title: Intracellular activation of trypsinogen in transgenic mice induces acute but not chronic pancreatitis.
abstract: OBJECTIVE
  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-tryp(on)). Hallmarks of pancreatitis were determined and findings were correlated to the level (zygosity) and extent (temporal and spatial) of conditional PACE-tryp(on) expression. Furthermore, the impact of acinar cell death in PACE-tryp(on) 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-tryp(on) expression. Subtotal (maximal-rapid induction) but not limited (gradual-repetitive induction) conditional PACE-tryp(on) 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.
authors.affiliation: Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gaiser
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Daniluk
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Lilian
authors.initials: L
authors.lastname: Tsou
authors.forename: Jun
authors.initials: J
authors.lastname: Chu
authors.forename: Woojin
authors.initials: W
authors.lastname: Lee
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Longnecker
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.forename: Baoan
authors.initials: B
authors.lastname: Ji
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000235:genetics*; D005786:Gene Expression Regulation; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019283:Pancreatitis, Acute Necrotizing / Q000201:enzymology / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055571:Secretory Pathway; D014362:Trypsinogen / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D014362:Trypsinogen