基于“肺与大肠相表里”理论对ATF4/CEBPβ-NLRP3炎性小体信号通路在急性胰腺炎肺损伤发病机制中的作用及清胰汤干预的研究

急性胰腺炎肺损伤（APALI）是重症急性胰腺炎早期最常见最严重的并发症，发病机制亟待阐明。近期肺泡巨噬细胞NLRP3炎性小体活化及细胞焦亡备受关注。课题组前期研究发现：①NLRP3炎性小体在APALI肺组织中激活并介导肺泡巨噬细胞焦亡的发生；②转录组学筛选出的ATF4和CEBPβ基因在APALI大鼠肺组织中高表达，清胰汤对两者具有明显抑制作用；③NR8383巨噬细胞过表达ATF4基因，促进NLRP3炎症小体活化及IL-1β的表达。结合文献分析推测：ATF4和CEBPβ基因可能协同作用促进NLRP3炎性小体的活化，诱导肺泡巨噬细胞焦亡，产生强烈炎性反应，加剧肺损伤。本项目拟通过动物模型和体外细胞学实验，应用RNAscope原位杂交、病毒转染、免疫共沉淀等方法探究“ATF4/CEBPβ-NLRP3炎性小体”信号通路在APALI发病机制中的作用，揭示“肺与大肠相表里”的科学内涵及清胰汤干预机制。

Acute pancreatitis-associated lung injury (APALI) is the most common and severe complication during the early stage of severe acute pancreatitis (SAP). Its pathogenesis needs further research. In recent years, NLRP3 inflammasome-mediated alveolar macrophages' pyroptosis attracted lots of attention. Previous studies from our group have shown that: ①NLRP3 inflammasome was activated in lung tissue of APALI and mediated the pyroptosis of alveolar macrophage; ②The up-regulated ATF4 and CEBPβ in lung tissue of APALI can be significantly decreased by Qingyi decoction (QYD) ; ③Overexpression ATF4 can significantly promote the level of NLRP3 and IL-1β in lung macrophage NR8383. Combined with the literatures, we speculated that ATF4 and CEBPβ might jointly participate in the activation of NLRP3 inflammasome and mediate lung injury caused by alveolar macrophages' pyroptosis during APALI. We construct a APALI rat model and vitro cell model, and perform multi-methods (such as RNAscope, virus transfection, co-immunoprecipitation etc.) to clarify the critical role of "ATF4/CEBPβ-NLRP3" signal pathway on regulating the pyroptosis of alveolar macrophages in SAP and to reveal the biological basis of “exterior-interior relation between lung and large intestine” and the therapeutical effects of QYD.