NSAIDs非经典途径在急性胰腺炎相关自噬调控中的作用

急性胰腺炎的防治仍为临床难题。申请者前期主持的临床研究表明，ERCP术前应用NSAIDs类药物可减少术后胰腺炎的发生（Lancet，2016）。目前，NSAIDs预防术后胰腺炎已写入多个指南。然而，其是否在各种急性胰腺炎中均有防治价值尚不清楚，相关作用机理也不明确。腺泡细胞的自噬异常是急性胰腺炎发生发展的关键事件。我们前期发现，NSAIDs可能通过促进自噬而抑制胰腺炎症，但调控机制不明。有证据显示，NSAIDs可能通过不依赖COX的非经典途径（AMPK、PLA2和NFκB等）预防胰腺炎。非经典途径在自噬启动、自噬后续炎症等多方面发挥重要调控作用，然而其在NSAIDs促进胰腺炎相关自噬中的具体作用尚需探索。本项目拟前瞻性评估NSAIDs在减少胰腺炎严重程度和复发方面的价值，体内外实验研究NSAIDs通过非经典通路影响胰腺炎相关自噬的分子机制，基于此进行干预，为开发更有效的新防治方法奠定基础。

The prevention and treatment of acute pancreatitis is currently still a clinical problem. Our previous study showed that pre-procedure administration of rectal indomethacin decreased the incidence of post-ERCP pancreatitis (Lancet, 2016). Currently, NSAIDs has been recommended for the prophylacxis of post-ERCP pancreatitis in guidelines. However, the effects of NSAIDs on different kinds of pancreatitis remain elusive. The mechanism of preventing pancreatitis by NSAIDs is unclear yet. Abnormal autophagy of acinal cells is a key step related to acute pancreatitis. Our previous work found that NSAIDs could promote autophagy flux, which might be the reason of reducing pancreatitis. It is unknown how NSAIDs affects the signal of autophagy and then protects pancreas. Previous studies indicated non-canonical pathways (including AMPK, PLA2 and NFκB et al.) instead of canonical COX pathway might be involved in preventing pancreatitis by NSAIDs. The non-canonical pathways had been found to participate in regulating the initiation of autophagy and the following activation of inflammation. The role of promoting autophagy by non-canonical pathways may protect the pancreas with the administraion of NSAIDs. However, this possible mechnism has not been reported. The current project planned to evaluate the values of NSAIDS in decreasing the severity and recurrence of acute pancreatitis prospectively. The molecular mechanisms would be investigated regarding the effects of NSAIDs on pancreatitis-related autophagy through non-canonical pathways. Bsed on the pathway findings and corresponding interferences, we hope to provide more effective and new methods for the prevention and treatment of acute pancreatitis.