肝纤维化逆转中MAPK/ERK信号转导通路的活化及其特征

目的探讨有丝分裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）／细胞外信号调节激酶（extracellular signal-regulated protein kinase，ERK）信号转导通路与肝纤维化自发逆转的相关性。方法采用CC14注射SD大鼠8周，随后停药6周建立肝纤维化自发逆转的动物模型。采用cDNA微阵列杂交检测纤维化消退期间MAPK／ERK级联反应中有丝分裂原活化的蛋白激酶激酶激酶（mitogen-activated protein kinase kinase kinase，MAPKKK）、MAPKK、MAPK等上下游激酶的表达变化。并通过Northern杂交加以验证。结果肝纤维化自发逆转过程中，H—raf、A—raf．MAPKK2、ERK1及核糖体S6蛋白激酶（S6 protein kinase，RSK1）等MAPK／ERK信号转导通路中的关键激酶表达水平均显著提高，并呈现顺序激活的时序关系，ras抑制物的转录则明显下调。结论MAPK／ERK信号通路在肝纤维化消退时明显活化，可能与纤维化的自发逆转密切相关。

Activation and characteristics of MAPK/ERK signal pathway during spontaneous resolution of hepatic fibrosis

[Objective] To investigate the relationship of MAPK/ERK signal pathway and the autoreversibility of hepatic fibrosis. [Methods] Animal model of hepatic fibrosis autoreversibility was established by CCl4 exposure for 8 weeks and then withdraw for 6 weeks. The MAPK/ERK cascade, thereafter, was detected by cDNA microarray hybridization and verified by northern blot during the resolution of hepatic fibrosis. [Results] Critical members of MAPK/ERK signal pathway including H-ras, A-raf, mitogen-activated protein kinase kinase 2 (MAPKK2), extracellular signal-regulated protein kinase 1 (ERK1), and S6 protein kinase (RSK1) exhibited greatly up-regulated expression levels, which were proved to reach the peak successively, throughout the hepatic fibrosis recovery. Contrastively, the mRNA level of ras inhibitor was significantly decreased. [Conclusion] The activation of MAPK/ERK signaling may play an important role in the hepatic fibrosis autoreversibility.