Original Articles: Liver Biology and Liver PathobiologyDexamethasone inhibits early regenerative response of rat liver after cold preservation and transplantation☆
Original Articles: Liver Biology and Liver PathobiologyDexamethasone inhibits early regenerative response of rat liver after cold preservation and transplantation☆
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DOI：
10.1053/jhep.2003.09036
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发表时间：
2003-12
期刊：
影响因子：
13.5
通讯作者：
F. Debonera;Alyssa M. Krasinkas;Andrew E. Gelman;X. Aldeguer;X. Que;A. Shaked;K. Olthoff
中科院分区：
文献类型：
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作者：
F. Debonera;Alyssa M. Krasinkas;Andrew E. Gelman;X. Aldeguer;X. Que;A. Shaked;K. Olthoff
再生是肝移植后肝块恢复的关键。糖皮质激素，免疫抑制剂和移植中常用的抗肿瘤剂，已知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），在肝再生的启动中起着关键作用。移植肝脏冷保存和再灌注后，正常恢复过程的标志是TNF-α和IL-6表达增加，随后是精氨酸应答转录因子的激活和细胞周期的进展，导致肝细胞增殖。我们推测糖皮质激素可能会影响长期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，在移植肝移植物时用地塞米松处理受体动物，并延长冷藏时间（16小时）。与未接受治疗的动物相比，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（STAT 3）以及活化蛋白1（AP-1）的活化。这种抑制伴随着差的细胞周期进展，延迟细胞周期蛋白D1核转位，和受损的BrdU摄取肝细胞增殖。在组织学上，治疗组动物的肝移植物比对照组表现出更多的损伤，似乎是坏死，而不是凋亡。总之，这些数据提供的证据表明，在移植时给予糖皮质激素抑制再生过程的启动，并可能对需要显着再生的肝移植物的恢复产生有害影响。这可能是特别相关的移植部分肝移植在活体供体设置。（Hepatology 2003;38：1563-1572.）
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 α (TNF-α) 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-α 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-α and IL-6 compared with animals receiving no treatment and attenuated downstream nuclear factor κB (NF-κB), 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. (Hepatology 2003;38:1563-1572.)