We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-γ dimer (Fib-γD) 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-γD compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-γD formation. Cerulein administration resulted in activation and stabilization of hypoxia-inducible factor-1α (HIF1α) in pancreata of oxygen-dependent degradation domain–luciferase HIF1α reporter mice. Cerulein also led to induction of genes regulated by HIF1α, including Vegfa and Ero1a, before evidence of Fib-γD 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-γD following administration of cerulein. Feeding mice increased pancreatic expression of HIF1α, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1α has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation.

我们调查了胰腺内凝血，纤维蛋白原-γ二聚体（Fib-γD）沉积和缺氧是否影响小鼠急性胰腺炎（AP）的严重程度。与对照胰脏相比，通过施用青霉素或L-精氨酸或患有胰腺炎的患者诱发的患有AP的小鼠的胰脏中Fib-γD的沉积增加。肝素的给药可以保护小鼠免受青霉素诱导的AP的侵害，并防止Fib-γD的形成。施用铜绿蛋白可导致氧依赖性降解域荧光素酶HIF1α报告基因小鼠胰腺中的缺氧诱导因子-1α（HIF1α）活化和稳定。Cerulein还诱导了受HIF1α调控的基因，包括Vegfa和Ero1a，在没有Fib-γD沉积或AP的组织学特征的证据之前。施用青霉素后，受血管内皮生长因子调节的组织因子的表达也增加。Hif1a（Hif1a ^{Ac – / –}）的腺泡细胞特异性破坏的小鼠发展出自发的内质网应激和较不严重的AP，但在施用铜蓝蛋白后并未积聚Fib-γD。喂养小鼠可增加HIF1α的胰腺表达，表明其在外分泌胰腺中具有生理作用。因此，HIF1α在胰腺内分泌稳态和胰腺内凝血促进的AP进程中具有双重功能。