重症急性胰腺炎(SAP)病情凶险，合并全身炎性反应综合征(SIRS)和多器官功能障碍(MODS)时死亡率高。炎性细胞凋亡异常是引起SIRS/MODS过度炎症反应的重要机制。程序性死亡受体1/程序性死亡受体配体1(PD1/PD-L1)是机体免疫重要调控分子,在炎性疾病中主要通过影响炎性细胞凋亡发挥作用。团队前期研究发现:PD-L1在SAP胰腺浸润的炎性细胞中呈阳性表达；外周血细胞类群分析显示PD-L1在SAP中性粒细胞中表达上调,且该上调伴随中性粒细胞凋亡水平升高。这些发现提示：在SAP中,存在PD1/PD-L1相关的炎症免疫调控。本项目拟以PD1/PD-L1调控中性粒细胞凋亡为切入点,通过基因敲除/敲入小鼠、体外共培养体系,结合SAP患者外周血检测分析,进一步探索PD1/PD-L1炎性调控对SAP发生发展的影响及机制,结果将对SAP发病提出新的认识,并为SAP治疗提供转化思路和实验依据。

Severe acute pancreatitis (SAP) is a serious disease, the mortality will be high when SAP progresses to systemic inflammatory response syndrome (SIRS) and/or multiple organ dysfunction syndrome (MODS). Abnormal apoptosis of inflammatory cells serves as an important pathogenic mechanism for the excessive inflammatory response of SIRS/MODS. Programmed Death 1/Programmed Death Ligand-l (PD-1/PD-Ll) is a important immune adaptor, and it could negatively regulate immune response of inflammatory diseases by inducing the apoptosis of inflammatory cells. The results from our preliminary study showed: PD-L1 was positively expressed on inflammatory cells which infiltrated in pancreas in SAP ; Flow cytometry analyze showed PD-L1 was upregulated on neutrophils in SAP , and the upregulation of PD-L1 was paralleled with the increased apoptosis rate. Based on these results, we propose that PD-L1 modulated immune response functions in the development AP/SAP. This project will focus on PD-1/PD-L1 regulated neutrophil apoptosis, by using PD-1/PD-L1 gene knockout/knock in mice, co-culture system and peripheral blood analyze of SAP patients, to further explore the exact role and effects of PD-1/PD-L1 regulated inflammation in AP/SAP. The results from this project will provide new insight for SAP pathogenesis, and provide research evidences for further transnational intervention or therapeutic strategy for SAP.