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

2020 ◽  
Vol 21 (11) ◽  
pp. 4005 ◽  
Author(s):  
Petra Pallagi ◽  
Tamara Madácsy ◽  
Árpád Varga ◽  
József Maléth
Keyword(s):  
Acute Pancreatitis ◽  
Digestive Enzyme ◽  
Ethyl Esters ◽  
Pancreatic Acinar Cells ◽  
Special Focus ◽  
Excitable Cells ◽  
Cell Dysfunction ◽  
Ductal Cells ◽  
Recent Advances ◽  
Epithelial Physiology

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.

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

2020 ◽  
Author(s):  
Júlia Fanczal
Keyword(s):  
Oxidative Stress ◽  
Acute Pancreatitis ◽  
Bile Acid ◽  
Bile Acids ◽  
Digestive Enzyme ◽  
Acinar Cells ◽  
Mitochondrial Damage ◽  
Enzyme Activation ◽  
Pancreatic Acinar Cells ◽  
Biliary Pancreatitis

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.

Ductal Cell Reprogramming to Insulin-Producing Beta-Like Cells as a Potential Beta Cell Replacement Source for Chronic Pancreatitis

2019 ◽  
Vol 14 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Aravinth P. Jawahar ◽  
Siddharth Narayanan ◽  
Gopalakrishnan Loganathan ◽  
Jithu Pradeep ◽  
Gary C. Vitale ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Beta Cell ◽  
Lineage Tracing ◽  
Clinical Tool ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Insulin Producing Cells ◽  
Ductal Cell ◽  
Recent Advances

Islet cell auto-transplantation is a novel strategy for maintaining blood glucose levels and improving the quality of life in patients with chronic pancreatitis (CP). Despite the many recent advances associated with this therapy, obtaining a good yield of islet infusate still remains a pressing challenge. Reprogramming technology, by making use of the pancreatic exocrine compartment, can open the possibility of generating novel insulin-producing cells. Several lineage-tracing studies present evidence that exocrine cells undergo dedifferentiation into a progenitor-like state from which they can be manipulated to form insulin-producing cells. This review will present an overview of recent reports that demonstrate the potential of utilizing pancreatic ductal cells (PDCs) for reprogramming into insulin- producing cells, focusing on the recent advances and the conflicting views. A large pool of ductal cells is released along with islets during the human islet isolation process, but these cells are separated from the pure islets during the purification process. By identifying and improving existing ductal cell culture methods and developing a better understanding of mechanisms by which these cells can be manipulated to form hormone-producing islet-like cells, PDCs could prove to be a strong clinical tool in providing an alternative beta cell source, thus helping CP patients maintain their long-term glucose levels.

scholarly journals Erythrocytes: Central Actors in Multiple Scenes of Atherosclerosis

2021 ◽  
Vol 22 (11) ◽  
pp. 5843
Author(s):  
Chloé Turpin ◽  
Aurélie Catan ◽  
Olivier Meilhac ◽  
Emmanuel Bourdon ◽  
François Canonne-Hergaux ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
The Body ◽  
Diabetic Patients ◽  
Special Focus ◽  
Plaque Progression ◽  
Cell Dysfunction ◽  
Circulating Cells ◽  
The Impact ◽  
Progression Of Atherosclerosis

The development and progression of atherosclerosis (ATH) involves lipid accumulation, oxidative stress and both vascular and blood cell dysfunction. Erythrocytes, the main circulating cells in the body, exert determinant roles in the gas transport between tissues. Erythrocytes have long been considered as simple bystanders in cardiovascular diseases, including ATH. This review highlights recent knowledge concerning the role of erythrocytes being more than just passive gas carriers, as potent contributors to atherosclerotic plaque progression. Erythrocyte physiology and ATH pathology is first described. Then, a specific chapter delineates the numerous links between erythrocytes and atherogenesis. In particular, we discuss the impact of extravasated erythrocytes in plaque iron homeostasis with potential pathological consequences. Hyperglycaemia is recognised as a significant aggravating contributor to the development of ATH. Then, a special focus is made on glycoxidative modifications of erythrocytes and their role in ATH. This chapter includes recent data proposing glycoxidised erythrocytes as putative contributors to enhanced atherothrombosis in diabetic patients.

scholarly journals Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ali A. Aghdassi ◽  
Daniel S. John ◽  
Matthias Sendler ◽  
Christian Storck ◽  
Cindy van den Brandt ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Serine Protease ◽  
Acinar Cells ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Pancreatic Acinar Cells ◽  
Neutrophil Granulocyte ◽  
Zymogen Activation ◽  
Trypsinogen Activation ◽  
Extracellular Matrix Components

AbstractAcute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG−/− mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG−/− mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected.

scholarly journals Corrigendum: Recent Advances on Nutrition in Treatment of Acute Pancreatitis

2018 ◽  
Vol 9 ◽  
Author(s):  
Li-Long Pan ◽  
Jiahong Li ◽  
Muhammad Shamoon ◽  
Madhav Bhatia ◽  
Jia Sun
Keyword(s):  
Acute Pancreatitis ◽  
Recent Advances

scholarly journals Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

2022 ◽  
Vol 9 ◽  
Author(s):  
Zhengru Liu ◽  
Mingming Qi ◽  
Shan Tian ◽  
Qian Yang ◽  
Jian Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Tight Junctions ◽  
Multiple Organ ◽  
Organ Injury ◽  
Pancreatic Acinar Cells ◽  
Stat3 Pathway ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Multiple Organ Injury

Ubiquitin-specific protease 25 (USP25) plays an important role in inflammation and immunity. However, the role of USP25 in acute pancreatitis (AP) is still unclear. To evaluate the role of USP25 in AP, we conducted research on clinical AP patients, USP25wild-type(WT)/USP25 knockout (USP25−/−) mice, and pancreatic acinar cells. Our results showed that serum USP25 concentration was higher in AP patients than in healthy controls and was positively correlated with disease severity. AP patients’ serum USP25 levels after treatment were significantly lower than that at the onset of AP. Moreover, USP25 expression was upregulated in cerulein-induced AP in mice, while USP25 deficiency attenuates AP and AP-related multiple organ injury. In vivo and in vitro studies showed that USP25 exacerbates AP by promoting the release of pro-inflammatory factors and destroying tight junctions of the pancreas. We showed that USP25 aggravates AP and AP-related multiple organ injury by activating the signal transducer and activator of transcription 3 (STAT3) pathway. Targeting the action of USP25 may present a potential therapeutic option for treating AP.

TRANSCRIPTION FACTOR PROFILING OF PANCREATIC ACINAR CELLS FOLLOWING TNF-α INDUCTION OF ACUTE PANCREATITIS.

Shock ◽  
2003 ◽  
Vol 19 (Supplement) ◽  
pp. 20
Author(s):  
L. Vona-Davis ◽  
K. Magabo ◽  
B. Jackson ◽  
T. Evans ◽  
D. Riggs ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Transcription Factor ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Tnf Α

Acinar Akt1 in pancreatic acinar cells supports proliferation and limits acinar-to-ductal metaplasia formation upon induction of acute pancreatitis

Pancreatology ◽  
2019 ◽  
Vol 19 ◽  
pp. S101
Author(s):  
Rong Chen ◽  
Ermanno Malagola ◽  
Maren Dietrich ◽  
Richard Zuellig ◽  
Marta Bombardo ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Acinar To Ductal Metaplasia
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