The role of pancreatic ductal secretion in protection against acute pancreatitis in mice

Petra Pallagi, Zsolt Balla, Anurag K. Singh, Sándor Dósa, B. Iványi, Z. Kukor, Adél Tóth, Brigitte Riederer, Yongjian Liu, Regina Engelhardt, K. Jármay, Andrea Szabó, Ágnes Janovszky, George Perides, V. Venglovecz, József Maléth, T. Wittmann, T. Takács, Mike A. Gray, A. GácserP. Hegyi, Ursula Seidler, Z. Rakonczay

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

OBJECTIVES:: A common potentially fatal disease of the pancreas is acute pancreatitis, for which there is no treatment. Most studies of this disorder focus on the damage to acinar cells since they are assumed to be the primary target of multiple stressors affecting the pancreas. However, increasing evidence suggests that the ducts may also have a crucial role in induction of the disease. To test this hypothesis, we sought to determine the specific role of the duct in the induction of acute pancreatitis using well-established disease models and mice with deletion of the Na/H exchanger regulatory factor-1 that have selectively impaired ductal function. DESIGN:: Randomized animal study. SETTING:: Animal research laboratory. SUBJECTS:: Wild-type and Na/H exchanger regulatory factor-1 knockout mice. INTERVENTIONS:: Acute necrotizing pancreatitis was induced by i.p. administration of cerulein or by intraductal administration of sodium taurocholate. The pancreatic expression of Na/H exchanger regulatory factor-1 and cystic fibrosis transmembrane conductance regulator (a key player in the control of ductal secretion) was analyzed by immunohistochemistry. In vivo pancreatic ductal secretion was studied in anesthetized mice. Functions of pancreatic acinar and ductal cells as well as inflammatory cells were analyzed in vitro. MEASUREMENTS AND MAIN RESULTS:: Deletion of Na/H exchanger regulatory factor-1 resulted in gross mislocalization of cystic fibrosis transmembrane conductance regulator, causing marked reduction in pancreatic ductal fluid and bicarbonate secretion. Importantly, deletion of Na/H exchanger regulatory factor-1 had no deleterious effect on functions of acinar and inflammatory cells. Deletion of Na/H exchanger regulatory factor-1, which specifically impaired ductal function, increased the severity of acute pancreatitis in the two mouse models tested. CONCLUSIONS:: Our findings provide the first direct evidence for the crucial role of ductal secretion in protecting the pancreas from acute pancreatitis and strongly suggest that improved ductal function should be an important modality in prevention and treatment of the disease..

Original languageEnglish
JournalCritical Care Medicine
Volume42
Issue number3
DOIs
Publication statusPublished - Mar 2014

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Pancreatitis
Acinar Cells
Pancreas
Cystic Fibrosis Transmembrane Conductance Regulator
Acute Necrotizing Pancreatitis
Ceruletide
Fluids and Secretions
Taurocholic Acid
Bicarbonates
Knockout Mice
sodium-hydrogen exchanger regulatory factor
Immunohistochemistry
Therapeutics

Keywords

  • acute pancreatitis
  • cystic fibrosis transmembrane conductance regulator
  • Na+/H+ exchanger regulatory factor-
  • pancreatic ducts
  • secretion

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

The role of pancreatic ductal secretion in protection against acute pancreatitis in mice. / Pallagi, Petra; Balla, Zsolt; Singh, Anurag K.; Dósa, Sándor; Iványi, B.; Kukor, Z.; Tóth, Adél; Riederer, Brigitte; Liu, Yongjian; Engelhardt, Regina; Jármay, K.; Szabó, Andrea; Janovszky, Ágnes; Perides, George; Venglovecz, V.; Maléth, József; Wittmann, T.; Takács, T.; Gray, Mike A.; Gácser, A.; Hegyi, P.; Seidler, Ursula; Rakonczay, Z.

In: Critical Care Medicine, Vol. 42, No. 3, 03.2014.

Research output: Contribution to journalArticle

Pallagi, P, Balla, Z, Singh, AK, Dósa, S, Iványi, B, Kukor, Z, Tóth, A, Riederer, B, Liu, Y, Engelhardt, R, Jármay, K, Szabó, A, Janovszky, Á, Perides, G, Venglovecz, V, Maléth, J, Wittmann, T, Takács, T, Gray, MA, Gácser, A, Hegyi, P, Seidler, U & Rakonczay, Z 2014, 'The role of pancreatic ductal secretion in protection against acute pancreatitis in mice', Critical Care Medicine, vol. 42, no. 3. https://doi.org/10.1097/CCM.0000000000000101
Pallagi, Petra ; Balla, Zsolt ; Singh, Anurag K. ; Dósa, Sándor ; Iványi, B. ; Kukor, Z. ; Tóth, Adél ; Riederer, Brigitte ; Liu, Yongjian ; Engelhardt, Regina ; Jármay, K. ; Szabó, Andrea ; Janovszky, Ágnes ; Perides, George ; Venglovecz, V. ; Maléth, József ; Wittmann, T. ; Takács, T. ; Gray, Mike A. ; Gácser, A. ; Hegyi, P. ; Seidler, Ursula ; Rakonczay, Z. / The role of pancreatic ductal secretion in protection against acute pancreatitis in mice. In: Critical Care Medicine. 2014 ; Vol. 42, No. 3.
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AU - Balla, Zsolt

AU - Singh, Anurag K.

AU - Dósa, Sándor

AU - Iványi, B.

AU - Kukor, Z.

AU - Tóth, Adél

AU - Riederer, Brigitte

AU - Liu, Yongjian

AU - Engelhardt, Regina

AU - Jármay, K.

AU - Szabó, Andrea

AU - Janovszky, Ágnes

AU - Perides, George

AU - Venglovecz, V.

AU - Maléth, József

AU - Wittmann, T.

AU - Takács, T.

AU - Gray, Mike A.

AU - Gácser, A.

AU - Hegyi, P.

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AU - Rakonczay, Z.

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N2 - OBJECTIVES:: A common potentially fatal disease of the pancreas is acute pancreatitis, for which there is no treatment. Most studies of this disorder focus on the damage to acinar cells since they are assumed to be the primary target of multiple stressors affecting the pancreas. However, increasing evidence suggests that the ducts may also have a crucial role in induction of the disease. To test this hypothesis, we sought to determine the specific role of the duct in the induction of acute pancreatitis using well-established disease models and mice with deletion of the Na/H exchanger regulatory factor-1 that have selectively impaired ductal function. DESIGN:: Randomized animal study. SETTING:: Animal research laboratory. SUBJECTS:: Wild-type and Na/H exchanger regulatory factor-1 knockout mice. INTERVENTIONS:: Acute necrotizing pancreatitis was induced by i.p. administration of cerulein or by intraductal administration of sodium taurocholate. The pancreatic expression of Na/H exchanger regulatory factor-1 and cystic fibrosis transmembrane conductance regulator (a key player in the control of ductal secretion) was analyzed by immunohistochemistry. In vivo pancreatic ductal secretion was studied in anesthetized mice. Functions of pancreatic acinar and ductal cells as well as inflammatory cells were analyzed in vitro. MEASUREMENTS AND MAIN RESULTS:: Deletion of Na/H exchanger regulatory factor-1 resulted in gross mislocalization of cystic fibrosis transmembrane conductance regulator, causing marked reduction in pancreatic ductal fluid and bicarbonate secretion. Importantly, deletion of Na/H exchanger regulatory factor-1 had no deleterious effect on functions of acinar and inflammatory cells. Deletion of Na/H exchanger regulatory factor-1, which specifically impaired ductal function, increased the severity of acute pancreatitis in the two mouse models tested. CONCLUSIONS:: Our findings provide the first direct evidence for the crucial role of ductal secretion in protecting the pancreas from acute pancreatitis and strongly suggest that improved ductal function should be an important modality in prevention and treatment of the disease..

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