Department of Animal Health, University of León, León, Spain.
Vet Res. 2010 Jan-Feb;41(1):2. doi: 10.1051/vetres/2009050. Epub 2009 Sep 3.
Management of fulminant hepatic failure (FHF) continues to be one challenging problem, and experimental animal models resembling its clinical conditions are still needed. Rabbit hemorrhagic disease (RHD) fullfils many requirements of an animal model of FHF. This work investigated changes in MAPK, NF-kappaB, AP-1 and STAT pathways during RHD-induced liver injury. Rabbits were infected with 2 x 10(4) hemagglutination units of an RHD virus isolate. Apoptosis was documented by the presence of caspase-3 activity and substantial PARP proteolysis at 36 and 48 h postinfection (pi). Infection induced a marked and maintained expression of TNF-alpha from 12 h pi, while there was only a transitory increase in IL-6 expression. Expression of phosphorylated (p)-JNK, p-p38 and p-ERK1/2 was significantly elevated at 12 h pi. At 48 h pi p-JNK expression was maintained at a maximum level, while that of p-p38 returned to normality and there was no p-ERK1/2 expression. Activation of NF-kappaB and AP-1 and increased expression of VCAM-1 and COX-2 were observed. No significant changes were detected in activation of STAT1 and STAT3, while SOCS3 expression increased significantly. The current findings suggest that activation of JNK is an essential component in liver injury mediated by the RHD virus and that lack of activation of STAT3, probably mediated by SOCS3 over-expression, would contribute to the inhibition of the regenerative response. Data show the presence of molecular mechanisms contributing to liver damage and the lack of regeneration and they support the usefulness of this model to investigate novel therapeutical modalities in FHF.
暴发性肝衰竭（FHF）的治疗仍然是一个具有挑战性的问题，仍然需要类似于其临床情况的实验动物模型。兔出血性疾病（RHD）符合 FHF 动物模型的许多要求。本研究探讨了 RHD 诱导的肝损伤过程中 MAPK、NF-κB、AP-1 和 STAT 通路的变化。用 2×104 血凝单位的 RHD 病毒分离株感染兔子。在感染后 36 和 48 小时通过 caspase-3 活性和大量 PARP 蛋白水解的存在来证明凋亡。感染诱导 TNF-α的显著和持续表达从感染后 12 小时开始，而 IL-6 的表达仅短暂增加。感染后 12 小时，磷酸化（p）-JNK、p-p38 和 p-ERK1/2 的表达明显升高。在感染后 48 小时，p-JNK 的表达保持在最高水平，而 p-p38 的表达恢复正常，没有 p-ERK1/2 的表达。NF-κB 和 AP-1 的激活以及 VCAM-1 和 COX-2 的表达增加。未检测到 STAT1 和 STAT3 的激活有显著变化，而 SOCS3 的表达显著增加。目前的研究结果表明，JNK 的激活是 RHD 病毒介导的肝损伤的一个重要组成部分，而 STAT3 的缺乏激活，可能是由 SOCS3 的过表达介导的，将有助于抑制再生反应。数据显示存在导致肝损伤和缺乏再生的分子机制，并支持该模型在研究 FHF 的新治疗方法方面的有用性。
