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Am J Physiol Gastrointest Liver Physiol 296: G1040-G1046, 2009. First published March 12, 2009; doi:10.1152/ajpgi.90642.2008
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INFLAMMATION/IMMUNITY/MEDIATORS

Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis

Vijay P. Singh,1 Gary D. Bren,2 Alicia Algeciras-Schimnich,2 David Schnepple,2 Sarah Navina,4 Stacey A. Rizza,2,3 Rajinder K. Dawra,5 Ashok K. Saluja,5 Suresh T. Chari,1 Santhi S. Vege,1 and Andrew D. Badley1,2,3

1Division of Gastroenterology, 2Division of Infectious Diseases, 3Translational Program in Immunology and Biodefense, Mayo Clinic, Rochester; and 4Department of Pathology, 5Department of Surgery, University of Minnesota, Minneapolis, Minnesota

Submitted 5 November 2008 ; accepted in final form 4 March 2009

There is no clinical treatment that reduces acinar injury during pancreatitis. Human immunodeficiency virus (HIV) protease inhibitors (PI), including nelfinavir (NFV) and ritonavir (RTV), may reduce the rate of pancreatitis in HIV-infected patients. Since permeability transition pore (PTPC)-mediated mitochondrial dysfunction occurs during pancreatitis, and we have shown that PI prevents PTPC opening, we studied its effects in a model of pancreatitis. The effect of NFV plus RTV (NFV/RTV) or vehicle on caerulein-induced pancreatitis in mice was compared by measuring changes in mitochondrial membrane potential in vitro and cytochrome c leakage in vivo. Histological and inflammatory makers were also compared. NFV/RTV improved DiOC6 retention in acini exposed to caerulein in vitro. In vivo NFV prevented cytosolic leakage of cytochrome c and reduced pancreatic acinar injury, active caspase-3 staining, TUNEL-positive acinar cells, and serum amylase (P < 0.05). Conversely, trypsin activity, serum cytokine levels, and pancreatic and lung inflammation were unaffected. NFV/RTV reduces pancreatic injury and acinar cell death in experimental mouse caerulein-induced pancreatitis but does not impact inflammation.

permeability transition pore inhibition; necrosis; apoptosis; protease inhibitors


Address for reprint requests and other correspondence: A. D. Badley, Mayo Clinic, 200 First St. SW, Guggenheim 5, Rochester, MN 55905 (e-mail: badley.andrew{at}mayo.edu)






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