STAT3介导组织因子启动的脓毒症凝血系统失衡的机制研究

Sepsis is a systemic inflammatory response caused by infection and activates the coagulation system. In severe sepsis, massive tissue factor (TF)activates the coagulation system, anticoagulation system and fibrinolytic system. Subsequently, the anticoagulants such as tissue factor pathway inhibitor (TFPI) are consumed and the activated fibrinolytic system is inhibited.The coagulation system is disordered, which finally results in a hypercoagulable state. TF is the key factor that initiates the coagulation system. Its expression is mainly mediated by nuclear factor-κB (NF-κB) and extracellular regulated protein kinases (ERK) signaling pathways. Our previous research showed that STAT3 inhibitors can inhibit the activation of NF-κB and ERK1/2 and down-regulate the expression of TF in macrophages stimulated by lipopolysaccharide. It has been reported that STAT3 promotes both NF-κB and ERK pathways with each other. This project is designed to inhibit STAT3 to down-regulate the expression of TF in macrophages and endothelial cells mediated by ERK and NF-κB signaling pathways. It will improve the disorder of septic coagulation system, protect organ function and improve the survival rate. This study will clarify the mechanism of STAT3 in regulation of septic coagulation system, and provide new thinking for exploring new clinical interventions.

脓毒症是感染导致的全身炎症反应，同时激活凝血系统。严重脓毒症大量产生的组织因子（TF）激活凝血，抗凝，纤溶系统。随即组织因子途径抑制物（TFPI）等抗凝物质消耗性减少，激活的纤溶系统受到抑制，机体凝血系统失衡，最终导致高凝状态。其中TF是凝血系统激活的的启动因子，核因子κB（NF-κB）和细胞外调节蛋白激酶（ERK）是促进TF表达的主要信号通路。我们前期研究发现，信号传导与活化转录因子3（STAT3）抑制剂可抑制脂多糖刺激下巨噬细胞中NF-κB和ERK1/2的激活，下调TF的表达。已有研究表明，STAT3与NF-κB，ERK均存在相互促进作用。本项目设计靶向抑制STAT3，介导ERK，NF-κB等信号通路下调巨噬细胞和内皮细胞TF的表达。改善脓毒症凝血系统失衡状态，保护器官功能，提高生存率。阐明STAT3在脓毒症凝血系统失衡调节中的机制，为探索新的临床干预途径提供新思路。

背景：脓毒症是一种由感染引起的侵袭性和危及生命的器官功能障碍，在全球范围内发病率和死亡率都很高。感染相关炎症和凝血促进败血症不良结局的进展。在这里，我们报道了STAT3的磷酸-Tyr705（pY-STAT3）在败血症中导致全身炎症和凝血紊乱。.方法：分别用BP-1-102、Napaucasin或对照治疗盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠，然后评估全身炎症、凝血反应、肺功能、肾功能和存活率。将人肺微血管内皮细胞（HPMECs）和Raw264.7细胞暴露于脂多糖（LPS），并对pY-STAT3进行药理学或基因抑制。评估细胞的炎症和凝血因子表达、细胞功能和信号传导。.结果：BP-1-102对pY-STAT3表达的药理学抑制降低了脓毒症小鼠的促炎因子，抑制了凝血激活，减轻了肺损伤和肾损伤，提高了存活率。对pY-STAT3进行药理学或点突变抑制，发现IL-6、JAK2/STAT3、NF-κB和MAPK信号通路减少LPS诱导的巨噬细胞细胞因子的产生并保护肺内皮细胞。此外，脓毒症诱导的促凝血指标（如组织因子（TF）、凝血酶抗凝血酶复合物（TAT）和D-二聚体）的增加被pY-STAT3抑制下调。.结论：结果揭示了pY-STAT3在脓毒症期间调节炎症反应和凝血紊乱中的治疗作用。