甘草皂苷抑制HMGB1预防ERCP术后胰腺炎的机制研究

Acute pancreatitis remains the most common and serious complication after ERCP, restricts the development of ERCP techniques. Mechanisms of the inflammatory reaction in the onset of post-ERCP pancreatitis(PEP) are still unclear. Pharmacologic prevention for PEP also needs to be researched. High mobility group box-1 protein(HMGB1), as a nuclear protein expressed by almost all mammalian cells, is a crucial cytokine of the inflammatory response. HMGB1 can be actively secreted from inflammatory cells or passively released by necrotic cells. Receptor for advanced glycation end products(RAGE) and Toll-like receptor 4(TLR4) mediate the pro-inflammtory properties of HMGB1. Glycyrrhizin, produced by the licorice plant, inhibits the pro-inflammtory activities of HMGB1. The study project is as follows: 1.The anti-inflammtory mechanisms of glycyrrhizin are investigated in vitro, including the effect of glycyrrhizin on the production of HMGB1 by pancreatic acinar cells and the binding of HMGB1 to RAGE or TLR4 expressed on macrophages. 2.A model of PEP in rats is made to evaluate the effect of glycyrrhizin on the expression of HMGB1, RAGE and TLR4 in the pancreas and the severity of PEP. 3.Peripheral blood samples of patients with PEP and post-ERCP hyperamylasemia are taken to confirm the expression of HMGB1, sRAGE and TLR4. This study will provide the experimental basis for pharmacologic prevention of PEP using glycyrrhizin.

ERCP术后胰腺炎(PEP)是ERCP最常见、最严重的并发症，制约ERCP技术发展。PEP发病中炎症反应机制仍未完全阐明，药物预防措施也有待研究。高迁移率族蛋白B1(HMGB1)是普遍存在于哺乳动物细胞内的核蛋白，介导炎症的关键细胞因子，由炎细胞主动或坏死细胞被动释放，可通过晚期糖基化终末产物受体(RAGE)、Toll样受体-4(TLR4)发挥促炎效应。甘草皂苷是甘草的主要成分，可抑制HMGB1的促炎活性。本课题拟开展下述研究:1）体外试验研究甘草皂苷是否可抑制胰腺腺泡细胞释放HMGB1，影响HMGB1与巨噬细胞RAGE、TLR4结合而发挥抗炎作用；2）建立大鼠PEP模型，观察甘草皂苷是否可影响HMGB1、RAGE、TLR4 的表达而减轻PEP；3）在PEP、ERCP术后高淀粉酶血症患者血标本中，验证HMGB1、sRAGE、TLR4的表达变化。为使用甘草皂苷作为预防PEP药物提供实验基础。