腺苷酸活化蛋白激酶是炎症损伤中的保护因子吗?

Is AMP-activated protein kinase a protective factor in inflammatory injury?

腺苷酸活化蛋白激酶(AMPK)是细胞的关键代谢调节酶,也在炎症这一高耗能分子反应中发挥广泛抗炎效应。我们及其他实验室均发现,AMPK激活剂预先处理可在多种炎症性疾病动物模型中表现出良好的保护效应,但这一干预方式不符合临床实际。我们近期采用治疗性后处理的干预方式意外发现,AMPK激活剂后处理反而会加重爆发性肝炎,而AMPK抑制剂后处理可有效减轻肝损伤。相关机制的研究揭示,AMPK在爆发性肝炎病程晚期被激活,主要通过激活c-Jun氨基末端激酶(JNK)促进肝细胞凋亡。通过这些研究,我们认为AMPK在病程的不同阶段可发挥抗炎或促凋亡的双重效应,炎症性疾病在治疗中应该使用AMPK激活剂还是抑制剂值得重新思考。

AMP-activated protein kinase （AMPK） is pivotal cellular metabolic regulatory enzyme. It exerts extensive anti-inflammatory effects in inflammatory response that is an energy intensive process. Our and other labs have previously found that the pretreatment with AMPK activators have profound beneficial effects in various animal models with inflammatory disorders. However, the pre-insult intervention is unpractical in clinic patients. In our recent study, we unexpectedly found that the post-insult treatment with AMPK activators aggravated fulminant hepatitis, whereas the posttreatment with AMPK inhibitors alleviated liver injury. Our study also found that AMPK was mainly activated at the late stage in the progression of fulminant hepatitis, which promoted cell apoptosis via the activation of JNK. These studies suggest that AMPK might have dual effects, including anti-inflammatory and pro-apoptotic activities, at different stages during the progression of inflammatory disorders. Thus, whether the AMPK activators or the AMPK inhibitors should be used for the intervention of inflammatory injury requires careful reconsideration.