Debonera F, Aldeguer X, Shen X, Gelman A E, Gao F, Que X, Greenbaum L E, Furth E E, Taub R, Olthoff K M
Department of Surgery, University of Pennsylvania, Philadelphia 19104, USA.
J Surg Res. 2001 Apr;96(2):289-95. doi: 10.1006/jsre.2001.6086.
Every liver that is procured, stored, and transplanted experiences injury from cold ischemia and reperfusion. Most recover quickly, but some grafts sustain enough injury to result in prolonged organ dysfunction or require retransplantation. The molecular mechanisms involved in early graft function and recovery following cold ischemia and reperfusion (I/R) after liver transplantation have not been well defined. Interleukin (IL)-6 is a critical factor in the mitogenic response within the liver, and is important for cell cycle progression and protection from injury. Activation of the latent transcription factor, STAT3, is dependent on IL-6 release. The role of the IL-6/STAT3 pathway and hepatocellular regeneration in graft recovery and cell cycle progression following cold ischemia and reperfusion was studied in a rat liver transplant orthotopic (OLT) model. Methods. Rat OLT was performed in a syngeneic model. The presence, time course, and magnitude of expression of IL-6, STAT3 activation, and upregulation of target immediate early genes were determined in liver grafts with minimal (<1 h) and prolonged (12 h) cold preservation times followed by transplantation. Progression of the cell cycle and replication was confirmed by BrdU uptake.
Prolonged cold ischemia resulted in increased IL-6 expression and STAT3 activation. This correlated with upregulation of junB, c-fos, c-myc, and c-jun, immediate early genes associated with hepatic regeneration. Extensive DNA replication was present in livers with 12-h ischemia, demonstrating successful completion of the cell cycle.
The participation of the IL-6/STAT3 pathway leading to cell cycle progression and regeneration is an important component in the recovery of organs immediately following cold preservation and transplantation.
每一个被获取、储存和移植的肝脏都会经历冷缺血和再灌注损伤。大多数肝脏能迅速恢复，但有些移植物会遭受足够的损伤，导致器官功能长期障碍或需要再次移植。肝移植后冷缺血和再灌注（I/R）后早期移植物功能和恢复所涉及的分子机制尚未明确。白细胞介素（IL）-6是肝脏有丝分裂反应中的关键因子，对细胞周期进程和免受损伤很重要。潜伏转录因子STAT3的激活依赖于IL-6的释放。在大鼠原位肝移植（OLT）模型中研究了IL-6/STAT3通路和肝细胞再生在冷缺血和再灌注后移植物恢复和细胞周期进程中的作用。方法：在同基因模型中进行大鼠OLT。在冷保存时间最短（<1小时）和延长（12小时）后进行移植的肝移植物中，测定IL-6的存在、时间进程和表达量、STAT3的激活以及靶标即刻早期基因的上调情况。通过BrdU摄取证实细胞周期的进展和复制。
长时间冷缺血导致IL-6表达增加和STAT3激活。这与junB、c-fos、c-myc和c-jun的上调相关，这些是与肝再生相关的即刻早期基因。在缺血12小时的肝脏中存在广泛的DNA复制，表明细胞周期成功完成。
导致细胞周期进程和再生的IL-6/STAT3通路的参与是冷保存和移植后器官立即恢复的重要组成部分。
