Pancreatic Ductal Bicarbonate Secretion: Challenge of the Acinar Acid Load

Acinar and ductal cells of the exocrine pancreas form a close functional unit. Although most studies contain data either on acinar or ductal cells, an increasing number of evidence highlights the importance of the pancreatic acinar-ductal functional unit. One of the best examples for this functional unit is the regulation of luminal pH by both cell types. Protons co-released during exocytosis from acini cause significant acidosis, whereas, bicarbonate secreted by ductal cells cause alkalization in the lumen. This suggests that the first and probably one of the most important role of bicarbonate secretion by pancreatic ductal cells is not only to neutralize the acid chyme entering into the duodenum from the stomach, but to neutralize acidic content secreted by acinar cells. To accomplish this role, it is more than likely that ductal cells have physiological sensing mechanisms which would allow them to regulate luminal pH. To date, four different classes of acid-sensing ion channels have been identified in the gastrointestinal tract (transient receptor potential ion channels, two-pore domain potassium channel, ionotropic purinoceptor and acid-sensing ion channel), however, none of these have been studied in pancreatic ductal cells. In this mini-review, we summarize our current knowledge of these channels and urge scientists to characterize ductal acid-sensing mechanisms and also to investigate the challenge of the acinar acid load on ductal cells

Intracellular Ca2+ Signalling in the Pathogenesis of Acute Pancreatitis: Recent Advances and Translational Perspectives

Intracellular Ca2+ signalling is a major signal transductional pathway in non-excitable cells, responsible for the regulation of a variety of physiological functions. In the secretory epithelial cells of the exocrine pancreas, such as acinar and ductal cells, intracellular Ca2+ elevation regulates digestive enzyme secretion in acini or fluid and ion secretion in ductal cells. Although Ca2+ is a uniquely versatile orchestrator of epithelial physiology, unregulated global elevation of the intracellular Ca2+ concentration is an early trigger for the development of acute pancreatitis (AP). Regardless of the aetiology, different forms of AP all exhibit sustained intracellular Ca2+ elevation as a common hallmark. The release of endoplasmic reticulum (ER) Ca2+ stores by toxins (such as bile acids or fatty acid ethyl esters (FAEEs)) or increased intrapancreatic pressure activates the influx of extracellular Ca2+ via the Orai1 Ca2+ channel, a process known as store-operated Ca2+ entry (SOCE). Intracellular Ca2+ overload can lead to premature activation of trypsinogen in pancreatic acinar cells and impaired fluid and HCO3- secretion in ductal cells. Increased and unbalanced reactive oxygen species (ROS) production caused by sustained Ca2+ elevation further contributes to cell dysfunction, leading to mitochondrial damage and cell death. Translational studies of AP identified several potential target molecules that can be modified to prevent intracellular Ca2+ overload. One of the most promising drugs, a selective inhibitor of the Orai1 channel that has been shown to inhibit extracellular Ca2+ influx and protect cells from injury, is currently being tested in clinical trials. In this review, we will summarise the recent advances in the field, with a special focus on the translational aspects of the basic findings

Cystic Fibrosis of the Pancreas: The Role of CFTR Channel in the Regulation of Intracellular Ca2+ Signaling and Mitochondrial Function in the Exocrine Pancreas

Cystic fibrosis (CF) is the most common genetic disorder that causes a significant damage in secretory epithelial cells due to the defective ion flux across the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. Pancreas is one of the organs most frequently damaged by the disease leading to pancreatic insufficiency, abdominal pain and an increased risk of acute pancreatitis in CF patients causing a significant decrease in the quality of life. CFTR plays a central role in the pancreatic ductal secretory functions by carrying Cl- and HCO3- ions across the apical membrane. Therefore pathophysiological studies in CF mostly focused on the effects of impaired ion secretion by pancreatic ductal epithelial cells leading to exocrine pancreatic damage. However, several studies indicated that CFTR has a central role in the regulation of intracellular signaling processes and is now more widely considered as a signaling hub in epithelial cells. In contrast, elevated intracellular Ca2+ level was observed in the lack of functional CFTR in different cell types including airway epithelial cells. In addition, impaired CFTR expression has been correlated with damaged mitochondrial function in epithelial cells. These alterations of intracellular signaling in CF are not well characterized in the exocrine pancreas yet. Therefore in this review we would like to summarize the complex role of CFTR in the exocrine pancreas with a special focus on the intracellular signaling and mitochondrial function

Reduction of intracellular oxidative stress with copper incorporated layered double hydroxide

Biocompatible Cu(II)-doped layered double hydroxide (CMA) nanoparticles were developed to combat reactive oxygen species. The 2-dimensional nanozymes showed both superoxide dismutase and catalase-like activity in chemical assays, while proved as..

OGG1 Inhibition Reduces Acinar Cell Injury in a Mouse Model of Acute Pancreatitis

Acute pancreatitis (AP) is a potentially life-threatening gastrointestinal disease with a complex pathology including oxidative stress. Oxidative stress triggers oxidative DNA lesions such as formation of 7,8-dihydro-8-oxo-2′-oxoguanine (8-oxoG) and also causes DNA strand breaks. DNA breaks can activate the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) which contributes to AP pathology. 8-oxoG is recognized by 8-oxoG glycosylase 1 (OGG1) resulting in the removal of 8-oxoG from DNA as an initial step of base excision repair. Since OGG1 also possesses a DNA nicking activity, OGG1 activation may also trigger PARP1 activation. In the present study we investigated the role played by OGG1 in AP. We found that the OGG1 inhibitor compound TH5487 reduced edema formation, inflammatory cell migration and necrosis in a cerulein-induced AP model in mice. Moreover, TH5487 caused 8-oxoG accumulation and reduced tissue poly(ADP-ribose) levels. Consistent with the indirect PARP inhibitory effect, TH5487 shifted necrotic cell death (LDH release and Sytox green uptake) towards apoptosis (caspase activity) in isolated pancreatic acinar cells. In the in vivo AP model, TH5487 treatment suppressed the expression of various cytokine and chemokine mRNAs such as those of TNF, IL-1β, IL1ra, IL6, IL16, IL23, CSF, CCL2, CCL4, CCL12, IL10 and TREM as measured with a cytokine array and verified by RT-qPCR. As a potential mechanism underlying the transcriptional inhibitory effect of the OGG1 inhibitor we showed that while 8-oxoG accumulation in the DNA facilitates NF-κB binding to its consensus sequence, when OGG1 is inhibited, target site occupancy of NF-κB is impaired. In summary, OGG1 inhibition provides protection from tissue injury in AP and these effects are likely due to interference with the PARP1 and NF-κB activation pathways

A pankreász vezeték sejtek bikarbonát szekréciójának kórélettana. = The pathophysiology of pancreatic ductal bicarbonate secretion.

A projekt fő célja a pankreász vezeték sejtek bikarbonát szekréciójának kórélettani vizsgálata volt. 1) Kísérleteinkben tisztázni tudtuk az epesavak pankreász duktuszt károsító hatásának okait: 1a) a nem konjugált epesavak a glükolitikus és oxidatív ATP szintézist jelentősen csökkentik ezáltal súlyos ATP depléciót alakítanak ki a pankreász duktális sejtjeiben. 1b) a nem-konjugált epesavak maxi-K+ csatornákat aktiválnak a pankreász duktális sejteken, mely új terápiás célpontot jelenthetnek akut biliáris pankreatitiszben. 2) Jelentős előrelépés történt a tripszin pankreász szekréciót gátló hatásának vizsgálatában is. Megtaláltuk azt a csatornát (CFTR Cl- csatorna) ami felelős a tripszin gátló hatásának kialakításáért. A kísérletekből megírt közlemény a Gastroenterology folyóiratban elbírálás alatt (under review) van. 3) Korábbi vizsgálataink arra utaltak, hogy a pankreatitisz súlyossága, a mitokondriális károsodás illetve a bikarbonát szekréció egymással szoros kapcsolatban van. A bázikus aminosavakkal kiváltott pankreatitisz során kimutattuk, hogy időrendi sorrendben a mitokondriális károsodás történik először, ami jelentősen befolyásolja a pankreatitisz súlyosságát. 4) Igazoltuk, hogy az iontranszporterek és a gyulladásos betegségek közötti összefüggések nem csak szerv specifikusak a pankreászra vonatkoztatva, hanem a teljes gasztrointesztinális traktusra (pl. vastagbél) is igazak lehetnek. | The main aim of the project was to investigate the role of bicarbonate secretion in pathophysiological conditions. 1) Our results helped us to understand the toxic effects of bile acids on pancreatic ductal epithelial cells. 1a) The non-conjugated bile acids cause mitochondrial damage followed by (ATP)i depletion. Bile acids inhibit the glycolytic metabolism of pancreatic ductal epithelial cells. 1b) We have shown for the first time that maxi-K+ channels have a crucial role in regulating HCO3 - secretion and are also essential for the bile acid-induced hypersecretion and, therefore, underlie the response of the pancreas to this noxious agent. 2) We showed for the first time that trypsin compromises pancreatic ductal bicarbonate secretion via a PAR-2 dependent inhibition of the apical anion exchanger and CFTR. This may contribute to the development of pancreatitis through promoting premature trypsinogen activation in the pancreatic ducts. Our manuscript is in revision at Gastroenterology. 3) We demonstrated that basic amino acids impair ATP synthase activity of isolated pancreatic, but not liver, mitochondria. Taken together, early mitochondrial injury caused by large doses of L-lysine may lead to the development of acute pancreatitis 4) We have also shown evidences that the relationship between the iontransporters and inflammatory disorders are not organ specific and it could be true in the whole GI tract