肺血管内皮细胞焦亡在失血性休克后急性肺损伤中的作用及机制

Hemorrhagic shock is the most common surgical shock and often results from trauma and large amount of blood loss during operation. Hemorrhagic shock often renders patients more susceptible to a secondary stimulus (e.g., infection) resulting in development of systemic inflammatory response syndrome and multiple organ dysfunction syndrome by activating and priming the inflammatory process. Acute lung injury is a major component of multiple organ dysfunction syndrome and often serves as a direct cause of patient death. The underlying mechanism of how hemorrhagic shock leads to acute lung injury has yet to be fully determined and there is paucity of efficient target for treatment. Pyroptosis is a caspase-1 dependent programmed cell death and plays an important role in the inflammatory process. In our preliminary studies we demonstrate LPS can induce Nlrp3 inflammasome resembling through TLR4, which leads to caspase-1 activation and pyroptosis of lung endothelial cell. While hemorrhagic shock can significantly augment lung endothelial cell pyroptosis in response for LPS by releasing of HMGB1. Our further observation suggests that RAGE is response for the HMGB1-augmented lung endothelial cell pyroptosis. These findings shed light on the potential important role of endothelial cell pyroptosis in the development of acute lung injury. In the current study we will determine the molecular mechanism of lung endothelial cell pyroptosis and its role in the process of hemorrhagic shock-induced acute lung injury through animal and cell experiments. This study will help revealing the pathogenesis of acute lung injury following hemorrhagic shock and provide novel targets for intervention.

失血性休克患者复苏后常容易受到第二次打击（如感染）而导致全身炎症反应和多器官功能障碍，其中急性肺损伤的发生是导致患者死亡的直接原因之一。目前对失血性休克导致急性肺损伤的发病机制并不完全清楚，因此缺乏有效的防治靶点。细胞焦亡是近期发现的caspase-1依赖的程序性细胞死亡形式，在炎症反应的发生中有重要作用。我们的前期研究发现LPS可通过TLR4激活Nlrp3炎症小体进而活化caspase-1，最终导致肺血管内皮细胞焦亡，而失血性休克可通过释放HMGB1作用于RAGE受体促进和放大LPS诱导的肺血管内皮细胞焦亡，因此对急性肺损伤的形成可能具有十分重要的意义。本研究将进一步通过动物和细胞实验阐明肺血管内皮细胞焦亡发生的分子机制并证实其在失血性休克所致的急性肺损伤中的作用。本研究结果将对揭示失血性休克所致的急性肺损伤的发病机制有重要科学意义，同时为其临床治疗提供新的靶点。

失血性休克患者复苏后常容易受到第二次打击（如感染）而导致全身炎症反应和多器官功能障碍，其中急性肺损伤的发生是导致患者死亡的直接原因之一。目前对失血性休克导致急性肺损伤的发病机制并不完全清楚，因此缺乏有效的防治靶点。本研究证实（1）LPS可通过TLR4 - Nlrp3信号通路诱导肺血管内皮细胞焦亡， 失血性休克可通过HMGB - RAGE信号通路增加LPS诱导的肺血管内皮细胞焦亡。1. LPS依赖TLR4并通过ROS - TXNIP - Nlrp3信号通路诱导肺血管内皮细胞Nlrp3炎症小体的激活以及下游caspase-1的剪切活化。（2）失血性休克-HMGB1在早期便可通过RAGE增加肺内皮细胞内ROS的产生并加重LPS诱导的Nlrp3炎症小体激活。（3）HMGB1通过RAGE和dynamin依赖途径内吞至细胞内，并诱导溶酶体破裂释放并活化CatB，进而造成晚期焦亡小体的合成以及caspase-1的激活。（4）肺内皮细胞焦亡可加重肺部炎症，增加肺损伤严重程度。本研究通过动物和细胞实验阐明肺血管内皮细胞焦亡发生的分子机制并证实其在失血性休克所致的急性肺损伤中的作用。本研究结果揭示失血性休克所致的急性肺损伤的发病机制有重要科学意义，同时为其临床治疗提供新的靶点。