Yoshizumi Tomoharu, Yonemitsu Yoshikazu, Ikeda Yasuhiro, Kaneda Yasufumi, Yanaga Katsuhiko, Sugimachi Keizo, Sueishi Katsuo
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Liver Int. 2006 May;26(4):451-6. doi: 10.1111/j.1478-3231.2006.01252.x.
Cold ischemia/reperfusion injury of the hepatic graft, an unsolved problem in liver transplantations, is attributed to the release of inflammatory cytokines, especially the tumor necrosis factor- (TNF) alpha, from activated Kupffer cells (KC). Therefore, the specific inhibition of TNF-alpha could improve the viability of the hepatic graft upon reperfusion.
We assessed the efficacy of TNF-alpha antisense (TNF-AS) oligodeoxynucleotides (ODNs) delivery to KC in a rodent liver transplantation model.
Seventy-one percent of the animals that received 6 hours preserved grafts in baths of lactated Ringer's solution (4 degrees C) and were treated with TNF-AS survived for over 14 days. Eighty percent of the animals treated with vehicle, sense ODNs, or balanced salt saline (BSS) died. Four hours after reperfusion of the liver, a significant reduction was noted in livers treated with TNF-AS in the release of cytosolic enzymes from the hepatocytes and the serum TNF-alpha (P<0.05). The expressions of TNF-alpha on KC and of intercellular adhesion molecule-1 on sinusoidal endothelial cells were completely suppressed in TNF-AS-treated livers.
TNF-AS delivery improves the viability of the hepatic graft, and this technique may solve hepatic graft nonfunction in a clinical setting.
肝移植中尚未解决的问题——肝移植冷缺血/再灌注损伤，归因于活化的库普弗细胞（KC）释放炎性细胞因子，尤其是肿瘤坏死因子-α（TNF-α）。因此，特异性抑制TNF-α可提高再灌注时肝移植的存活率。
我们在啮齿动物肝移植模型中评估了向KC递送TNF-α反义（TNF-AS）寡脱氧核苷酸（ODN）的效果。
在乳酸林格氏液（4℃）浴中保存6小时移植物并接受TNF-AS治疗的动物中，71%存活超过14天。接受载体、正义ODN或平衡盐溶液（BSS）治疗的动物中，80%死亡。肝脏再灌注4小时后，用TNF-AS治疗的肝脏中，肝细胞胞质酶释放和血清TNF-α显著降低（P<0.05）。在接受TNF-AS治疗的肝脏中，KC上TNF-α的表达以及窦状内皮细胞上细胞间黏附分子-1的表达被完全抑制。
递送TNF-AS可提高肝移植的存活率，该技术可能解决临床环境中的肝移植无功能问题。
