NELFINAVIR/RITONAVIR REDUCE ACINAR INJURY IN MOUSE CAERULEIN PANCREATITIS

Abstract

Introduction: The mechanisms leading to the extensive pancreatic acinar cell death seen in mouse caerulein pancreatitis are unclear. Permeability transition pore (PTP) mediated mitochondrial dysfunction occurs in the later part in both apoptotic and necrotic pathways. We have previously shown that the HIV protease inhibitor (PI) Nelfinavir prevents PTP opening- thus preventing cytochrome C leakage and improving survival in mouse models of sepsis, hepatitis and stroke. We thus studied its effects on caerulein induced acute pancreatitis in mice. Methods: Pancreatitis was induced in 20 g C57bl/6 male mice by hourly intraperitoneal (IP) injections of 50 mcg/kg caerulein (0.1 ml) for 12 hours. Controls received hourly IP injections of 0.1 ml saline. Starting 25 hours prior to induction of pancreatitis, the prophylaxis group received nelfinavir (125 mg/kg) and ritonavir (13 mg/kg) dissolved in 0.1 ml water and the vehicle group was given 0.1 ml water. Three such doses were given as 8 hourly gavage feeds. Mice were sacrificed 1 hour after the last injection or 30 minutes after one injection for trypsin activity. Various parameters were measured as previously described (J Clin Invest. 2001 Nov;108(9):1387-95). Lung injury was assessed histologically and apoptosis was measured by TUNEL. Results: Mice pretreated with PI had a reduction in pancreatic acinar injury at 12 hours (26.8% vs. 7.6%, p < 0.005), in TUNEL positive acinar cells (<0.0005) and serum amylase (<0.05). Trypsin activity was not reduced and the extent of pancreatic or lung infiltration by neutrophils, and pancreatic edema were unaffected. Conclusions: The mechanisms of cell death in pancreatitis may be in part distinct from those leading to local and systemic inflammation. Our data suggest that acinar cell injury subsequent to trypsinogen activation results from mitochondrial dysfunction, and PI prophylaxis targeting the PTP may be beneficial in situations where the pancreas is predisposed to acinar injury such as high risk ERCP procedures and/or situations with recurrent acute pancreatitis.