Abstract: Objective To investigate the role of purinergic 2X7 receptor (P2X7R) and its downstream target-NLRP3 inflammasome activation in the process of pancreatic fibrosis in a mouse model of chronic pancreatitis (CP). Methods Forty C57BL/6 mice were randomly divided into normal control group, CP group, P2X7R antagonist oxidized ATP (OxATP) group and brilliant blue G (BBG) group. The chronic pancreatitis model was induced by repeated intraperitoneal injection of the cholecystokinin analogue caerulein with the dose of 50 μg/kg for six weeks. Normal saline, OxATP (20 μL, 300 μmol/L) or BBG (20 μL, 10 μmol/L) were administered for CP group, OxATP group and BBG group for two weeks after the last caerulein injection. Then all mice were sacrificed and the histopathological changes of the pancreas, especially the fibrotic degrees were evaluated by HE stain, fibrosis score, Sirius red staining and α-SMA immunohistochemical stain. The pancreatic P2X7R, NLRP3 and Caspase-1 expressions were detected by immunohistochemistry respectively to compare the changes between the groups, and explore the role of P2X7R-NLRP3 signaling pathway in pancreatic fibrosis. Results Compared with the normal control group, the scores of pancreatic fibrosis and the expressions of P2X7R, NLRP3 and Caspase- 1 in pancreas were significantly increased in CP model group (P＜ 0.05). Compare to CP group, the pancreatic chronic inflammation and the fibrosis indices such as HE fibrosis score, Sirius red staining and α- SMA immunohistochemical stain were ameliorated obviously in OxATP and BBG groups (P＜ 0.05). And expressions of P2X7R, NLRP3 and Caspase-1 in the pancreas were all reduced greatly in both OxATP and BBG groups (P<0.05). Conclusion P2X7R antagonist OxATP and BBG can significantly decrease pancreatic chronic inflammation and fibrosis in the mouse model of CP, which suggests that the blockade of P2X7R NLRP3 inflammasome signaling pathway may represent a novel therapeutic strategy for CP and its fibrotic process.

Key words: pancreatitis, chronic, fibrosis, purinergic P2X7 receptor, nucleotide- binding oligomerization domain like receptor 3, oxidized adenosine triphosphate, brilliant blue G, Caspase-1