The role of intracellular Ca2+signaling in the exocrine pancreatic damage during acute pancreatitis

Fanczal Júlia
The role of intracellular Ca2+signaling in the exocrine pancreatic damage during acute pancreatitis.
Doctoral thesis (PhD), University of Szeged.
(2020) (Unpublished)

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Abstract in foreign language

Acute biliary pancreatitis poses a significant clinical challenge as currently no specific pharmaceutical treatment exists. Disturbed intracellular Ca2+ signalling caused by bile acids is a hallmark of the disease, which induces increased reactive oxygen species (ROS) production, mitochondrial damage, intra-acinar digestive enzyme activation and cell death. Because of this mechanism of action, prevention of toxic cellular Ca2+ overload is a promising therapeutic target. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel that has recently emerged as an important contributor to oxidative-stress-induced cellular Ca2+ overload across different diseases. However, the expression and possible functions of TRPM2 in the exocrine pancreas remain unknown. Here we found that TRPM2 is expressed in the plasma membrane of mouse pancreatic acinar, which can be activated by increased oxidative stress induced by H2O2 treatment. TRPM2 activity was found to contribute to bile acid-induced extracellular Ca2+ influx in acinar cells. The generation of intracellular ROS in response to bile acids was remarkably higher in pancreatic acinar cells. This activity promoted acinar cell necrosis in vitro independently from mitochondrial damage or mitochondrial fragmentation. In addition, bile-acid-induced experimental pancreatitis was less severe in TRPM2 knockout mice, whereas the lack of TRPM2 had no protective effect in cerulein-induced acute pancreatitis. Our results suggest that the inhibition of TRPM2 may be a potential treatment option for biliary pancreatitis.

Item Type: Thesis (Doctoral thesis (PhD))
Creators: Fanczal Júlia
Hungarian title: Az intracelluláris Ca2+ szignalizáció szerepe az exokrin hasnyálmirigy sejtek károsodásának kialakulásában heveny hasnyálmirigy gyulladás során
Position, academic title, institution
MTMT author ID
Maléth József
M.D., Ph.D., I. sz. Belgyógyászati Klinika SZTE / ÁOK
Hegyi Péter
M.D., Ph.D., DS.c, I. sz. Belgyógyászati Klinika SZTE / ÁOK
Subjects: 03. Medical and health sciences > 03.02. Clinical medicine > 03.02.19. Gastroenterology and hepatology
Divisions: Doctoral School of Theoretical Medicine
Discipline: Medicine > Theoretical Medicine
Language: English
Date: 2020. June 30.
Uncontrolled Keywords: acinar cell necrosis, acute pancreatitis, bile acid, Ca2+ signalling, epithelial ion transport, TRPM2 channel
Item ID: 10488
MTMT identifier of the thesis: 31933101
Date Deposited: 2020. Jun. 16. 10:48
Last Modified: 2022. Jul. 25. 15:02
Defence/Citable status: Defended.

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