Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice

Xianbao Zhan, Jianhua Wan, Guowei Zhang, Lele Song, Fu Gui, Yuebo Zhang, Yinghua Li, Jia Guo, Rajinder K. Dawra, Ashok K. Saluja, Ashley N. Haddock, Lizhi Zhang, Yan Bi, Baoan D Ji

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Intra-acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra-acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. NEW & NOTEWORTHY Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis.

Original languageEnglish (US)
Pages (from-to)G816-G825
JournalAmerican journal of physiology. Gastrointestinal and liver physiology
Volume316
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Chronic Pancreatitis
Pancreatitis
Trypsin
Trypsinogen
Transgenic Mice
Ceruletide
Acinar Cells
Pancreas
Amylases
Heat-Shock Proteins
Atrophy
Edema
Fibrosis
Apoptosis
Serum

Keywords

  • cell death
  • digestive enzyme
  • inflammation
  • mouse models
  • pancreatic disorders

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice. / Zhan, Xianbao; Wan, Jianhua; Zhang, Guowei; Song, Lele; Gui, Fu; Zhang, Yuebo; Li, Yinghua; Guo, Jia; Dawra, Rajinder K.; Saluja, Ashok K.; Haddock, Ashley N.; Zhang, Lizhi; Bi, Yan; Ji, Baoan D.

In: American journal of physiology. Gastrointestinal and liver physiology, Vol. 316, No. 6, 01.06.2019, p. G816-G825.

Research output: Contribution to journalArticle

Zhan, X, Wan, J, Zhang, G, Song, L, Gui, F, Zhang, Y, Li, Y, Guo, J, Dawra, RK, Saluja, AK, Haddock, AN, Zhang, L, Bi, Y & Ji, BD 2019, 'Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice', American journal of physiology. Gastrointestinal and liver physiology, vol. 316, no. 6, pp. G816-G825. https://doi.org/10.1152/ajpgi.00004.2019
Zhan, Xianbao ; Wan, Jianhua ; Zhang, Guowei ; Song, Lele ; Gui, Fu ; Zhang, Yuebo ; Li, Yinghua ; Guo, Jia ; Dawra, Rajinder K. ; Saluja, Ashok K. ; Haddock, Ashley N. ; Zhang, Lizhi ; Bi, Yan ; Ji, Baoan D. / Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice. In: American journal of physiology. Gastrointestinal and liver physiology. 2019 ; Vol. 316, No. 6. pp. G816-G825.
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AU - Zhang, Yuebo

AU - Li, Yinghua

AU - Guo, Jia

AU - Dawra, Rajinder K.

AU - Saluja, Ashok K.

AU - Haddock, Ashley N.

AU - Zhang, Lizhi

AU - Bi, Yan

AU - Ji, Baoan D

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