Khandoga Andrej, Biberthaler Peter, Enders Georg, Krombach Fritz
Institute for Surgical Research, University of Munich, Germany.
Crit Care Med. 2004 Feb;32(2):472-7. doi: 10.1097/01.CCM.0000109448.51468.E3.
The aim of this study was to investigate the impact of the novel, potent, water-soluble inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP) 5-aminoisoquinolinone (5-AIQ) on hepatic microcirculation, hepatocellular injury, and survival in a murine model of hepatic ischemia-reperfusion.
Randomized animal study.
Research laboratory.
C57BL6 mice were subjected to warm either partial (90 mins) or total (75 mins) ischemia of the liver.
Either PARP inhibitor 5-AIQ (3 mg/kg) or vehicle was administered to mice intravenously immediately before the start of reperfusion. Sham-operated animals served as controls.
As shown by intravital fluorescence microscopy after 30-60 mins of reperfusion, ischemia-reperfusion significantly enhanced platelet- and leukocyte-endothelial cell interactions in hepatic microvessels and impaired sinusoidal perfusion. Hepatocellular injury was characterized by an increase in the number of necrotic and apoptotic cells, dramatic elevation of aspartate aminotransferase/alanine aminotransferase serum activity, and lipid peroxidation in liver tissue. 5-AIQ treatment attenuated ischemia-reperfusion-induced increases in the numbers of adherent platelets and leukocytes as well as of necrotic and apoptotic cells and ameliorated perfusion failure. Furthermore, PARP inhibition prevented the increase in aspartate aminotransferase activity after ischemia-reperfusion but did not affect postischemic alanine aminotransferase release. However, no protective impact of 5-AIQ on postischemic oxidative stress was observed. Although PARP inhibition did not alter the survival percentage after ischemia-reperfusion (22% in both groups), this approach prolonged survival from 1 to 24 hrs (ischemia-reperfusion + vehicle) up to 48-72 hrs in the treated group.
PARP inhibition with 5-AIQ during hepatic ischemia-reperfusion attenuates microvascular injury and reduces the extent of necrotic/apoptotic cell damage but does not protect from oxidative injury and does not improve postoperative survival rate.
本研究旨在探讨新型、强效、水溶性聚（腺苷二磷酸核糖）聚合酶（PARP）抑制剂5-氨基异喹啉酮（5-AIQ）对肝缺血再灌注小鼠模型肝微循环、肝细胞损伤及存活率的影响。
随机动物研究。
研究实验室。
C57BL6小鼠接受肝脏部分（90分钟）或完全（75分钟）热缺血。
在再灌注开始前立即给小鼠静脉注射PARP抑制剂5-AIQ（3mg/kg）或赋形剂。假手术动物作为对照。
再灌注30-60分钟后活体荧光显微镜检查显示，缺血再灌注显著增强了肝微血管中血小板与白细胞-内皮细胞的相互作用，并损害了肝窦灌注。肝细胞损伤表现为坏死和凋亡细胞数量增加、血清天冬氨酸氨基转移酶/丙氨酸氨基转移酶活性显著升高以及肝组织脂质过氧化。5-AIQ治疗减轻了缺血再灌注诱导的黏附血小板和白细胞数量增加以及坏死和凋亡细胞数量增加，并改善了灌注衰竭。此外，PARP抑制可防止缺血再灌注后天冬氨酸氨基转移酶活性升高，但不影响缺血后丙氨酸氨基转移酶释放。然而，未观察到5-AIQ对缺血后氧化应激的保护作用。虽然PARP抑制并未改变缺血再灌注后的存活率（两组均为22%），但该方法将未治疗组（缺血再灌注+赋形剂）的存活时间从1至24小时延长至治疗组的48-72小时。
肝缺血再灌注期间用5-AIQ抑制PARP可减轻微血管损伤，减少坏死/凋亡细胞损伤程度，但不能预防氧化损伤，也不能提高术后存活率。
