Recombinant human activated protein C (Xigris) attenuates murine cerulein-induced acute pancreatitis via regulation of nuclear factor κb and apoptotic pathways

Objectives: Microvascular thrombosis occurs in severe acute pancreatitis (AP). Exploiting this knowledge, we used human recombinant activated protein C (Xigris; Eli Lilly, Indianapolis, Ind) known to preserve microvascular patency, in evaluating the role of Xigris in experimental AP. Methods: In accordance with European union experimentation regulations, AP was induced by hourly injection of cerulein 50 μg/kg body weight over 6 hours. Male rats of median weight of 231 g (range, 176-312 g) were allocated at random into groups: group 1, control; group 2, vehicle; group 3, AP; group 4, cerulein + Xigris at induction of AP and killing at 24 h; and group 5, cerulein + Xigris 24 hours after induction and killing at 48 hours. In addition to enzymatic and histological markers of pancreatic injury, apoptosis, nuclear factor κB (NF-κB) p65/IκB, cytokine response, and endothelial injury were assessed. Western blot quantified by densitometry was used to assess marker of apoptosis and endothelial injury. Results: Cerulein injection resulted in acute necrotizing pancreatitis. Intervention with recombinant human activated protein C did not modify coagulation parameters or lead to hemorrhage but ameliorated pancreatic injury with preservation of IκB and reduction of NF-κB p65 and modulation of apoptosis. Conclusions: Our study indicates that recombinant human activated protein C ameliorates experimental cerulein-induced pancreatitis through apoptotic and NF-κB pathways without causing pancreatic hemorrhage.