PhD Scientific Days 2020

Theoretical and Translational V. Lectures

Exploring the Pathomechanism of Thiopurnie-Induced Acute Pancreatitis: Azathioprine Impairs Pancreatic Ductal Exocrine Functions in Mice

Előadó neve

Dr. Tél, Bálint

Előadó munkahelye

1st. Department of Paediatrics, Semmelweis University, Budapest, Hungary; 1st Department of Medicine, University of Szeged, Szeged, Hungary

Előadó telefonszáma

+36204535129

Előadó e-mail címe

tel.balint@gmail.com

Az előadás címe

Exploring the Pathomechanism of Thiopurnie-Induced Acute Pancreatitis: Azathioprine Impairs Pancreatic Ductal Exocrine Functions in Mice

Szerző(k) neve és munkahelye

Bálint Tél 1,2; Noémi Papp 2; Péter Hegyi 2,3; József Maléth 2; Gábor Veres† 4; Petra Pallagi 2

1 First Department of Paediatrics, Semmelweis University, Budapest, Hungary;
2 MTA-SZTE Momentum Epithelial Cell Signaling and Secretion Research Group, First Department of Medicine, University of Szeged, Szeged, Hungary;
3 Institute for Translational Medicine, University of Pécs, Pécs, Hungary;
4 Paediatric Institute-Clinic, University of Debrecen, Debrecen, Hungary

Szekció

Theoretical and Translational V. Lectures

Language of the presentation

English

Section, first choice

Theoretical and Translational Medicine

Section, second choice

Pharmaceutical Sciences

Összefoglaló szövege

Introduction: Thiopurine-induced pancreatitis (TIP) is a major difficulty in the treatment of Inflammatory Bowel Diseases, the exact pathomechanism of TIP is, however, currently unknown. It was shown recently, that other risk factors, such as ethanol, can impair the ductal HCO3- secretion, which can ultimately lead to pancreatic injury and acute pancreatitis (AP). Therefore, we wanted to investigate what effects do thiopurines have on pancreatic ductal functions and HCO3- secretion.

Methods: C57BL6 mice were selected to receive daily 1.5 and 15 mg/kg azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanin (6-TG) or physiologic saline (PS) for one and for four weeks. After the oral treatment mice were either euthanized and used for further measurements or selected for in vivo fluid-secretion measurements as previously descried. For ex vivo experiments, pancreatic ductal segments (PD) were isolated from euthanized mice and PDs were transferred to perfusion chambers and were loaded with a pH-sensitive fluorescent dye (BCECF-AM). Intracellular pH and rate of HCO3- secretion was determined using ratio microfluorimetry. To assess the in vitro effects of thiopurines, the above mentioned microfluorimetric measurements were also conducted on ex vivo PDs from non-treated animals perfused with solutions containing different concentrations of AZA, 6-MP, and 6-TG.

Results: Acute exposition in vitro to 1, 10 or 100 ug/ml AZA significantly decreased the luminal HCO3- secretion rates in a dose-dependent manner. Per os treatment with AZA for one and four weeks impaired the ductal HCO3- secretion rate and in vivo fluid-secretion was decreased after four weeks of 1.5 mg/kg AZA treatment. Animals treated with 15 mg/kg AZA didn’t survive the ketamine-sedation. Preliminary results showed that one week of 1.5 mg/kg 6-MP and 6-TG treatment didn’t alter the ductal HCO3- secretion rates. Further in vitro and in vivo measurements with 6-MP and 6-TG are running currently.

Conclusion: AZA can impair ductal HCO3- secretion both in vitro and in vivo, in a dose-dependent manner. These results suggest that in TIP, beside immune-mediated mechanisms, inhibitory effects on ductal exocrine functions might also play an important role. In order to fully understand the pathomechanism of TIP, further experiments, including both pancreatic ducts and acini, are needed.

Additional Information

This study was supported by supported by OTKA, MTA and the ÚNKP-19-3-I-SE-80 and ÚNKP-19-4-SZTE-21 New National Excellence Program of the Ministry for Innovation and Technology.

Supervisor: Gábor Veres

Bemutatás módja

Szóbeli

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

2929

Start

16:30

End

16:45

Authors (legacy)

Bálint Tél 1,2; Noémi Papp 2; Péter Hegyi 2,3; József Maléth 2; Gábor Veres† 4; Petra Pallagi 2

1 First Department of Paediatrics, Semmelweis University, Budapest, Hungary;
2 MTA-SZTE Momentum Epithelial Cell Signaling and Secretion Research Group, First Department of Medicine, University of Szeged, Szeged, Hungary;
3 Institute for Translational Medicine, University of Pécs, Pécs, Hungary;
4 Paediatric Institute-Clinic, University of Debrecen, Debrecen, Hungary