Age-dependent effects of UCP2 deficiency on experimental acute pancreatitis in mice.
Reactive oxygen species (ROS) have been implicated in the pathogenesis of acute pancreatitis (AP) for many years but experimental evidence is still limited. Uncoupling protein 2 (UCP2)-deficient mice are an accepted model of age-related oxidative stress. Here, we have analysed how UCP2 deficiency affects the severity of experimental AP in young and older mice (3 and 12 months old, respectively) triggered by up to 7 injections of the secretagogue cerulein (50 μg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of alpha-amylase, intrapancreatic trypsin activation and levels of myeloperoxidase (MPO) in lung and pancreatic tissue. Furthermore, in vitro studies with pancreatic acini were performed. At an age of 3 months, UCP2-/- mice and wild-type (WT) C57BL/6 mice were virtually indistinguishable with respect to disease severity. In contrast, 12 months old UCP2-/- mice developed a more severe pancreatic damage than WT mice at late time points after the induction of AP (24 h and 7 days, respectively), suggesting retarded regeneration. Furthermore, a higher peak level of alpha-amylase activity and gradually increased MPO levels in pancreatic and lung tissue were observed in UCP2-/- mice. Interestingly, intrapancreatic trypsin activities (in vivo studies) and intraacinar trypsin and elastase activation in response to cerulein treatment (in vitro studies) were not enhanced but even diminished in the knockout strain. Finally, UCP2-/- mice displayed a diminished ratio of reduced and oxidized glutathione in serum but no increased ROS levels in pancreatic acini. Together, our data indicate an aggravating effect of UCP2 deficiency on the severity of experimental AP in older but not in young mice. We suggest that increased severity of AP in 12 months old UCP2-/- is caused by an imbalanced inflammatory response but is unrelated to acinar cell functions.
Division of Gastroenterology, Department of Medicine II, University Medicine Rostock, Rostock, Germany.
Sarah
S
Müller
Division of Gastroenterology, Department of Medicine II, University Medicine Rostock, Rostock, Germany.
Hannah
H
Kaiser
Division of Medical Biology, University Medicine Rostock, Rostock, Germany.
Burkhard
B
Krüger
Division of Gastroenterology, Department of Medicine II, University Medicine Rostock, Rostock, Germany; Department of Neurology, University Medicine Rostock, Rostock, Germany.
Brit
B
Fitzner
Division of Gastroenterology, Department of Medicine II, University Medicine Rostock, Rostock, Germany; Oscar-Langendorff-Institute of Physiology, University Medicine Rostock, Rostock, Germany.
Falko
F
Lange
Division of Gastroenterology, Department of Medicine II, University Medicine Rostock, Rostock, Germany.
Cristin N
CN
Bock
Institute of Pathology, University Medicine Rostock, Rostock, Germany.
Horst
H
Nizze
Department of Dermatology, University of Lübeck, Lübeck, Germany.
Saleh M
SM
Ibrahim
Institute for Biostatistics and Informatics in Medicine and Ageing Research, University Medicine Rostock, Rostock, Germany.
Georg
G
Fuellen
Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany; Stellenbosch Institute for Advanced Study, Wallenberg Research Centre at Stellenbosch University, Stellenbosch, South Africa.
Olaf
O
Wolkenhauer
Division of Gastroenterology, Department of Medicine II, University Medicine Rostock, Rostock, Germany.
Robert
R
Jaster
D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002108:Ceruletide; D005260:Female; D005978:Glutathione / Q000097:blood; D007473:Ion Channels / Q000172:deficiency* / Q000235:genetics; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000097:blood; D012720:Severity of Illness Index; D014357:Trypsin / Q000378:metabolism; D000071246:Uncoupling Protein 2; D000516:alpha-Amylases / Q000097:blood
D015415:Biomarkers; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D002108:Ceruletide; D009195:Peroxidase; D000516:alpha-Amylases; D014357:Trypsin; D005978:Glutathione