调节环氧化物合酶-2对慢性肝损伤过程中维持肝脏内稳态的机制研究

Incapability of liver regeneration due to the effect of chronic pathogenic factor on hepatocytes leads to disruption of hepatostat, and ultimately renders liver cirrhosis and liver failure. The unlimited hepatic inflammation hampers liver regeneration, and pyroptosis has adverse impact on the fate of residue hepatocytes. Moreover, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome could not only induce inflammation directly, but also generate pyroptosis to trigger inflammatory cascade. Furthermore, our previous study found cyclooxygenase-2 (COX-2) probably functioned as damage/danger associated molecular pattern molecules (DAMPs) during the activation of NLRP3 inflammasome. Based on the current evidence and our preliminary study, we aims to prove the followings: 1) the accumulated COX-2 within the cytoplasm could activate NLRP3 inflammasome, induce pyroptosis of hepatocytes, and destroy the capability of liver regeneration under the context of chronic liver injury; 2) Targeting inhibition of COX-2 could inhibit the activation of NLRP3 inflammasome, reduce pyroptosis of hepatocytes and liver inflammation, and ultimately restore hepatostat. Our project suggests COX-2 is the culprit resulting in the loss of liver regeneration, which provides novel insights into the pathophysiology of liver cirrhosis. Though other markers might be related to the pyroptosis of hepatocytes, targeting COX-2 to inhibit pyroptosis is more rapid to transform the work from benchside to bedside, which is the best utilization of drugs currently in hand and has great cost effectiveness.

肝细胞在慢性致病因素作用下丧失再生能力导致肝脏内稳态失衡，其结局往往是肝硬化及肝衰竭。肝脏难以自限性炎症致使肝细胞再生受阻，而肝细胞焦亡过程对残留肝细胞命运有重大负面影响。NLRP3炎性小体既可直接诱导炎症反应，又可诱导肝细胞焦亡扩大炎症反应，我们研究发现COX-2在肝细胞NLRP3炎性小体活化过程中极可能扮演DAMPs的角色。基于目前相关碎片理论及团队前期研究，我们拟求证：1）堆积在胞浆内的COX-2在慢性肝损伤环境下激活NLRP3炎性小体、增加肝细胞焦亡、摧毁肝再生能力；2）调节COX-2可降低肝细胞NLRP3炎性小体活性、减少肝细胞焦亡及肝脏炎症，恢复肝脏内稳态。本项目提出COX-2是肝细胞失去再生能力的DAMPs，尽管其它靶点也可能联系肝细胞焦亡，选择COX-2作为减少肝细胞焦亡的靶点，有望使这项基础研究快速转化至临床，是对现有药物资源的最好应用，转化医学研究性价比甚高。

肝细胞在慢性致病因素作用下丧失再生能力导致肝脏内稳态失衡，其结局往往是肝硬化及肝衰竭。肝脏难以自限性炎症致使肝细胞再生受阻，而肝细胞焦亡过程对残留肝细胞命运有重大负面影响。NLRP3炎性小体既可直接诱导炎症反应，又可诱导肝细胞焦亡扩大炎症反应。我们的项目证实：（1）STING-NLRP3-GSDMD信号通路可通过肝细胞焦亡促进肝脏炎症和肝纤维化。（2）COX-2促进肝门脉高压和肠上皮失稳态。（3）内皮p300通过CCL2介导的血管分泌信号促进门静脉高压和肝纤维化。项目执行期间在Hepatology等期刊已发表论文24篇，接收1篇，修回1篇。并且在学术交流、人才培养和项目负责人成长方面完成预期目标。