TLR4介导的TRIF信号通路调控RIP1/RIP3介导的细胞死亡在急性胰腺炎中的机制研究

The mortality of severe acute pancreatitis (SAP) is still as high as 15%-30% and challenging doctors worldwide. The severity of acute pancreatitis is paralleled with the predominance of a given type of cell death, and inflammatory attack in AP could be alleviated by regulating the different types of cell death development. Pancreatic acinar cell necrosis is considered to be a key factor in regulating the severity of AP. Receptor-interacting protein kinase 3 (RIP3) was a key molecular in swticing cell death from apotosis to necroptosis, RIP3-mediated necroptosis can be activated through RIP1 dependent or independent pathway. Moreover, activation of RIP1 can induce cell autophagy. Based on our preliminary results, which evidenced pancreatic injury was reduced in mice with absence of Toll like receptor 4 (TLR4) during AP, however, aggravated pancreatic injury and significantly increased pancreatic necrosis were found in MyD88 knock out mice during AP. we proposed that TLR4 mediated MyD88 independent TRIF pathway might potentially be involved in the regulation of cell death in AP. This project focuses on the potential role of TRIF pathway in regulating RIP1/RIP3 mediated cell death in the development of AP, to explore the role of TLR4 medicated TRIF signaling in regulating different types of cell death in the development of AP. This study will provide new insights for understanding the pathogenesis of AP, and provide research evidences for further translational diagnosis and treatment of AP.

重症急性胰腺炎(SAP)病死率高达15-30%,是世界范围内的医学难题。急性胰腺炎(AP)的严重程度与细胞死亡方式相关,调控胰腺细胞死亡方式将影响AP的发展与转归。腺泡细胞坏死被认为是促进AP重症演变的关键因素。RIP3是调控细胞凋亡向程序性坏死转换的分子开关，可通过RIP1依赖与非依赖途径激活调控坏死，且RIP1亦可诱导自噬的发生。我们前期发现：TLR4基因缺失小鼠诱导AP后，胰腺炎症减轻；而MyD88基因缺失小鼠诱导AP后，胰腺炎症反而加重，胰腺细胞坏死明显增加；提示TLR4介导的MyD88非依赖TRIF信号通路可能参与了AP病程中细胞死亡方式的调控。本课题以TLR4介导的TRIF信号调控RIP1/RIP3介导的细胞死亡为切入点，探索 AP中TLR4-TRIF信号通路调控胰腺细胞死亡的规律及对AP病程影响，结果将对AP发病机理提出新的认识，并为AP/SAP的预防及诊治提供理论依据。

重症急性胰腺炎(SAP)病死率高达15-30%,是世界范围内的医学难题。急性胰腺炎(AP)的严重程度与细胞死亡方式相关,调控胰腺细胞死亡方式将影响AP的发展与转归。通过建立体内、体外AP/SAP模型，探索急性胰腺炎中腺泡细胞死亡方式调控机制，得出以下研究结果：➊ MyD88基因缺失小鼠诱导AP后，通过上调MyD88非依赖TRIF信号通路介导的细胞坏死，急性胰腺炎症反而加重。➋通过基因敲除XIAP建立AP/SAP动物模型，揭示AP腺泡凋亡、坏死的AP个体化特征、规律；提示SAP早期干预，可致XIAP等细胞凋亡抑制蛋白功能缺失，使细胞死亡程序逆向由坏死向凋亡转化，从而阻止胰腺炎的重症化。➌外源性给予消退素RvD1治疗，能够通过抑制NF-κB活化，减少细胞因子释放，从而减轻雨蛙素联合LPS诱导SAP的严重程度以及相关肺损伤；❹通过抑制SAPIL-6炎症信号传导的研究发现：IL-6受体抗体Tocilizumab（妥珠单抗）对SAP及其肺损伤模型的有效治疗作用。给予妥珠单抗后，胰腺炎和肺的组织病理学评分降低，SAP及其肺损伤的严重性相关参数显著下降，以及2mg/Kg干预的最佳治疗剂量,为SAP治疗的个体化提供了有价值的标志物及靶点。