Nelfinavir/ritonavir reduces acinar injury but not inflammation during mouse caerulein pancreatitis.
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.
Singh
Vijay P
VP
Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Bren
Gary D
GD
Algeciras-Schimnich
Alicia
A
Schnepple
David
D
Navina
Sarah
S
Rizza
Stacey A
SA
Dawra
Rajinder K
RK
Saluja
Ashok K
AK
Chari
Suresh T
ST
Vege
Santhi S
SS
Badley
Andrew D
AD
D000681:Amylases / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002108:Ceruletide; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D019888:Nelfinavir / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019438:Ritonavir / Q000494:pharmacology*; D014357:Trypsin / Q000378:metabolism
D017320:HIV Protease Inhibitors; D018836:Inflammation Mediators; D002108:Ceruletide; D045304:Cytochromes c; D000681:Amylases; D014357:Trypsin; C505410:Casp3 protein, rat; D053148:Caspase 3; D019888:Nelfinavir; D019438:Ritonavir