Src激酶介导中性粒细胞胞外陷阱形成在急性胰腺炎中的作用及机制研究

中性粒细胞胞外陷阱（NETs）介导的过度炎症反应是急性胰腺炎（AP）进展的关键因素之一。NADPH/ROS通路是NETs形成的关键。Src激酶是慢性粒细胞白血病的临床治疗靶点之一，且Src激酶可介导多种信号通路加剧非感染性炎症反应。我们前期研究①RNA-seq显示AP胰腺组织Src激酶显著上调，并验证AP小鼠中性粒细胞Src激酶活化;②Src激酶特异性抑制剂减少AP小鼠NETs生成、降低炎症反应、保护胰腺和肺损伤。我们推测：Src激酶通过NADPH/ROS介导NETs形成，诱发AP过度炎症反应，加剧胰腺和远隔脏器损伤。拟将①观察中性粒细胞Src激酶水平与NETs形成和AP患者预后的相关性；②明确Src激酶对NETs形成、AP炎症反应、胰腺和远隔脏器损伤的调控作用；③阐明Src激酶介导NETs形成的分子机制。本课题从中性粒细胞角度鉴定NETs形成的关键靶点，为AP治疗提供理论依据和实验基础。

The excessive inflammatory response mediated by neutrophil extracellular traps (NETs) is one of the key factors for the progress of acute pancreatitis (AP), and the NADPH / ROS pathway is the key to the formation of NETs. Src kinase is one of the clinical therapeutic targets of chronic myeloid leukemia and it can mediate a variety of signaling pathways to exacerbate non-infectious inflammatory responses. Our previous study found that ①Src kinase in AP pancreas tissue was significantly up-regulated by RNA-seq detection, and verified that Src kinase was activated in neutrophils in AP mice; ②Src kinase specific inhibitor reduced the generation of NETs and inflammatory response in AP pancreatic tissue, also protected the pancreatic tissue injury and related lung injury. Hence, we assume that Src kinase mediates the formation of NETs through NADPH /ROS, so that it could induce the excessive inflammation response of AP and exacerbate the pancreatic tissue and remote organ damage. We will: ① observe the correlation between neutrophil Src kinase level and the formation of NETs and the prognosis of AP patients; ②identify the regulatory role of Src kinase on NETs formation, inflammation response, pancreatic tissue and remote organ damage in AP; ③clarify the molecular mechanism of Src kinase on the formation of NETs. This study will identify a key target for the formation of NETs from the perspective of neutrophil, and provide a theoretical and experimental basis for AP treatment.