title: Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis.
abstract: OBJECTIVE
  The role of trypsinogen activation in the pathogenesis of acute pancreatitis (AP) has not been clearly established.
  
  
  METHODS
  We generated and characterized mice lacking trypsinogen isoform 7 (T7) gene (T(-/-)). The effects of pathologic activation of trypsinogen were studied in these mice during induction of AP with cerulein. Acinar cell death, tissue damage, early intra-acinar activation of the transcription factor nuclear factor κB (NF-κB), and local and systemic inflammation were compared between T(-/-) and wild-type mice with AP.
  
  
  RESULTS
  Deletion of T7 reduced the total trypsinogen content by 60% but did not affect physiologic function. T(-/-) mice lacked pathologic activation of trypsinogen, which occurs within acinar cells during early stages of AP progression. Absence of trypsinogen activation in T(-/-) mice led to near complete inhibition of acinar cell death in vitro and a 50% reduction in acinar necrosis during AP progression. However, T(-/-) mice had similar degrees of local and systemic inflammation during AP progression and comparable levels of intra-acinar NF-κB activation, which was previously shown to occur concurrently with trypsinogen activation during early stages of pancreatitis.
  
  
  CONCLUSIONS
  T7 is activated during pathogenesis of AP in mice. Intra-acinar trypsinogen activation leads to acinar death during early stages of pancreatitis, which accounts for 50% of the pancreatic damage in AP. However, progression of local and systemic inflammation in AP does not require trypsinogen activation. NF-κB is activated early in acinar cells, independently of trypsinogen activation, and might be responsible for progression of AP.
authors.affiliation: Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Dawra
authors.forename: Raghuwansh P
authors.initials: RP
authors.lastname: Sah
authors.forename: Vikas
authors.initials: V
authors.lastname: Dudeja
authors.forename: Loveena
authors.initials: L
authors.lastname: Rishi
authors.forename: Rupjoyti
authors.initials: R
authors.lastname: Talukdar
authors.forename: Pramod
authors.initials: P
authors.lastname: Garg
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Saluja
mesh_terms: D061354:Acinar Cells / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D016923:Cell Death; D004789:Enzyme Activation; D007249:Inflammation / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010195:Pancreatitis / Q000201:enzymology* / Q000473:pathology; D014362:Trypsinogen / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D014362:Trypsinogen