Nitric Oxide Protects Against Pancreatic Subcellular Damage in Acute Pancreatitis

Sánchez-Bernal, Carmen; García-Morales, Onel H.; Domı́nguez, Carmen; Martı́n-Gallán, Pilar; Calvo, José F.; Ferreira, Laura; Pérez-González, Nieves

doi:10.1097/00006676-200401000-00021

Cited by 23 publications

(20 citation statements)

References 44 publications

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“…Activation of both caspases-8 and -9 and their cross-talk has been reported previously (2,37,50), possibly through inhibitor of apoptosis proteins; however, the precise mechanism remains unclear. Our results are in agreement with the notion that oxidative damage can occur in lysosomes and microsomes, as well as mitochondria (16,54).…”

Section: Discussionsupporting

confidence: 93%

Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins

Baumgartner¹,

Gerasimenko²,

Thorne³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cell-death programs executed in the pancreas under pathological conditions remain largely undetermined, although the severity of experimental pancreatitis has been found to depend on the ratio of apoptosis to necrosis. We have defined mechanisms by which apoptosis is induced in pancreatic acinar cells by the oxidant stressor menadione. Real-time monitoring of initiator caspase activity showed that caspase-9 (66% of cells) and caspase-8 (15% of cells) were activated within 30 min of menadione administration, but no activation of caspase-2, -10, or -12 was detected. Interestingly, when caspase-9 activation was inhibited, activation of caspase-8 was increased. Half-maximum activation (t(0.5)) of caspase-9 occurred within approximately 2 min and was identified at or in close proximity to mitochondria, whereas t(0.5) for caspase-8 occurred within approximately 26 min of menadione application and was distributed homogeneously throughout cells. Caspase-9 but not caspase-8 activation was blocked completely by the calcium chelator BAPTA or bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore. In contrast, caspase-8 but not caspase-9 activation was blocked by the destruction of lysosomes (preincubation with Gly-Phe beta-naphthylamide, a cathepsin C substrate), loss of lysosomal acidity (bafilomycin A1), or inhibition of cathepsin L or D. Using pepstatin A-BODIPY FL conjugate, we confirmed translocation of cathepsin D out of lysosomes in response to menadione. We conclude that the oxidative stressor menadione induces two independent apoptotic pathways within pancreatic acinar cells: the classical mitochondrial calcium-dependent pathway that is initiated rapidly in the majority of cells, and a slower, caspase-8-mediated pathway that depends on the lysosomal activities of cathepsins and is used when the caspase-9 pathway is disabled.

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Section: Discussionsupporting

confidence: 93%

Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins

Baumgartner¹,

Gerasimenko²,

Thorne³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Therefore, commercial preparations of xanthine oxidase may activate PAR-2 receptors and, consequently, bring about Ca 2C oscillations (Namkung et al 2004), and contribute to some effects attributed to ROS. Microsomes, lysosomes and mitochondria were found to be the organelles most susceptible to oxidative damage in caerulein-induced AP (Sanchez-Bernal et al 2004). Another study showed that isolated zymogen granules were markedly more sensitive to oxidative stress than intact acinar cells (Niederau et al 1996).…”

Section: Mechanisms Of Ros and Rns Induced Damage In Pancreatic Acinamentioning

confidence: 98%

Free radicals and the pancreatic acinar cells: role in physiology and pathology

Chvanov

Petersen

Tepikin

2005

Phil. Trans. R. Soc. B

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Reactive oxygen and nitrogen species (ROS and RNS) play an important role in signal transduction and cell injury processes. Nitric oxide synthase (NOS)-the key enzyme producing nitric oxide (NO)-is found in neuronal structures, vascular endothelium and, possibly, in acinar and ductal epithelial cells in the pancreas. NO is known to regulate cell homeostasis, and its effects on the acinar cells are reviewed here. ROS are implicated in the early events within the acinar cells, leading to the development of acute pancreatitis. The available data on ROS/RNS involvement in the apoptotic and necrotic death of pancreatic acinar cells will be discussed.

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“…Oxidative damage in the acinar cells of pancreas is further triggered by an activation of intrapancreatic trypsinogen [38][39][40], and this activated form of trypsin initiates the activity of other digestive zymogens, resulting from rupturing of ZG and, consequently, their number reduction in the acinar cells of groups II and III in the present study (Figs. 1, 2, 3, 4), leading to its autodigestion [41].…”

Section: Discussionmentioning

confidence: 52%

“…5 and 6). The protection of the acinar cells of the pancreas can be attributed to the presence of higher Cu content and vitamin E in the ME Y , which increased the total antioxidant status and Cu concentrations in the cell by displacing excessive Zn ions and increased Se retention in the tissues, leading to decreased oxidative stress in the acinar cells of the pancreas of groups IIME and IIIME rats, respectively [38][39][40]58].…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Zn-Induced Acute Pancreatitis in Wistar Rat Fed on Cu- and Mg- Enriched Modified Poultry % MathType!Translator!2!1!AMS LaTeX.tdl!TeX -- AMS-LaTeX!% MathType!MTEF!2!1!+-% feaaeaart1ev0aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaacbeGaa8xrai% aa-DgacaWFNbWaaWbaaSqabeaaiiqacqGFOoqwaaaaaa!3

Taneja

Mandal

2008

Biol Trace Elem Res

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Zinc (Zn) consumption has increased in many populations either due to the increased intake of Zn-fortified foods as in the USA or in agricultural food stuffs as in some Indian states during the last decade. Its excessive intake has been reported to induce acute pancreatitis (AP) in many studies due to increase in oxidative stress that was further reported to cause Cu and Mg deficiencies. This led us to design a modified poultry egg (ME(Psi)) enriched with Cu and Mg along with other antioxidants, and its efficacy on Zn-induced AP was studied in male Wistar rats. In one set, the rats were fed on equacaloric semi-synthetic basal diet containing 20 mg Zn/kg diet (control, group I), and Zn-induced AP-I diet and AP-II diet containing 40 and 80 mg Zn/kg diet (groups II and III) for 180 days, respectively. In another set, the rats were initially fed on Zn-induced AP-I and AP-II diets for 90 days and then shifted to ME(Psi)-mixed Zn-induced AP-I and AP-II diets in groups IIME and IIIME for another 90 days. At the end of the experiment, data displayed increased serum and urinary Zn, Cu, and Mg levels in groups II and III rats, which were reduced and approached closer to control group I after ME(Psi) feeding in groups IIME and IIIME rats. Transmission electron microscopic studies of acinar cells revealed progressive dilation, vesicularization, and degeneration of endoplasmic reticulum (ER), and decrease in zymogen granules (ZG) in groups II and III rats in contrast to their curvilinear or concentric long parallel running cisternal profile of ER in control group I. The treatment of ME(Psi) helped in the restoration of the ER profile and ZG number, approaching closer to the control group I. The degree of recovery was dependent upon the degree of toxicity caused by the amount of Zn given in the diet. The results of this study suggest that ME(Psi)-mixed diet can protect the acinar cells from the deleterious effects of Zn by decreasing the oxidative stress.

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Nitric Oxide Protects Against Pancreatic Subcellular Damage in Acute Pancreatitis

Cited by 23 publications

References 44 publications

Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins

Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins

Free radicals and the pancreatic acinar cells: role in physiology and pathology

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