Treprostinil, a Prostacyclin Analog, Ameliorates Ischemia-Reperfusion Injury in Rat Orthotopic Liver Transplantation
Treprostinil, a Prostacyclin Analog, Ameliorates Ischemia-Reperfusion Injury in Rat Orthotopic Liver Transplantation
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DOI：
10.1111/j.1600-6143.2011.03568.x
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发表时间：
2011-11-01
影响因子：
8.8
通讯作者：
Venkataramanan, R.
中科院分区：
文献类型：
--
作者：
Ghonem, N.;Yoshida, J.;Venkataramanan, R.
前列腺素已被评估其减少肝移植后IRI的能力;然而，稳定性差，副作用和无法显示主要终点的显著差异限制了其临床应用。曲前列环素是一种前列环素（PGI（2））类似物，与其他市售的PGI 2类似物相比，具有更高的效力和更长的消除半衰期。我们研究了曲前列环素预防奥尔特期间IRI的有效性。同系刘易斯大鼠在UW溶液中冷保存（4 ℃）18 h后进行奥尔特。IRI显著增加血清ALT和AST水平、中性粒细胞浸润、肝坏死和OLT后促炎细胞因子的mRNA水平，而曲前列环素治疗降低了所有参数。肝移植物的冷藏显著降低了ATP水平，曲前列尼尔恢复了再灌注后早期肝移植物的能量水平。此外，与安慰剂相比，曲前列尼尔保留了窦内皮细胞衬里并减少了移植后早期的血小板沉积。安慰剂组的肝组织血流量显著受损，而曲前列环素维持血流量与正常水平相似。曲前列环素在奥尔特期间保护肝移植物免受IRI。曲前列环素有可能作为一种治疗选择，以保护肝移植物免受接受奥尔特的患者的I/R损伤。
Prostaglandins have been evaluated for their ability to reduce IRI after liver transplantation; however, poor stability, side effects and the inability to show a significant difference in primary endpoint have limited their clinical application. Treprostinil, a prostacyclin (PGI(2)) analog, has a higher potency and longer elimination half-life than other commercially available PGI2 analogs. We examined the efficacy of treprostinil to prevent IRI during OLT. OLT was performed in syngeneic Lewis rats after 18 h of cold preservation (4 degrees C) in the UW solution. IRI significantly increased serum ALT and AST levels, neutrophil infiltration, hepatic necrosis and mRNA levels of proinflammatory cytokines post-OLT, while treatment with treprostinil decreased all the parameters. Cold storage of liver grafts significantly reduced ATP levels and treprostinil restored energy levels in liver grafts early postreperfusion. In addition, treprostinil preserved the sinusoidal endothelial cell lining and reduced platelet deposition early post-transplantation compared to placebo. Hepatic tissue blood flow was significantly compromised in the placebo group, whereas treprostinil maintained blood-flow similar to normal levels. Treprostinil protected the liver graft against IRI during OLT. Treprostinil has the potential to serve as a therapeutic option to protect the liver graft against I/R injury in patients undergoing OLT.