The potential effect of proteasome inhibitor PS-341 on severe acute pancreatitis detected by positron emission tomography in ICR mice.
BACKGROUND
Severe acute pancreatitis is a life threatening disease with a high rate of mortality, and its treatments are still controversial. The purpose of this study is to investigate the potential effects of proteasome inhibitor PS-341 on severe acute pancreatitis induced by cerulein and lipopolysaccharide in mice.


METHODS
Severe acute pancreatitis was induced by seven intraperitoneal injections of 50 ug/kg cerulein at hourly intervals and one injection of 10mg/kg lipopolysaccharide in mice. Thirty min before the administration of lipopolysaccharide, mice were treated either with PS-341 or vehicle. The severity of acute pancreatitis was then evaluated by serum and pancreatic biochemical assays as well as histologic examination. Positron emission tomography (PET) was used for the first time to determine the therapeutic effects of interventions in situ.


RESULTS
PS-341 significantly inhibited NF-kappaB activation, while the pancreatic cell apoptosis was significantly enhanced, resulting in the improved parameters such as serum amylase, C-reactive protein, lactate dehydrogenase, interleukin-1beta, interleukin-6, and pancreatic myeloperoxidase activity. Accordingly, pancreatic damage, including inflammatory cell infiltration, hemorrhage, and necrosis, was markedly reduced. (18)F-fluorodeoxyglucose-positron emission tomography demonstrated that PS-341 significantly reduced the uptake of (18)F-fluorodeoxyglucose within the pancreas.


CONCLUSIONS
These observations demonstrate that PS-341 was able to significantly reduce the severity of acute pancreatitis induced by cerulein and lipopolysaccharide in mice. The potential effect is associated with the inhibition of NF-kappaB activation and increased pancreatic cell apoptosis within the pancreas. (18)F-fluorodeoxyglucose-positron emission tomography could be a sensitive and promising means in evaluating the therapeutic effect and adjusting medical interventions for pancreatitis.
Dong
Xin
X
Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
Zhan
Yin Chu
YC
Jiang
Ren Ya
RY
Xie
Qiu Ping
QP
Peng
Jia Ping
JP
Wang
Jing
J
Gao
Shun Liang
SL
Wu
Yu Lian
YL
D000681:Amylases / Q000097:blood; D000818:Animals; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002097:C-Reactive Protein / Q000378:metabolism; D002108:Ceruletide / Q000008:administration & dosage; D005260:Female; D007249:Inflammation / Q000000981:diagnostic imaging / Q000473:pathology; D053583:Interleukin-1beta / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D051379:Mice; D008813:Mice, Inbred ICR; D010195:Pancreatitis / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D049268:Positron-Emission Tomography; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D011859:Radiography
D001897:Boronic Acids; D053583:Interleukin-1beta; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D002108:Ceruletide; D002097:C-Reactive Protein; D007770:L-Lactate Dehydrogenase; D000681:Amylases