Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

Abstract

Background & Aims 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 histological features and inflammatory response of pancreatic tissues from these mice to those from wild-type after 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 caerulein (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, histo-morphologic 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 caerulein. Pancreatic tissues samples from patients CP had increased activation of NF-B (based on nuclear translocation p65 in acinar cells) compared with controls. Conclusion Induction of CP in mice by caerulein 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 pathogenesis of CP.

Endoplasmic Reticulum Stress Is Chronically Activated in Chronic Pancreatitis

“…Trypsinogen activation is known to peak at about 30 min after caerulein injection (6,27,28), which was confirmed in WT mice. Trypsinogen activation was not observed in T Ϫ/Ϫ mice ( Fig.…”

“…Comparable features of CP were seen in WT and T Ϫ/Ϫ mice (6). Histological features are demonstrated in H&E-stained sections in Fig.…”

“…) Mice-These mice were generated in C57BL/6 background by targeted deletion of trypsinogen-7 gene as described by us previously (5,6).…”

“…2A). The time course of trypsinogen activation during caerulein-induced pancreatitis and its absence in T Ϫ/Ϫ as well as the absence of activation of other digestive proteases (elastase and chymotrypsinogen) in T Ϫ/Ϫ have been published separately (6).…”

Genetics of endocrine and exocrine diseases of the pancreas

“…In our experiments we used unstimulated mouse pancreas and it is possible, even likely, that upon hormonal stimulation, the trypsinogen expression pattern may change, as shown previously for rat p23, the ortholog of mouse T4 and T5, which becomes drastically upregulated upon cerulein stimulation [64]. Marked upregulation of T5 was observed in a knock-out mouse strain deficient in interferon regulatory factor 2 [44].…”