Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis

Rajinder Dawra, Raghuwansh P. Sah, Vikas Dudeja, Loveena Rishi, Rupjoyti Talukdar, Pramod Garg, Ashok Saluja

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Background & Aims: 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.

Original languageEnglish (US)
JournalGastroenterology
Volume141
Issue number6
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Fingerprint

Trypsinogen
Pancreatitis
Inflammation
Wounds and Injuries
Acinar Cells
Complement Factor B
Protein Isoforms
Cell Death
Ceruletide

Keywords

  • Inflammatory Response
  • Mouse Model
  • Pancreas
  • Protease
  • PRSS1
  • Regulation

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. / Dawra, Rajinder; Sah, Raghuwansh P.; Dudeja, Vikas; Rishi, Loveena; Talukdar, Rupjoyti; Garg, Pramod; Saluja, Ashok.

In: Gastroenterology, Vol. 141, No. 6, 01.01.2011.

Research output: Contribution to journalArticle

@article{2f7b87e8a4eb4bdf8bd9bbaa42663321,
title = "Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis",
abstract = "Background & Aims: 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.",
keywords = "Inflammatory Response, Mouse Model, Pancreas, Protease, PRSS1, Regulation",
author = "Rajinder Dawra and Sah, {Raghuwansh P.} and Vikas Dudeja and Loveena Rishi and Rupjoyti Talukdar and Pramod Garg and Ashok Saluja",
year = "2011",
month = "1",
day = "1",
doi = "10.1053/j.gastro.2011.08.033",
language = "English (US)",
volume = "141",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "6",

}

TY - JOUR

T1 - Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis

AU - Dawra, Rajinder

AU - Sah, Raghuwansh P.

AU - Dudeja, Vikas

AU - Rishi, Loveena

AU - Talukdar, Rupjoyti

AU - Garg, Pramod

AU - Saluja, Ashok

PY - 2011/1/1

Y1 - 2011/1/1

N2 - Background & Aims: 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.

AB - Background & Aims: 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.

KW - Inflammatory Response

KW - Mouse Model

KW - Pancreas

KW - Protease

KW - PRSS1

KW - Regulation

UR - http://www.scopus.com/inward/record.url?scp=81855228093&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81855228093&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2011.08.033

DO - 10.1053/j.gastro.2011.08.033

M3 - Article

VL - 141

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 6

ER -