机械通气对已有损伤肺组织的影响一直是临床医师关注的重点。在前期工作中，我们通过建立“二次打击”模型，发现当存在内毒素血症时，机械通气是炎症性肺损伤的危险因素。通过基因芯片生物信息学分析结合动物和细胞水平工作，我们发现机械通气可增加肺组织中Sphingosine kinase 1（SphK1）的表达，而SphK2的表达并无明显改变；此外SphK1抑制剂可减轻肺血管内皮焦亡和机械通气肺损伤(VILI)。通过免疫沉淀和高通量蛋白质组学方法结合细胞水平工作，我们发现SphK1可能通过结合PKM2, AMPK α1和Annexin A2参与肺血管内皮焦亡和肺损伤。由此我们推测机械牵拉增加SphK1的表达与肺血管内皮焦亡之间具有相关性；并从上述三种蛋白参与的信号通路等方面探讨相关机制。本项目将有助于阐明VILI的发生机制，并从应用SphK1抑制剂治疗VILI的角度为临床治疗提供新思路。

The effect of mechanical ventilation (MV) on pre-existed lung injury has always been the focus of clinicians. In our preliminary study, we found that the combination treatment of LPS and mechanical ventilation resulted in molecular and histological evidence of lung injury, while MV or LPS alone could only result in mild changes not meeting the criteria for ALI or ARDS. By using bioinformatics analysis of three microarray studies of ventilated mouse lung samples, we found that it was Sphingosine kinase 1（SphK1）, but not SphK2, was significantly elevated in the lung tissues of mice subjected to the two stimuli of LPS+MV. In addition, we found that SphK1 inhibitor could attenuate both in vivo mechanical ventilation-induced acute lung injury (VILI) mouse models and in vitro cyclic stretch-treated pulmonary vascular endothelial cells via inhibiting the pyroptosis of endothelial cells. In corporation with immunoprecipitation (IP) and high-throughput proteomics studies, we screened potential target proteins that may interact with SphK1. It was found PKM2, AMPK α1 and Annexin A2 may be involved in the procedure of endothelial pyroptosis. Therefore, we speculated that the expression of SphK1 might be correlated with the severity of pulmonary vascular endothelial pyroptosis, and then investigate the mechanisms play central roles in the protective effect of SphK1 inhibitor against VILI from the signal pathway of the three proteins involved. The present study will provide reliable evidence to elucidate the mechanisms involved in the pathogenesis of VILI. SphK1 inhibitor may become one of the future treatment options of VILI.