α-乳糖干预Tim-3信号通路维护肝脏免疫稳态改善脓毒症预后的机制研究

Sepsis is the clinical syndrome with high case-fatality. It is estimated that more than 3 million patients in China were present annually with sepsis. Sepsis is the chief cause of death in intensive care units. The most important cause of high case-fatality in sepsis was confirmed by sepsis-induced multiple organs dysfunction syndromes (MODS) caused by a dysregulated host immune inflammatory responses to infection. The liver has a central role during sepsis, and the hepatic immune system is essential to the regulation of immune inflammatory responses during systemic infections, and hepatic dysfunction directly contribute to disease progression of MODS in sepsis．Current studies suggest that immune dysfunction in liver is the core mechanism in sepsis-induced liver injury, and the survival rate of sepsis patients is closely related to the recovery of hepatic immune system homeostasis and the recovery from hepatic dysfunction. Recently, our study shown that the Tim-3 signaling pathway plays a critical role in the regulation of hepatic Kupffer-NKT cells immune feedback loop and accurately maintains local immune homeostasis in the liver. Furthermore, our study shown Tim-3 signaling was thought to be significant promoters of the sepsis-induced hepatic immune dysfunction, and then administration α-lactose to interfere Tim-3 signaling pathway significantly improved the survival of septic mice through ameliorating hepatic immunity disorder. However, it is still little known to the underlying mechanism. To better understand the mechanism of interfering Tim-3 signaling to improve hepatic immunity dysfunction, we designed the project to investigate the underlying mechanism of regulating Tim-3 expression after sepsis, to investigate the interfering Tim-3 signaling for improving with hepatic immune turbulent and liver injury induced by sepsis. This study will deepen our understanding of the relationship among Tim-3 signaling and sepsis-induced hepatic immune dysfunction and liver injury, then will contribute to construct a new strategy to recover the organ function post-sepsis and to improve the prognosis of septic patients .

脓毒症是一种伴超高死亡率的临床综合征，我国每年新发超300万例，居危重症患者死因首位。脓毒症诱发的失控免疫炎症反应导致的多器官功能障碍（MODS）是其超高死亡率的主因。肝脏免疫紊乱是脓毒症后失控免疫炎症反应的“倍增器”及诱发MODS的“启动子”。脓毒症患者预后与肝免疫稳态恢复及肝功能改善密切相关。我们前期研究显示Tim-3信号双向调控了肝内枯否-NKT免疫反馈调节环，维护了肝脏免疫稳态。Tim-3信号与脓毒症诱发的肝免疫紊乱亦密切相关，应用α-乳糖干预Tim-3信号通路可改善肝免疫紊乱及肝功能障碍，极大提高脓毒症小鼠生存率。但这些研究多为现象的观察，对其深层机制了解不多。本项目拟深入研究脓毒症后Tim-3信号表达调控，及α-乳糖干预Tim-3信号通路改善脓毒症后肝免疫紊乱的潜在机制。该研究将加深对脓毒症后肝免疫调控机制的认识，探索新型免疫干预治疗措施，以期临床转化后可提高脓毒症患者预后。

脓毒症被定义为由宿主对感染的反应失调引起的危及生命的器官功能障碍。据估计，2017年脓毒症的死亡率为1100万，占全球所有死亡人数的近20%。尽管通过了30多年的研究和200多项随机对照试验，但目前尚无一种治疗方法能够持续挽救脓毒症患者的生命。越来越多的证据支持免疫系统在脓毒症病变机制中的核心作用，且脓毒症诱发的失控免疫炎症反应导致的多器官功能障碍（MODS）是其超高死亡率的主因。肝脏免疫紊乱是脓毒症后失控免疫炎症反应的“倍增器”及诱发MODS的“启动子”。脓毒症患者预后与肝免疫稳态恢复及肝功能改善密切相关。我们前期研究显示Tim-3信号双向调控了肝内枯否-NKT免疫反馈调节环，维护了肝脏免疫稳态。但这些研究多为现象的观察，对其深层机制了解不多。本项目深入研究脓毒症后Tim-3信号表达调控，及α-乳糖干预Tim-3信号通路改善脓毒症后肝免疫紊乱的潜在机制。我们的研究结果提示： Tim-3在NKT细胞中上调，并与脓毒症患者的细胞凋亡相关. 脓毒症时肝脏NKT细胞中Tim-3的表达以双相模式增强。NKT细胞上Tim-3的表达与脓毒症患者的疾病严重程度和预后相关。Tim-3表达和肝内NKT细胞的表型特征与功能状态密切相关，包括细胞活化、细胞因子产生和增殖等。LPS刺激的DC细胞分泌的IL-12增强了脓毒症时肝内NKT细胞表达Tim-3。α-乳糖干预减轻脓毒症诱导的细胞因子风暴。α-乳糖抑制Galectin-9诱导的DC细胞产生IL-12,从而下调脓毒症时Tim-3的表达及减少了NKT细胞凋亡。α-乳糖干预Tim-3信号通路可以减少脓毒症时的肝脏炎症和肝脏损害。该研究加深了我们对脓毒症后肝免疫调控机制的认识，探索新型免疫干预治疗措施，以及有助于后期临床转化以提高脓毒症患者预后。