AMPK调控HMGB1自分泌诱导的胰腺腺泡细胞pyroptosis在急性胰腺炎发生发展中的作用及机制

Emerging evidence shows that the inflammatory response of pancreatic acinar cells (PACs) is the core event at the early stage of acute pancreatitis (AP), after trypsin center theory has been widely accepted as key pathogenesis of acute pancreatitis. Pyroptosis is discovered as a new kind of programmed cell death, which is termed “inflammatory necrosis” due to the death accompanied by plenty of inflammatory mediators release. Our previous study shows that HMGB1 autocrine mediates PACs pyroptosis induced by cerulein, and AMPK inhibitor upregulates PACs pyroptosis induced by cerulein. Here, we put forward the hypothesis that AMPK regulates PACs pyroptosis through inhibiting HMGB1 release and modulating intracellular signal of pyroptosis; and obesity, hypertriglyceridemia and hyperglycemia aggravates AP via the same mechanism of suppressing AMPK signal. This project will launch in-depth study at cellular, molecular and animal level to verify this hypothesis. It is expected to provide a new way to prevent pancreatitis aggravation, and supply theoretical evidence for clinical treatment using AMPK agonist and HMGB1 antagonism in acute pancreatitis.

在胰酶中心学说统治急性胰腺炎（AP）发病机制数十年后，近年的研究表明胰腺腺泡细胞（PACs）炎症反应才是AP早期的核心事件。Pyroptosis是新发现的一种细胞程序性死亡方式，因为伴有大量炎症因子释放被称为“炎性坏死”。项目组的前期研究发现，高迁移率族蛋白1（HMGB1）自分泌介导了雨蛙素诱导的PACs pyroptosis，AMP活化激酶（AMPK）抑制剂上调雨蛙素诱导的PACs pyroptosis。结合相关研究，项目组提出AMPK通过抑制HMGB1释放和直接通过细胞内信号调控PACs pyroptosis的机制假说，并提出肥胖、高甘油三脂血症和高血糖可能通过抑制AMPK活化这一共同机制导致AP重症化。项目组拟在动物、细胞和分子三个层次上对上述假说展开深入研究。本项目的完成将为制定防止AP重症化的治疗策略提供新的思路，为AMPK激动剂和拮抗HMGB1的治疗在AP中的应用提供理论依据。

在胰酶中心学说统治急性胰腺炎发病机制数十年后，近年的研究表明胰腺腺泡细胞（PACs）炎症反应才是AP早期的核心事件。焦亡是新发现的一种细胞程序性死亡方式，因为伴有大量炎症因子释放被称为“炎性坏死”或“焦亡”。项目组发现雨蛙素通过激活caspase-1（焦亡经典激活途径）诱导胰腺腺泡细胞焦亡；脂多糖（LPS）通过激活caspase-11（焦亡非经典激活途径）上调雨蛙素诱导的PACs焦亡。高迁移率族蛋白1介导了雨蛙素和LPS诱导的胰腺腺泡细胞焦亡；AMPK激动剂AICAR减轻雨蛙素诱导的PACs焦亡和LPS联合雨蛙素诱导的PACs焦亡；AMPK抑制剂compound c加重雨蛙素诱导的PACs焦亡和LPS联合雨蛙素诱导的PACs焦亡。在动物实验中，AMPK激动剂AICAR减轻两种重症急性胰腺炎模型（雨蛙素诱导的肥胖小鼠重症急性胰腺炎模型和LPS联合雨蛙素诱导的小鼠重症急性胰腺炎模型）胰腺和肺损伤，改善生存率；AMPK抑制剂compound c加重两种重症急性胰腺炎小鼠胰腺和肺损伤，降低生存率。上述结果证实，AMPK通过调控经典和非经典途径诱导的胰腺腺泡细胞焦亡，影响重症急性胰腺炎小鼠疾病严重程度。本项目的完成为制定防止AP重症化的治疗策略提供了新的思路，为AMPK激动剂和拮抗HMGB1的治疗在AP中的应用提供理论依据。