Prdx1作为一种新的DAMPs对急性肝衰竭的作用及机制研究

Acute liver failure is a serious liver damage caused by various factors, characterized by acute onset and high mortality. DAMPs-induced inflammatory response plays a key role in acute liver failure. Peroxiredoxin1 (Prdx1) is an intracellular antioxidant protein. However, recent studies have showed that extracellular Prdx1, as a novel and critical DAMP, could activate TLR2/4 to affect NF-κB signaling pathways and promote inflammatory responses. Our previous research showed that Prdx1 is significantly increased in serum of patients with acute liver failure and animal models of acute liver failure, and knocking out Prdx1 has a significant protective effect on mice with acute liver failure. Our recent results shows that Prdx1 may exist as decamers and dimmers in the serum of mice with acute liver failure; and activation of NLRP3 inflammasome may be a novel mechanism by which Prdx1 promotes inflammatory responses. As a kind of DAMPs, the effect and mechanism of Prdx1 in acute liver failure remains unclear. We intend to use Prdx1 conditional knockout mice, recombinant proteins, neutralizing antibodies and other means to further explore its effect and mechanism in acute liver failure, and reveal whether Prdx1 is a therapeutic target for acute liver failure.

急性肝衰竭是多种因素引起的肝脏严重损害，起病急，病死率高。损伤相关分子模式（DAMPs）诱导的炎症反应在急性肝衰竭中发挥关键作用。Peroxiredoxin1（Prdx1）是细胞内的一种抗氧化蛋白，然而最新研究表明，细胞外的Prdx1是一种新的重要的DAMPs。Prdx1可激活TLR2/4影响NF-κB信号通路，促进炎症反应。本课题组前期研究表明：Prdx1在急性肝衰竭患者和动物模型血清中的含量明显增加；敲除Prdx1对急性肝衰竭小鼠具有显著的保护作用。我们近期实验发现：急性肝衰竭小鼠血清中的Prdx1可能以十聚体和二聚体存在；激活NLRP3炎性体可能是Prdx1促进炎症反应的新机制。Prdx1作为一种DAMPs，在急性肝衰竭中的作用及机制仍不清楚。我们拟运用Prdx1条件性敲除小鼠、重组蛋白、中和抗体等手段深入探讨其在急性肝衰竭中的作用及机制，并揭示Prdx1是否为急性肝衰竭的治疗靶点。

急性肝衰竭是多种因素引起的肝脏严重损害，其起病急、病死率高。研究表明损伤相关分子模式（DAMPs）诱导的炎症反应在急性肝衰竭中发挥关键作用。Peroxiredoxin 1（Prdx1）是一种新近发现的重要的DAMPs，但其在急性肝衰竭中的作用还有待探究。本课题组发现： Prdx1在患者血清中升高且与转氨酶、总胆红素等指标呈正相关。通过动物实验发现，Prdx1在急性肝衰竭动物模型血清中早期升高，敲除小鼠体内的Prdx1后对于多种类型的急性肝衰竭模型动物均具有保护作用。Prdx1的主要促炎形式为单体或二聚体，而急性肝衰竭动物血清中Prdx1存在的主要形式为二聚体。通过构建Prdx1髓系细胞及肝细胞条件性敲除鼠，我们证实了髓系细胞及肝细胞都是急性肝衰竭时动物循环Prdx1的重要来源。Prdx1蛋白主要通过激活下游的NF-κB通路与NLRP3炎性体发挥作用。进一步，本课题组发现Prdx1中和抗体对于急性肝衰竭小鼠模型具有治疗作用，明确了Prdx1可作为一种新的急性肝衰竭治疗靶点。综上，本课题发现：Prdx1在急性肝衰竭中发挥重要作用，而中和循环中的Prdx1蛋白可以有效治疗小鼠急性肝衰竭。