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Reactive oxygen species induced by bile acid induce apoptosis and protect against necrosis in pancreatic acinar cells

Booth, David, Murphy, John, Mukherjee, Rajarshi, Awais, Muhammad, Neoptolemos, John, Gerasimenko, Oleg Vsevolodovich, Tepikin, Alexei, Petersen, Ole Holger, Sutton, Robert and Criddle, David 2011. Reactive oxygen species induced by bile acid induce apoptosis and protect against necrosis in pancreatic acinar cells. Gastroenterology 140 (7) , pp. 2116-2125. 10.1053/j.gastro.2011.02.054

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Abstract

Background & Aims: Oxidative stress is implicated in the pathogenesis of pancreatitis, but clinical trials of antioxidants have produced conflicting results. We examined the role of intracellular reactive oxygen species (ROS) in pancreatic acinar cell injury. Methods: Freshly isolated murine and human pancreatic acinar cells were studied using confocal microscopy to measure changes in intracellular and mitochondrial ROS concentrations ([ROS]I and [ROS]M), cytosolic and mitochondrial calcium concentrations ([Ca2+]C and [Ca2+]M), reduced nicotinamide adenine dinucleotide phosphate levels, and death pathways in response to taurolithocholate acid sulfate (TLC-S) or the oxidant menadione. Ca2+-activated Cl– currents were measured using whole-cell patch clamp, with or without adenosine triphosphate (ATP). Results: TLC-S induced prolonged increases in [Ca2+]C and [Ca2+]M, which led to dose-dependent increases in [ROS]I and [ROS]M, impaired production of ATP, apoptosis, and necrosis. Inhibition of the antioxidant reduced nicotinamide adenine dinucleotide phosphate quinine oxidoreductase by 2,4-dimethoxy-2-methylnaphthalene potentiated the increases in [ROS]I and apoptosis but reduced necrosis, whereas the antioxidant N-acetyl-l-cysteine reduced [ROS]I and apoptosis but increased necrosis. Inhibition of mitochondrial ROS production prevented apoptosis but did not alter necrosis; autophagy had no detectable role. Patched ATP prevented sustained increases in [Ca2+]C and necrosis. Conclusions: Increases in [ROS]M and [ROS]I during bile acid injury of pancreatic acinar cells promote apoptosis but not necrosis. These results indicate that alternative strategies to antioxidants are required for oxidative stress in acute pancreatitis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > Q Science (General)
Uncontrolled Keywords: pancreas; free radicals; NQO1; caspase activation
Publisher: Elsevier
ISSN: 0016-5085
Funders: MRC
Last Modified: 04 Jun 2017 03:31
URI: http://orca.cf.ac.uk/id/eprint/22297

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