Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Shock. 2018 Jul;50(1):103-111. doi: 10.1097/SHK.0000000000000976.
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.
血管渗漏是导致脓毒症高发病率和高死亡率的原因之一。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）会导致通透性增加。我们最近观察到，自噬作为一种蛋白质代谢的细胞过程，参与了巨噬细胞移动抑制因子（MIF）诱导的内皮通透性增加。尽管已知凝血酶诱导内皮细胞分泌 MIF 并增加血管通透性，但自噬在此过程中的可能作用尚不清楚。在这项研究中，我们提出并检验了以下假说：MIF 诱导的自噬在凝血酶诱导的内皮通透性增加中起重要作用。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估了凝血酶对内皮通透性、自噬诱导和 MIF 分泌的影响。检测了内皮通透性和自噬形成的几种机制/指标。我们观察到，阻断自噬可减弱凝血酶诱导的内皮通透性增加。此外，凝血酶诱导的 MIF 分泌参与了这一过程，因为 MIF 抑制可减少凝血酶诱导的自噬和通透性增加。最后，我们表明，阻断 MIF 或自噬可有效减轻内毒素血症小鼠的血管渗漏和死亡率。因此，MIF 诱导的自噬可能代表脓毒症中导致血管渗漏的共同机制。
