Cerulein-induced chronic pancreatitis does not require intra-acinar activation of trypsinogen in mice.
OBJECTIVE
Premature activation of trypsinogen activation can cause pancreatic injury and has been associated with chronic pancreatitis (CP). Mice that lack intra-acinar activation of trypsinogen, such as trypsinogen-7-null (T(-/-)) and cathepsin B-null (CB(-/-)) mice, have been used to study trypsin-independent processes of CP development. We compared histologic features and inflammatory responses of pancreatic tissues from these mice with those from wild-type mice after the development of CP.


METHODS
CP was induced in wild-type, T(-/-), and CB(-/-) mice by twice-weekly induction of acute pancreatitis for 10 weeks; acute pancreatitis was induced by hourly intraperitoneal injections of cerulein (50 μg/kg × 6). Pancreatic samples were collected and evaluated by histologic and immunohistochemical analyses. Normal human pancreas samples, obtained from the islet transplant program at the University of Minnesota, were used as controls and CP samples were obtained from surgical resections.


RESULTS
Compared with pancreatic tissues from wild-type mice, those from T(-/-) and CB(-/-) mice had similar levels of atrophy, histomorphologic features of CP, and chronic inflammation. All samples had comparable intra-acinar activation of nuclear factor (NF)-κB, a transcription factor that regulates the inflammatory response, immediately after injection of cerulein. Pancreatic tissue samples from patients with CP had increased activation of NF-κB (based on nuclear translocation of p65 in acinar cells) compared with controls.


CONCLUSIONS
Induction of CP in mice by cerulein injection does not require intra-acinar activation of trypsinogen. Pancreatic acinar cells of patients with CP have increased levels of NF-κB activation compared with controls; regulation of the inflammatory response by this transcription factor might be involved in the pathogenesis of CP.
Division of Basic and Translational Research, Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA.
Raghuwansh P
RP
Sah
Vikas
V
Dudeja
Rajinder K
RK
Dawra
Ashok K
AK
Saluja
D061354:Acinar Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D002108:Ceruletide / Q000633:toxicity; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014362:Trypsinogen / Q000378:metabolism*
D002108:Ceruletide; D014362:Trypsinogen