Inhibition of hypoxia-inducible factor-1α alleviates acinar cell necrosis in a mouse model of acute pancreatitis

Hypoxia-inducible factor-1 alpha (Hif1 alpha) is activated in hypoxia and is closely related to oxidative stress, immunity and cell metabolism. Recently, it is reported that Hif1 alpha is involved in atherosclerosis, ischemiareperfusion (I/R) injury, alcoholic liver disease and pancreatic tumors. In this study, we found that Hif1 signal pathway is significantly changed in pancreas of acute pancreatitis (AP) mice. Meanwhile, we verified that the high expression of Hif1 alpha injured pancreatic tissues of cerulean-induced AP mice, which prompting that Hif1 alpha participated in the progress of histopathology on AP. We applied a Hif1 alpha inhibitor PX478 and observed that it could alleviate histological injury of pancreas as well as the levels of serum amylase, lipase and proinflammatory cytokine in the murine model of AP induced by caerulein. In addition, PX478 could reduce the formation of necrosome (RIP3 and p-MLKL) and the generation of reactive oxygen species (ROS) in AP mice. Correspondingly, we further confirmed the effectiveness of PX478 in vitro and found that inhibiting Hif1 alpha could mitigated the necrosis of pancreatic acinar cells via reducing the RIP3 and p-MLKL expression and the ROS production. In conclusion, inhibiting Hif1 alpha could protect against acinar cells necrosis in AP, which may provide a new target for the prevention and treatment of AP clinically. (C) 2021 Elsevier Inc. All rights reserved.