Department of Intensive Care Medicine, RWTH-Aachen University, Aachen, Germany.
Department of Surgery and Transplantation, RWTH-Aachen University, Aachen, Germany.
Shock. 2019 Nov;52(5):e124-e134. doi: 10.1097/SHK.0000000000001307.
Macrophage migration inhibitory factor (MIF) is an important stress-regulating mediator of acute ischemia/reperfusion (I/R) injury and ischemic conditioning. The present study aimed to investigate whether MIF is involved in the effects of remote ischemic conditioning (RIC) in a rat model of orthotopic liver transplantation (OLT).
OLTs were performed in male Lewis rats (245 g-340 g). Recipients were allocated in a randomized fashion into three experimental groups: remote preconditioning-RIPC, remote post-conditioning-RIPOST, control. RIC was applied as 4×5-5 min I/R via clamping of the infrarenal aorta. Animals were followed for 1, 3, 24, 168 h post-reperfusion (n = 6 recipient/group/time point). Graft micro- and macrocirculation and hepatocellular damage were assessed. Messenger ribonucleic acid (mRNA) expression, serum, and tissue protein levels of MIF, as well as additional markers of I/R injury, were measured.
RIC resulted in a prominent downregulation of MIF mRNA, serum, and tissue protein. Compared with control, hepatocellular damage was significantly mitigated after RIPC or RIPOST (serum ALT; RIPC, RIPOST vs. Control, P = 0.008, P = 0.030, respectively). Graft circulation was better preserved in the RIC groups. Furthermore, there was a significant positive correlation between serum MIF and transaminase levels (r = 0.330; P = 0.02). RIC showed a significant effect on iNOS and STAT5 mRNA expressions. Supporting findings were obtained from the measurements of tissue CXCL12 mRNA expression and pAkt/Akt, pErk/Erk.
In this sophisticated experimental model of OLT, RIC-induced hepatoprotective effects were associated with a downregulation of MIF at mRNA and protein levels, suggesting the role of MIF as a mediator in RIC-induced protection following OLT.
巨噬细胞移动抑制因子（MIF）是急性缺血/再灌注（I/R）损伤和缺血预处理的重要应激调节介质。本研究旨在探讨 MIF 是否参与大鼠原位肝移植（OLT）模型中远程缺血预处理（RIC）的作用。
雄性 Lewis 大鼠（245-340g）进行 OLT。受者随机分为三组：远程预处理-RIPC、远程后处理-RIPOST、对照组。RIC 通过夹闭肾下主动脉进行 4×5-5min 的 I/R。动物在再灌注后 1、3、24、168h 进行随访（每组/时间点 6 只受体）。评估移植物的微血管和宏观循环以及肝细胞损伤。测量 MIF 及其他 I/R 损伤标志物的信使核糖核酸（mRNA）表达、血清和组织蛋白水平。
RIC 导致 MIF mRNA、血清和组织蛋白明显下调。与对照组相比，RIPC 或 RIPOST 后肝细胞损伤明显减轻（血清 ALT；RIPC、RIPOST 与对照组相比，P=0.008、P=0.030）。RIC 组移植物循环更好。此外，血清 MIF 与转氨酶水平呈显著正相关（r=0.330；P=0.02）。RIC 对 iNOS 和 STAT5 mRNA 表达有显著影响。组织 CXCL12 mRNA 表达和 pAkt/Akt、pErk/Erk 的测量结果也支持这一发现。
在这种复杂的 OLT 实验模型中，RIC 诱导的肝保护作用与 MIF 在 mRNA 和蛋白水平的下调有关，这表明 MIF 作为 OLT 后 RIC 诱导保护的介质发挥作用。
