凝血功能障碍是脓毒症重要发病机制之一，血管内皮细胞功能紊乱是其关键环节。人α-防御素1-3（HNP1-3）是机体在感染等刺激下由中性粒细胞释放的阳离子抗菌肽，具有杀菌和免疫调节等功能。最新研究发现HNP1-3能加速纤维蛋白的聚集、促进血栓形成。我们前期研究已证实转基因小鼠脓毒症后高浓度HNP1-3能引起血管内皮细胞焦亡，导致组织损伤加重、死亡率增加；进一步预实验发现HNP1-3高表达小鼠脓毒症后血浆组织因子微粒（TF-MPs）的含量较野生小鼠明显升高，重要脏器中纤维蛋白沉积与血栓增多；此外，高浓度HNP1-3引起活化的内皮细胞GSDME水平增加。因此我们提出假设：高浓度HNP1-3可能通过调控内皮细胞TF-MPs释放水平，介导脓毒症凝血功能障碍的发病过程。本项目拟从整体、细胞和分子水平证实该科学假设，阐明高浓度HNP1-3调控内皮细胞释放TF-MPs的具体信号，为脓毒症免疫防治提供新靶标。

Coagulopathy is one of the important pathophysiologic hallmarks in sepsis. The vascular endothelial cell dysfunction is a key contributor to the pathogenesis of coagulopathy. The α-defensins, human neutrophil peptides(HNPs) 1-3, is a cationic antimicrobial peptide released from neutrophils in response to phagocytic stimuli such as infection. HNP1-3 have multiple functions in host defense and inflammation, including antimicrobial activities and immunomodulatory effects. In the latest study, HNP1-3 promote thrombosis by altering fibrin formation, structure, and stability. Our previous studies have confirmed that the transgenic mice with high HNP protein levels have more severe sepsis-related vital organ damage and mortality than the wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. In the pilot study, we also found that the mice with high HNP protein levels have more tissue factor microparticles(TF-MPs) in plasma and more fibrin deposition and thrombus in tissues than the wild-type mice. In addition, a higher concentration of HNP1-3 could activate more GSDME in primed endothelial cell line. Thus, we speculate that HNP1-3 will be involved in the pathogenesis of sepsis-induced coagulopathy via regulating the release of TF-MPs. The present project will, from the systemic, cellular and molecular levels, analyze the role of higher concentration of HNP1-3 in sepsis-induced coagulopathy via regulating TF-MPs in pyroptotic endothelial cells and sebsquent to explore the signal pathway how a higher concentration of HNP1-3 regulate TF-MPs releasing. This study will provide new targets in the management of sepsis.