Crucial role of pancreatic ducts in the initiation and progression of pancreatitis

Maléth József
Crucial role of pancreatic ducts in the initiation and progression of pancreatitis.
Doctoral thesis (PhD), University of Szeged.
(2014) (Unpublished)

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Abstract in foreign language

Background: Alcohol-induced and biliary pancreatitis are the two most common forms of acute pancreatitis. Notably, there is no specific treatment against this inflammatory disease suggesting the lack of knowledge of pathophysiological mechanisms involved in the initiation and progression of the diseases. Although recent evidence suggest that pancreatic ductal epithelial cells (PDEC) play important role in the pathogenesis of pancreatitis the effects of ethanol, fatty acids and their metabolites on PDEC has not been investigated yet. On the other hand bile acid in millimolar concentration has been shown to inhibit the pancreatic ductal HCO3- secretion, however the exact mechanism of inhibition remained elusive. The aim of this study was to characterize the effects of ethanol and ethanol metabolites on the pancreatic ductal epithelial HCO3- secretion and to dissect the inhibitory effect of non-conjugated bile acids on the pancreatic HCO3- secretion. Methods: We studied the effects of ethanol, fatty acids, and fatty acid ethyl esters on secretion of pancreatic fluid and HCO3-, levels and function of CFTR, and exchange of Cl- for HCO3-, in pancreatic cell lines, as well as in tissues from guinea pigs and CFTR-knockout mice following administration of alcohol and fatty acids. We detected the changes of intracellular Ca2+ concentration ([Ca2+]i), ATP level ((ATP)i), and mitochondrial membrane potential ((ΔΨ)m) upon the administration of ethanol, ethanol metabolites, or chendoxycholate using fluorescent indicators. The mitochondrial morphology was assessed by electron microscopy. Results: Low concentration of ethanol stimulated the pancreatic HCO3- secretion via IP3 mediated Ca2+ release from the endoplasmic reticulum (ER). High concentration of ethanol and fatty acids inhibited secretion of fluid and HCO3-, as well as CFTR activity, in pancreatic ductal epithelial cells. These effects were mediated by sustained increases in [Ca2+]i, depletion of (ATP)i, and depolarization of mitochondrial membranes. Moreover in pancreatic cell line and guinea pig pancreatic tissue administration of ethanol, or non-oxidative ethanol metabolites reduced the expression of CFTR. Similarly, high concentration of the non-conjugated bile acid chenodeoxycholate disrupted the mitochondrial structure and consequently depleted (ATP)i in guinea pig pancreatic ductal cells. The (ATP)i depletion induced by the inhibition of the cellular ATP production significantly impaired the HCO3- secretion. Conclusions: In this present work we have demonstrated that ethanol, as well as its non-oxidative metabolites cause impairment of pancreatic ductal fluid and HCO3- secretion via toxic cellular Ca2+ signaling and break down of the mitochondrial ATP production. Very similar mitochondrial damage was found in these cells upon the administration of non-conjugated bile acid. These results highlight the central role of mitochondrial damage in the pathogenesis of acute pancreatitis.

Item Type: Thesis (Doctoral thesis (PhD))
Creators: Maléth József
Hungarian title: A hasnyálmirigy duktuszok központi szerepe az akut pankreatitisz kialakulásában és progressziójában
Position, academic title, institution
MTMT author ID
Hegyi Péter
egyetemi tanár, DSc, SZTE ÁOK I. sz. Belgyógyászati Klinika
Rakonczay Jr. Zoltán
tudományos főmunkatárs, DSc, SZTE ÁOK I. sz. Belgyógyászati Klinika
Subjects: 03. Medical and health sciences > 03.01. Basic medicine
Divisions: Doctoral School of Theoretical Medicine
Discipline: Medicine > Theoretical Medicine
Language: English
Date: 2014. December 04.
Item ID: 2499
MTMT identifier of the thesis: 2813606
Date Deposited: 2014. Nov. 27. 09:07
Last Modified: 2020. Apr. 17. 14:52
Depository no.: B 5815
Defence/Citable status: Defended.

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