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ResearchIn-Press PreviewCell biologyGastroenterology Open Access | 10.1172/jci.insight.167645

Orai1 calcium channel inhibition prevents progression of chronic pancreatitis

Viktória Szabó,1 Noémi Csákány-Papp,1 Marietta Görög,1 Tamara Madacsy,1 Árpád Varga,1 Aletta Kiss,1 Balint Tel,2 Boldizsár Jójárt,1 Tim Crul,1 Krisztina Dudás,1 Mária Bagyánszki,3 Nikolett Bódi,3 Ferhan Ayaydin,4 Shyam Jee,4 Laszlo Tiszlavicz,5 Kenneth A. Stauderman,6 Sudarshan Hebbar,6 Petra Pallagi,1 and József Maléth1

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Szabó, V. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Csákány-Papp, N. in: JCI | PubMed | Google Scholar

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Görög, M. in: JCI | PubMed | Google Scholar

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Madacsy, T. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Varga, Á. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Kiss, A. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Tel, B. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Jójárt, B. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Crul, T. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Dudás, K. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Bagyánszki, M. in: JCI | PubMed | Google Scholar

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Bódi, N. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Ayaydin, F. in: JCI | PubMed | Google Scholar

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Jee, S. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Tiszlavicz, L. in: JCI | PubMed | Google Scholar

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Stauderman, K. in: JCI | PubMed | Google Scholar |

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Hebbar, S. in: JCI | PubMed | Google Scholar

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Pallagi, P. in: JCI | PubMed | Google Scholar

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

2First Department of Pediatrics, Semmelweis University, Budapest, Hungary

3Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

4Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

5Department of Pathology, University of Szeged, Szeged, Hungary

6CalciMedica, Inc., La Jolla, United States of America

Find articles by Maléth, J. in: JCI | PubMed | Google Scholar |

Published May 25, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.167645.
Copyright © 2023, Szabó et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 25, 2023 - Version history
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Abstract

Patients with recurrent acute pancreatitis (RAP) are at significant risk of developing early chronic pancreatitis (CP), which progresses into irreversible, end-stage CP with severe symptoms. There is no specific therapy in RAP or in early CP that may hinder disease progression. The pathogenesis of CP is complex and involves interactions among multiple cell types, including pancreatic acinar, ductal, and stellate cells (PSC). Therefore, it is pivotal to identify common pathogenic pathways in these cells that could be targeted pharmacologically. The Orai1-mediated store-operated Ca2+ entry (SOCE) is a ubiquitous signaling mechanism, which may become overactivated in pathological states resulting intracellular Ca2+ overload. In this study, we used ex vivo and in vivo preclinical disease models to demonstrate that Orai1 inhibition prevents progression of RAP and early CP. The selective Orai1 inhibitor CM5480 restored the expression of SOCE-associated regulatory factor in acinar cells, prevented uncontrolled Ca2+ elevation, protected acinar and ductal functions, mitigated immune cell infiltration, and diminished PSC activation, proliferation and migration. We suggest that the overactivation of Orai1 is a crucial pathogenetic event in the progression of early CP, and inhibition of Orai1 could prevent the development of end-stage CP.

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