Submitted on November 5, 2008
Revised on February 24, 2009
Accepted on March 4, 2009
Nelfinavir/Ritonavir Reduces Acinar Injury But Not Inflammation During Mouse Caerulein Pancreatitis
Vijay P Singh1, Gary D. Bren2, Alicia Algeciras-Schimnich1, David Schnepple1, Sarah Navina3, Stacey A Rizza1, Rajinder K. Dawra3, Ashok K Saluja3, Suresh T Chari1, Santhi S Vege1, and Andrew D. Badley2*
1 Mayo Clinic
2 Mayo Clinic College of Medicine
3 University of Minnesota
* To whom correspondence should be addressed. E-mail: Badley.Andrew{at}mayo.edu.
Background: There is no clinical treatment which reduces acinar injury during pancreatitis. 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. Methods: The effect of NFV/RTV or vehicle on caerulein induced pancreatitis in mice was compared by measuring changes in mitochondrial membrane potential (MMP) in vitro and cytochrome C leakage in vivo. Histologic and inflammatory makers were also compared. Results: 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, pancreatic and lung inflammation were unaffected. Conclusions: NFV/RTV reduces pancreatic injury and acinar cell death in experimental mouse caerulein induced pancreatitis, but does not impact inflammation.
