胍丁胺经RSK2-IκBα-NF-κB通路PD-PK双向调控治疗脓毒症肝损伤的作用及机制研究

肝损伤是脓毒症最严重的并发症，RSK2-IκBα-NF-κB通路激活介导的炎症反应可加速脓毒症肝损伤，抑制肝脏代谢酶活性，进一步加重脓毒症多器官衰竭。胍丁胺是L-精氨酸经精氨酸脱羧酶（ADC）转化的内源性递质，经胍丁胺酶(AGM)代谢生成多胺类代谢产物，与其发挥协同抗炎作用。团队前期研究发现脓毒症时胍丁胺可经RSK2-IκBα-NF-κB通路减轻炎症反应，但炎症因子风暴可引发ADC活性下降导致胍丁胺生成减少。基于此，我们提出补充胍丁胺是否可经RSK2-IκBα-NF-κB通路逆转炎症因子风暴所致的脓毒症肝损伤，同时打破炎症反应导致的ADC合成酶活性抑制，进而从PD-PK双向调控发挥治疗脓毒症肝损伤的作用。本课题拟采用RSK2表达水平不同的脓毒症肝损伤细胞及动物模型进行胍丁胺药效学及药动学相互作用研究，获得其经RSK2-IκBα-NF-κB通路PD-PK双向调控治疗脓毒症肝损伤的证据。

Liver injury is the severe complications of sepsis. Over-expression of inflammatory cytokine mediated by activation of RSK2-IκBα-NF-κB pathway could accelerate sepsis-induced liver injury and hepatic metabolic enzyme activity, and further aggravate multiple organ failure in sepsis. Agmatine is an endogenous transmitter converted from L-arginine by arginine decarboxylase (ADC). Agmatine is metabolized by Agmatinase(AGM) to produce polyamine metabolites, which could play a synergistic anti-inflammatory role. Our previous research shows that agmatine could alleviate the inflammatory response through the RSK2-IκBα-NF-κB pathway when sepsis occurs, but the ADC activity is reduced due to the inflammatory factors widely expressed and lead to the synthesis of agmatine reduced. Based on the above backgrounds, we propose that the reasonable supplementation of agmatine in the early stage of sepsis could reverse the occurrence of liver injury caused by inflammatory cytokine storm through the RSK2-IκBα-NF-κB pathway, and break down the inhibition of ADC synthesis activity caused by inflammatory regulation disorder, so as to play a role in the treatment of sepsis-induced liver injury through the bi-directional regulation mechanism of PD-PK. In this project, we intended to establish in vitro cells and sepsis animal models with different expression levels of RSK2 to explore its pharmacodynamics and pharmacokinetic interactions, and obtain evidence of the PD-PK bi-directional regulation of Agmatine on sepsis-induced liver injury through the RSK2-IκBα-NF-κB pathway.