Debonera Fotini, Krasinkas Alyssa M, Gelman Andrew E, Aldeguer Xavier, Que Xingye, Shaked Abraham, Olthoff Kim M
Department of Surgery, University of Pennsylvania, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Hepatology. 2003 Dec;38(6):1563-72. doi: 10.1016/j.hep.2003.09.036.
Regeneration is crucial for the recovery of hepatic mass following liver transplantation. Glucocorticoids, immunosuppressive and antiinflammatory agents commonly used in transplantation, are known to inhibit the expression of specific cytokines and growth factors. Some of these proteins, namely tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), play a critical role in the initiation of liver regeneration. Following cold preservation and reperfusion of the transplanted liver, the normal recovery process is marked by increased expression of TNF-alpha and IL-6, followed by activation of cytokine-responsive transcription factors and progression of the cell cycle resulting in hepatocyte proliferation. We hypothesized that glucocorticoids may influence the repair mechanisms initiated after extended cold preservation and transplantation. Using a rat orthotopic liver transplant model, recipient animals were treated with dexamethasone at the time of transplantation of liver grafts with prolonged cold storage (16 hours). Treatment with dexamethasone suppressed and delayed the expression of TNF-alpha and IL-6 compared with animals receiving no treatment and attenuated downstream nuclear factor kappaB (NF-kappaB), signal transduction and activator of transcription 3 (STAT3), and activation protein 1 (AP-1) activation. This suppression was accompanied by poor cell-cycle progression, delayed cyclin D1 nuclear transposition, and impaired hepatocyte proliferation by BrdU uptake. Histologically, the liver grafts in treated animals demonstrated more injury than controls, which appeared to be necrosis, rather than apoptosis. In conclusion, these data provide evidence that the administration of glucocorticoids at the time of transplantation inhibits the initiation of the regenerative process and may have a deleterious effect on the recovery of liver grafts requiring significant regeneration. This may be particularly relevant for transplantation of partial liver grafts in the living donor setting.
肝移植后肝脏质量的恢复，再生至关重要。糖皮质激素是移植中常用的免疫抑制和抗炎药物，已知其可抑制特定细胞因子和生长因子的表达。其中一些蛋白质，即肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6），在肝脏再生起始过程中起关键作用。移植肝脏经冷保存和再灌注后，正常恢复过程的特征是TNF-α和IL-6表达增加，随后细胞因子反应性转录因子激活，细胞周期进展，导致肝细胞增殖。我们推测糖皮质激素可能影响长时间冷保存和移植后启动的修复机制。使用大鼠原位肝移植模型，在移植长时间冷保存（16小时）的肝移植物时，对受体动物给予地塞米松治疗。与未治疗的动物相比，地塞米松治疗抑制并延迟了TNF-α和IL-6的表达，并减弱了下游核因子κB（NF-κB）、信号转导和转录激活因子3（STAT3）以及激活蛋白1（AP-1）的激活。这种抑制伴随着细胞周期进展不良、细胞周期蛋白D1核转位延迟以及通过BrdU摄取检测到的肝细胞增殖受损。组织学上，治疗动物的肝移植物显示出比对照更多的损伤，似乎是坏死，而非凋亡。总之，这些数据表明移植时给予糖皮质激素会抑制再生过程的起始，并且可能对需要显著再生的肝移植物恢复产生有害影响。这对于活体供肝部分肝移植可能尤为重要。
