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The Role of Pancreatic Ductal Secretion in Protection Against Acute Pancreatitis in Mice*

Pallagi, Petra PhD1; Balla, Zsolt MSc1; Singh, Anurag K. PhD2; Dósa, Sándor MD3; Iványi, Béla MD, PhD, DSc3; Kukor, Zoltán MD, PhD4; Tóth, Adél MSc5; Riederer, Brigitte PhD2; Liu, Yongjian MSc2; Engelhardt, Regina2; Jármay, Katalin MD, PhD1; Szabó, Andrea MD, PhD6; Janovszky, Ágnes MD6; Perides, George PhD7; Venglovecz, Viktória PhD8; Maléth, József MD1; Wittmann, Tibor MD, PhD1; Takács, Tamás MD, PhD, DSc1; Gray, Mike A. PhD9; Gácser, Attila PhD5; Hegyi, Péter MD, PhD, DSc1; Seidler, Ursula MD, PhD2; Rakonczay, Zoltán Jr MD, PhD, DSc1

doi: 10.1097/CCM.0000000000000101
Online Laboratory Investigations

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.

Supplemental Digital Content is available in the text.

1First Department of Medicine, University of Szeged, Szeged, Hungary.

2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

3Department of Pathology, University of Szeged, Szeged, Hungary.

4Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.

5Department of Microbiology, University of Szeged, Szeged, Hungary.

6Institute of Surgical Research, University of Szeged, Szeged, Hungary.

7Department of Surgery, Tufts Medical Center, Boston, MA.

8Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.

9Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, United Kingdom

* See also p. 757.

Dr. Pallagi, Mr. Balla, and Dr. Singh contributed equally.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

This study was supported by National Development Agency grants (TÁMOP-4.2.2.A-11/1/KONV-2012-0035, TÁMOP-4.2.2-A-11/1/KONV-2012-0052, TÁMOP-4.2.2.A-11/1/KONV-2012-0073), the Hungarian Scientific Research Fund (NF105758 to Z.R., NF100677 to P.H., K101116 to T.T., and PD78087 to V.V.), the Hungarian Academy of Sciences (BO 00174/10/5 to Z.R., and DFG/192 to Z.R. and P.H.), the Deutsche Forschungsgemeinschaft (Se460/13-4, SFB621/C9), the Deutsch-Ungarisches Kooperationsprojekt DFG-436 UNG 113/190/01 to U.S.), and the National Institutes of Health (NIH) (DK 091327). Dr. Rakonczay’s institution received grant support from the Hungarian Scientific Research Fund (NF105758) and the Hungarian Academy of Science (BO00174/10/5). Dr. Rakonczay received support for article research from the Hungarian Scientific Research Fund, Hungarian Academy of Sciences and the National Development Agency. Dr. Perides received support for article research from the NIH (DK:091327-01). Dr. Venglovecz’s institution received grant support from the Hungarian Scientific Research Fund (PD78087). Dr. Maléth’s institution received grant support from the National Development Agency (TAMOP -4.2.2.A-11/1/KONV-2012-0052). Dr. Wittmann’s institution received grant support from the National Development Agency (TAMOP -4.2.2.A-11/1/KONV-2012-0035). Dr. Wittman received support for article research from the Hungarian Scientific Research Fund, and the Hungarian Academy of Sciences (TAMOP -4.2.2.A-11/KONV-2012-0035, TAMOP -4.2.2.A-11/1/KONV-2012- 0052, TAMOP -4.2.2.A-11/KONV-2012-0073). Dr. Takács’ institution received grant support from the National Development Agency and the Hungarian Scientific Research Fund. Dr. Takács received support for article research from the Hungarian Scientific Research Fund, and the Hungarian Academy of Sciences (TAMOP -4.2.2.A-11/KONV-2012-0035, TAMOP - 4.2.2.A-11/1/KONV-2012-0052, TAMOP -4.2.2.A-11/KONV-2012-0073). Dr. Hegyi’s institution received grant support from the Hungarian Scientific Research Fund (NF 100677) and the Hungarian Academy of Science (DFG/192). Dr. Hegyi received support for article research from the Hungarian Scientific Research Fund, Hungarian Academy of Sciences and the National Development Agency. Dr. Seidler’s institution received grant support from Deutsche Forschungsgemeinschaft. Dr. Seidler received support for article research from NIH and Deutsch-Ungarisches Kooperationsprojekt (DFG-436 UNG 113/190/01). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Zoltán Rakonczay, MD, PhD, DSc, First Department of Medicine, University of Szeged, P.O. Box: 427, H-6701 Szeged, Hungary. E-mail: rakonczay.zoltan@med.u-szeged.hu

© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins