Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, London, UK.
Transplantation. 2012 May 15;93(9):880-6. doi: 10.1097/TP.0b013e31824cd59d.
Remote ischemic preconditioning (RIPC) protects against liver ischemia reperfusion (IR) injury. An essential circulating mediator of this protection is nitric oxide (NO) induced by lower limb RIPC. One of the mechanisms through which NO generally acts is the soluble guanylyl cyclase-cyclic GMP (sGC-cGMP) pathway. The present study aimed to assess the role of hepatic sGC-cGMP in lower limb RIPC-induced protection against liver IR injury.
Mice were allocated to 4 groups: 1.Sham; 2.IR: 40 min of lobar hepatic ischemia and 2 hr reperfusion; 3.RIPC+IR: 6 cycles of 4x4 min IR of the lower limb followed by IR group procedure; (4) 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ)+RIPC+IR: ODQ (sGC inhibitor) was administered followed by RIPC+IR group procedure. Hepatic microcirculatory blood flow (MBF) was measured throughout the experiment. Plasma transaminases, hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic cGMP levels were measured in groups 1-3 in addition to an RIPC alone group.
Compared to liver IR alone, RIPC+IR increased hepatic MBF during liver reperfusion (P<0.05), and reduced plasma transaminases (P<0.05) and ultrastructural markers of injury. In contrast compared to RIPC+IR, ODQ+RIPC+IR decreased hepatic MBF (P<0.05) and ultrastructural markers of injury. However, plasma transaminases were not significantly different in the ODQ+RIPC+IR compared to the RIPC+IR group. Hepatic cGMP levels were significantly elevated in the RIPC compared to sham group.
The hepatic sGC-cGMP pathway is required for mediating the protective effects of lower limb RIPC on hepatic MBF in liver IR injury.
远程缺血预处理（RIPC）可保护肝脏免受缺血再灌注（IR）损伤。这种保护作用的一个重要循环介质是由下肢 RIPC 诱导的一氧化氮（NO）。NO 通常作用的机制之一是可溶性鸟苷酸环化酶-cGMP（sGC-cGMP）途径。本研究旨在评估肝 sGC-cGMP 在下肢 RIPC 诱导的肝 IR 损伤保护中的作用。
将小鼠分为 4 组：1.假手术组；2.IR 组：肝脏叶缺血 40 分钟，再灌注 2 小时；3.RIPC+IR 组：下肢 4x4 分钟 IR 循环 6 次，然后进行 IR 组程序；（4）1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮（ODQ）+RIPC+IR 组：给予 ODQ（sGC 抑制剂），然后进行 RIPC+IR 组程序。整个实验过程中测量肝微循环血流（MBF）。实验结束时进行血浆转氨酶、肝组织病理学和透射电镜研究。除 RIPC 单独组外，还测量了组 1-3 的肝 cGMP 水平。
与单独肝 IR 相比，RIPC+IR 增加了肝再灌注期间的肝 MBF（P<0.05），并降低了血浆转氨酶（P<0.05）和损伤的超微结构标志物。相比之下，与 RIPC+IR 相比，ODQ+RIPC+IR 降低了肝 MBF（P<0.05）和损伤的超微结构标志物。然而，ODQ+RIPC+IR 组与 RIPC+IR 组之间的血浆转氨酶差异无统计学意义。与假手术组相比，RIPC 组肝 cGMP 水平显著升高。
肝 sGC-cGMP 途径是介导下肢 RIPC 对肝 IR 损伤肝 MBF 保护作用所必需的。
