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ORAI1 CALCIUM CHANNEL INHIBITION PREVENTS PROGRESSION OF RECURRENT ACUTE AND CHRONIC PANCREATITIS

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Introduction

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.

Aims & Methods

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. CP was induced in wild type FVB/N mice by repeated administration of cerulein (50 µg/kg) for two weeks, followed by administration of a selective Orai1 inhibitor (CM5480; 20 mg/kg) on the last five days, and histological parameters, fibrosis, pancreas weight/body weight ratio, and hydroxyproline (HyP) content were quantified. Functional and morphological assays were used to evaluate acinar and ductal functions. In vitro experiments were performed on PSCs.

Results

Our findings show that SARAF, an endoplasmic reticulum resident protein that inhibits Orai1 activity, is significantly reduced in pancreatic acinar cells from mouse and human CP tissue, leading to an increase in Orai1-mediated extracellular Ca²⁺ influx. In contrast, inhibiting Orai1 significantly reduced tissue damage during experimental CP in mice, as well as the extent of fibrosis and immune cell infiltration. Furthermore, CM5480-treated mice had significantly improved pancreatic acinar and ductal functions. Finally, Orai1 inhibition reduced PSC activation in vitro and in vivo, as well as migration and proliferation, while causing a cell cycle arrest and accumulation of PSCs in the S phase.

Conclusion

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.

Disclosure

The selective Orai1 inhibitor CM5480 was provided by CalciMedica.

ORAI1 CALCIUM CHANNEL INHIBITION PREVENTS PROGRESSION OF RECURRENT ACUTE AND CHRONIC PANCREATITIS

Viktória Szabó 1, Noémi Csákány-Papp 1, Marietta Görög 2, Tamara Madacsy 1, Arpad Varga 2, Aletta Kata Kiss 1, Bálint Tél 3, Boldizsár Jójárt 1, Tim Crul 2, Krisztina Dudás 2, Mária Bagyánszki 4, Nikolett Bódi 4, Ferhan Ayaydin 4, Shyam Jee 4, László Tiszlavicz 4, Kenneth Stauderman 5, Sudarshan Hebbar 5, Petra Pallagi 1, József Maléth 1

1 University of Szeged, Albert Szent-Györgyi Medical School, Szeged, Hungary|||University of Szeged, Szeged, Hungary|||University of Szeged, Szeged, Hungary

2 University of Szeged, Albert Szent-Györgyi Medical School, Szeged, Hungary|||University of Szeged, Szeged, Hungary

3 Semmelweis University, Budapest, Hungary

4 University of Szeged, Szeged, Hungary

5 CalciMedica, Inc., La Jolla, CA, United States

Event

UEG Week Copenhagen 2023

Topics

Digestive Oncology Pancreas

Submission format

Abstract

Session

New insights into pancreatic diseases: From inflammation to cancer

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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Long-term benefit of FIT and subsequent colonoscopy

Carlo Senore 1

1 University Hospital Città della Salute e della Scienza, Torino, Italy

Event

UEG Week Copenhagen 2023

Topics

Colorectal Endoscopy Surgery

Session

Colorectal cancer screening and surveillance: How far should we go?

Published

2023

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NANO HYDROGEN AMELIORATES SEVERE ACUTE PANCREATITIS

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Introduction

During severe acute pancreatitis (SAP), large amounts of reactive oxygen species (ROS) are produced in the abdominal cavity, which can directly damage abdominal organs and be absorbed into the blood, causing systemic inflammatory response syndrome and multiple organ dysfunction. Molecular hydrogen (H₂) can target to eliminate harmful ROS such as hydroxyl radical^[1]. When severe inflammatory damage occurs in the pancreas, microthrombosis are widely produced, and the antioxidant effect is difficult to be fully exerted if H₂ is administered through circulation.

Aims & Methods

We have developed hydrogen-loaded nanoparticles (nano hydrogen) to bring H₂ into direct contact with the pancreas by intraperitoneal administration, providing a new strategy for the anti-inflammatory treatment of SAP. In this study, we investigated the pathophysiological mechanisms by which nano hydrogen ameliorates SAP.
In vivo, SAP was established by retrograde injection of sodium taurocholate through the rat pancreatic duct. Nano hydrogen (37.5 mg/kg) was injected intraperitoneally in the SAP + nano hydrogen group. The survival rate was calculated. Pathological scoring was performed. Neutrophil and macrophage infiltration, ultrastructural changes of acinar cells and vascular endothelial cells, and microthrombosis of pancreatic tissue were detected. In vitro, intracellular ROS of AR42J cells were measured using hydroxyphenyl fluorescein solution. Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-α, and nano hydrogen was used for intervention. RNA-seq was performed on rat pancreatic tissue and HUVEC samples. The expression of VCAM-1, ICAM-1 and NF-κB p65 in HUVECs was compared. β-galactosidase staining and markers of cellular senescence such as phosphorylated γ-H₂A.X, p53, p21, and p16 were detected. The opening of the mitochondrial permeability transition pore (MPTP) and mitochondrial membrane potential of HUVECs were assessed.

Results

After intraperitoneal administration of nano hydrogen into SAP rats, the survival rate increased by 66%, and the pathological score of pancreas dramatically decreased (p < 0.01). The neutrophil infiltration was significantly reduced (p < 0.01), and the ultrastructure of acinar cells and vascular endothelial cells was significantly improved. The pancreatic tissue of SAP rats had a large number of microthrombi, which were significantly reduced by nano hydrogen. Pancreatic vascular endothelial cells in SAP rats expressed p21.
Nano hydrogen significantly downregulated the dominant transcriptional events in SAP pancreas, such as leukocyte chemotaxis and migration and oxidative stress, and also significantly reduced the production of ROS in the acinar cells and the expression of VCAM-1, ICAM-1 and phosphorylated p65 after TNF-α stimulation of HUVECs (p < 0.01). RNA-seq analysis of HUVECs indicated that TNF-α induced cellular senescence, confirmed by positive β-galactosidase staining and significantly increased expression of phosphorylated γ-H₂A.X, total p53, phosphorylated p53, p21 (p < 0.05) and p16 (p < 0.01). MPTP opened and mitochondrial membrane potential disappeared in TNF-α-stimulated HUVECs. Nano hydrogen significantly attenuated the abovementioned manifestation.

Conclusion

Nano hydrogen can effectively eliminate ROS brought to the pancreas by neutrophil infiltration and etc., and improve vascular endothelial cell function, thus significantly improving pathological damage such as pancreatic necrosis, which has important translational value for clinical treatment.

References

1. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6): 688-694.

NANO HYDROGEN AMELIORATES SEVERE ACUTE PANCREATITIS

Xianhui Zeng 1, Xianglei Yuan 2, chong zhao 3, Jinhang Gao 3, Chengwei Tang 3

1 West China Hospital, Sichuan University, Chengdu, China|||West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China

2 West China Hospital, Sichuan University, Chengdu, China

3 West China Hospital, Sichuan University, Chengdu, China|||West China Hospital, Sichuan University, Chengdu, China