IL-18通路在体外循环术后肝损伤中的作用及瑞芬太尼对该损伤的保护作用研究

体外循环(CPB)术后急性肝损伤在临床上十分常见。该损伤的发生与CPB期间全身炎症反应综合征(SIRS)和肝脏缺血再灌注损伤(IRI)等病理生理过程有关，但其分子生物学机制尚未明。IL-18通路在SIRS和IRI的发生发展中均起重要作用，提示其很可能是介导CPB术后肝损伤的关键通路。IL-18的生物活性受其结合蛋白(IL-18BP)有效抑制,后者的表达主要受STAT1和C/EBP等转录因子活性调控。已知u阿片受体激动剂具有激活上述转录因子的作用，因此我们推测该类药物能够诱导IL-18BP基因转录和表达，从而中和IL-18介导的组织损伤。本课题将应用大鼠CPB模型，在体研究IL-18通路在CPB术后肝损伤中的作用并检测新一代u受体激动剂瑞芬太尼对该损伤的保护作用；接着培养人肝脏上皮细胞，体外深入研究瑞芬太尼诱导IL-18BP基因转录的机制。以期为CPB围术期肝脏保护策略的制定提供理论依据。

Cardiopulmonary bypass (CPB)-induced acute liver injury is very common in patients after cardiac surgery. While the injury is thought to be associated with systemic inflammatory response syndrome (SIRS) and ischemia/reperfusion injury (IRI), the underlying molecular mechanism is not known yet. IL-18 pathway plays an important role in the development of both SIRS and IRI, indicating the possibility that this is the critical pathway mediating the CPB-induced liver injury. Biological activities of IL-18 are modulated and suppressed by its natural antagonist, IL-18 binding protein (IL-18BP). The regulation of IL-18BP expression occurs mainly at transcriptional level, with transcription factors STAT1 and C/EBP playing an essential role in this progress. Previous studies demonstrate that u opioid receptor agonists are able to induce activation of STAT1 and C/EBP in various situations. Therefore, we hypothesize that these agonists can upregulate the transcription of IL-18BP gene and increase its expression levels, thereby attenuating IL-18-mediated tissue injuries. The present research project will utilize a rat CPB model to investigate the role of IL-18 signaling pathway in the development of CPB-induced liver injury in vivo, and to study the protective effects of remifentanil, a novel u opioid receptor agonist, in this progress. We will then culture human hepatic epithelial cells to further explore the mechanisms underlying remifentanil induction of IL-18BP gene transcription using molecular biology techniques such as luciferase reporter assay and CHIP. This project will help expanding our understandings of the molecular mechanisms of CPB-induced liver injury and the pharmacological effects of remifentanil, providing important implications for preventive and therapeutic interventions during the perioperative periods.