Intracellular activation of trypsinogen in transgenic mice induces acute but not chronic pancreatitis

Abstract

Background and aims Premature intra-acinar activation of trypsinogen is widely considered key for both the initiation of acute pancreatitis and the development of chronic pancreatitis. However, the biological consequences of intracellular trypsinogen activation have not been directly examined. To do so, a new mouse model was developed. Methods Mice were engineered to conditionally express an endogenously activated trypsinogen within pancreatic acinar cells (PACE-trypon). Hallmarks of pancreatitis were determined and findings were correlated to the level (zygosity) and extent (temporal and spatial) of conditional PACE-trypon expression. Furthermore, the impact of acinar cell death in PACE-trypon mice was assessed and compared with a model of selective diphtheria toxin (DT)-mediated induction of acinar apoptosis. Results Initiation of acute pancreatitis was observed with high (homozygous), but not low (heterozygous) levels of PACE-trypon expression. Subtotal (maximal-rapid induction) but not limited (gradual-repetitive induction) conditional PACE-trypon expression was associated with systemic complications and mortality. Rapid caspase-3 activation and apoptosis with delayed necrosis was observed, and loss of acinar cells led to replacement with fatty tissue. Chronic inflammation or fibrosis did not develop. Selective depletion of pancreatic acinar cells by apoptosis using DT evoked similar consequences. Conclusions Intra-acinar activation of trypsinogen is sufficient to initiate acute pancreatitis. However, the primary response to intracellular trypsin activity is rapid induction of acinar cell death via apoptosis which facilitates resolution of the acute inflammation rather than causing chronic pancreatitis. This novel model provides a powerful tool to improve our understanding of basic mechanisms occurring during pancreatitis.

RAB26 coordinates lysosome traffic and mitochondrial localization

“…Acute pancreatitis is caused by inappropriate interaction between lysosomal enzymes and zymogen constituents of secretory granules (Gaiser et al, 2011;Halangk et al, 2000;Saluja et al, 1997), which leads to mitochondrial disorganization (Mareninova et al, 2006;Odinokova et al, 2009). Thus, one mechanism for how MIST1 might suppress acute pancreatitis is by trafficking of lysosomes and mitochondria through RAB26.…”

Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice

“…Nonetheless, genetic alterations that increase or decrease pancreatitis risk were identified in genes that encode digestive proteases or their inhibitors, such as cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (SPINK1), and chymotrypsinogen C (CTRC) (1). Yet intra-acinar trypsinogen activation does not lead to chronic pancreatitis accompanied by fibrosis and inflammation (5). Clearly, other pathways also play critical roles in acute and chronic pancreatitis.…”

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

“…Early events, as described above, show NF-κB as the key initiator to the pro-inflammatory cascade of cytokines and other mediators. However, NF-κB can reduce inflammation by limiting apoptosis, necroptosis, and the inflammasome (Algul et al, 2007;Gaiser et al, 2011;Strowig et al, 2012). In addition, NF-κB activation in inflammatory cells may be quite different, if not opposite, than that observed in acinar cells .…”