shk.0000000000000976
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发表时间：
2018-07-01
期刊：
影响因子：
3.1
通讯作者：
Yeh, Trai-Ming
中科院分区：
文献类型：
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作者：
Chao, Chiao-Hsuan;Chen, Hong-Ru;Yeh, Trai-Ming
血管渗漏是败血症的高发病率和高死亡率的原因之一。在脓毒症期间，内皮细胞暴露于炎症介质，如凝血酶和细胞因子，导致高通透性。我们最近观察到，自噬是一种蛋白质周转的细胞过程，参与了巨噬细胞移动抑制因子(MIF)诱导的内皮高通透性。尽管已知凝血酶诱导内皮细胞分泌MIF并增加血管通透性，但自噬在这一过程中可能发挥的作用尚不清楚。在这项研究中，我们提出并验证了MIF诱导的自噬在凝血酶诱导的内皮高通透性中起重要作用的假设。我们使用人微血管内皮细胞系-1和人脐静脉内皮细胞，在体外评价凝血酶对内皮通透性、自噬诱导和MIF分泌的影响。研究了内皮通透性和自噬形成的几种机制。我们观察到，阻断自噬可以减轻凝血酶诱导的内皮高通透性。此外，凝血酶诱导的MIF分泌参与了这一过程，因为抑制MIF减少了凝血酶诱导的自噬和高通透性。最后，我们发现阻断MIF或自噬有效地减轻了内毒素血症小鼠的血管渗漏和死亡率。因此，MIF诱导的自噬可能是导致脓毒症血管渗漏的常见机制。
Vascular leakage contributes to the high morbidity and mortality associated with sepsis. Exposure of the endothelium to inflammatory mediators, such as thrombin and cytokines, during sepsis leads to hyperpermeability. We recently observed that autophagy, a cellular process for protein turnover, is involved in macrophage migration inhibitory factor (MIF)-induced endothelial hyperpermeability. Even though it is known that thrombin induces endothelial cells to secrete MIF and to increase vascular permeability, the possible role of autophagy in this process is unknown. In this study, we proposed and tested the hypothesis that MIF-induced autophagy plays an important role in thrombin-induced endothelial hyperpermeability. We evaluated the effects of thrombin on endothelial permeability, autophagy induction, and MIF secretion in vitro using the human microvascular endothelial cell line-1 and human umbilical vein endothelial cells. Several mechanisms/read outs of endothelial permeability and autophagy formation were examined. We observed that blocking autophagy attenuated thrombin-induced endothelial hyperpermeability. Furthermore, thrombin-induced MIF secretion was involved in this process because MIF inhibition reduced thrombin-induced autophagy and hyperpermeability. Finally, we showed that blocking MIF or autophagy effectively alleviated vascular leakage and mortality in endotoxemic mice. Thus, MIF-induced autophagy may represent a common mechanism causing vascular leakage in sepsis.