Activated Pancreatic Stellate Cells Promote Acinar Duct Metaplasia by Disrupting Mitochondrial Respiration and Releasing Reactive Oxygen Species

2021 ◽  
Vol 01 ◽  
Author(s):  
Hong Xiang ◽  
Fangyue Guo ◽  
Qi Zhou ◽  
Xufeng Tao ◽  
Deshi Dong
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Respiration ◽  
Reactive Oxygen ◽  
Acinar Cells ◽  
Stellate Cells ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Oxygen Species

Background: Chronic pancreatitis (CP) is a long-term risk factor for pancreatic ductal adenocarcinoma (PDAC), and both diseases share a common etiology. The activation of Pancreatic stellate cells (PaSCs) caused by inflammation of the chronic pancreas plays a pivotal role in the pathology of pancreatic fibrosis and the malignant phenotype of PDAC. However, the central role of activated PaSCs in acinar-to-ductal metaplasia (ADM) remains unknown. Objective: In the present study, we investigated the link between pancreatic fibrosis and ADM and the possible underlying mechanism. Methods: A caerulein-treated mouse CP model was established, and Masson trichrome histochemical stain and transmission electron microscope (TEM) were used to observe stromal fibrosis and cell ultrastructure, respectively. The expression of amylase and cytokeratin 19 (CK19), mitochondria respiration, and reactive oxygen species (ROS) were detected in vitro in the co-culture model of primary pancreatic acinar cells and PaSCs. Results: The activation of PaSCs and pancreatic fibrosis were accompanied by ADM in pancreatic parenchyma in caerulein-treated mice, which was verified by the co-cultivation experiment in vitro. Furthermore, we showed that activated PaSCs promote ADM by disrupting mitochondrial respiration and releasing ROS. The expression of inflammation-and ADM-related genes, including S100A8, S100A9, and CK19, was observed to be up-regulated in pancreatic acinar cells in the presence of activated PaSCs. The expression of S100A9 and CK19 proteins was also up-regulated in acinar cells co-cultured with activated PaSCs. Conclusion: The manipulation of mitochondrial respiration and ROS release is a promising preventive and/or therapeutic strategy for PDAC, and S100A9 is expected to be a therapeutic target to block the ADM process induced by the activation of PaSCs.

Melatonin induces reactive oxygen species generation and changes in glutathione levels and reduces viability in human pancreatic stellate cells

2019 ◽  
Vol 75 (2) ◽  
pp. 185-197 ◽  
Author(s):  
Matias Estaras ◽  
Noelia Moreno ◽  
Patricia Santofimia-Castaño ◽  
Salome Martinez-Morcillo ◽  
Vicente Roncero ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Oxygen Species

Mitochondrial DNA damage and altered membrane potential (ΔΨ) in pancreatic acinar cells induced by reactive oxygen species

Surgery ◽  
1999 ◽  
Vol 126 (2) ◽  
pp. 148-155 ◽  
Author(s):  
Richard A. Ehlers ◽  
Ambrosio Hernandez ◽  
L.Scott Bloemendal ◽  
Richard T. Ethridge ◽  
Buckminster Farrow ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Mitochondrial Dna ◽  
Membrane Potential ◽  
Reactive Oxygen ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Oxygen Species ◽  
Mitochondrial Dna Damage

Reactive Oxygen Species Induced by Bile Acid Induce Apoptosis and Protect Against Necrosis in Pancreatic Acinar Cells

2011 ◽  
Vol 140 (7) ◽  
pp. 2116-2125 ◽  
Author(s):  
David M. Booth ◽  
John A. Murphy ◽  
Rajarshi Mukherjee ◽  
Muhammad Awais ◽  
John P. Neoptolemos ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Bile Acid ◽  
Reactive Oxygen ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Oxygen Species

Externally applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species

2007 ◽  
Vol 293 (5) ◽  
pp. G972-G978 ◽  
Author(s):  
Hiroshi Asaumi ◽  
Shiro Watanabe ◽  
Masashi Taguchi ◽  
Mitsuo Tashiro ◽  
Makoto Otsuki
Keyword(s):  
Reactive Oxygen Species ◽  
Chronic Pancreatitis ◽  
Smooth Muscle Actin ◽  
Applied Pressure ◽  
Reactive Oxygen ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Ros Generation ◽  
Oxygen Species ◽  
Tissue Pressure

Local tissue pressure is higher in chronic pancreatitis than in the normal pancreas. We reported recently that pressure application induces synthesis of extracellular matrix (ECM) and cytokines in pancreatic stellate cells (PSCs) and that epigallocatechin gallate (EGCG), a potent antioxidant, inhibits the transformation of PSCs from quiescent to activated phenotype and ethanol-induced synthesis of ECM and cytokines in PSCs. These results suggest that oxidative stress and reactive oxygen species (ROS) are important in PSC activation. The aim of this study was to clarify the effects of ROS on activation and functions of pressure-stimulated PSCs. We used freshly isolated rat PSCs and culture-activated PSCs. Pressure was applied on rat cultured PSCs by adding compressed helium gas into a pressure-loading apparatus. PSCs were cultured with or without antioxidants (EGCG and N-acetyl cysteine) under normal or elevated pressure. Externally applied high pressure (80 mmHg) resulted in a gradual decrease of superoxide dismutase activity in PSCs and increased intracellular ROS generation as early as 30 s, reaching a peak level at 1 h. Antioxidants significantly inhibited ROS generation. Pressure increased the expression levels of α-smooth muscle actin, α1(I)-procollagen, and TGF-β1 in PSCs. EGCG suppressed these alterations, abolished pressure-induced phosphorylation of p38 MAPK, and suppressed pressure-induced PSC transformation to activated phenotype. Our results indicated that ROS is a key player in pressure-induced PSC activation and ECM synthesis. Antioxidants could be potentially effective against the development of pancreatic fibrosis in patients with chronic pancreatitis.

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