HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas

We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-gamma dimer (Fib-gamma D) and hypoxia, affect the severity of acute pancreatitis (AP) in mice. Pancreata of mice with AP induced by administration of cerulein or by L-arginine, or from patients with pancreatitis, had increased deposition of Fib-gamma D compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-gamma D formation. Cerulein administration resulted in activation and stabilization of hypoxiainducible factor-1 alpha(HIF1 alpha) in pancreata of oxygendependent degradation domain-luciferase HIF1 alpha reporter mice. Cerulein also led to induction of genes regulated by HIF1 alpha, including Vegfa and Ero1 alpha, before evidence of Fib-gamma D deposition or histologic features of AP. Expression of tissue factor, which is regulated by vascular endothelial growth factor, also increased following cerulein administration. Mice with acinar cell-specific disruption of Hif1a (Hif1a(Ac-/-)) developed spontaneous endoplasmic reticulum stress and less severe AP, but did not accumulate Fib-gamma D following administration of cerulein. Feeding mice increased pancreatic expression of HIF1 alpha, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1 alpha has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation.