Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH<sub>2</sub>-terminal kinase activation

Hong, Ji Young; Lebofsky, Margitta; Farhood, Anwar; Jaeschke, Hartmut

doi:10.1152/ajpgi.90435.2008

Cited by 61 publications

(62 citation statements)

References 60 publications

(96 reference statements)

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“…In our view, this is because wild-type hepatocytes are equipped with efficient antioxidant defenses that make them resistant to iron-induced ROS. Swelling of hepatocytes, causing ALT/AST release, as observed in Nrf2 -/-mice fed iron-rich diet, are typical features of ROS-induced necrosis in vivo [18]. Further evidence of iron-mediated oxidative stress is provided by the increased levels of a specific marker of oxidative DNA damage (8-OHdG) in hepatocytes from Nrf2 -/-mice fed iron-rich diet and the abrogation of the hepatotoxicity of dietary iron via the use of an antioxidant that is targeted to the mitochondria (mito-TEMPOL), which is capable of trapping free radicals and inhibiting the catalytic action of Fe 2+ [30].…”

Section: Discussionmentioning

confidence: 98%

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Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Silva‐Gomes

Santos

Caldas

et al. 2014

Journal of Hepatology

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Background & Aims:The l i v e r , being the major site of i r o n storage, is particularly exposed to the toxic effects of iron. Tran-scription factor NRF2 is critical for protecting the l i v e r a g a i n s t disease by activating the transcription of genes encoding detoxification/antioxidant enzymes. We aimed to determine if the NRF2 pathway plays a significant role in the protection against hepatic iron overload. Methods: Wild type and Nrf2 _ /_ mouse primary hepatocytes Wereincubated with ferric ammonium citrate. Wild type and Nrf2 -/-mice w e r e fed s t anda rd rodent chow or iron-rich diet for 2 weeks, with or without daily i n j e c t i o n of the a n t i o x i d a n t mito-TEMPOL. Results: In mouse hepatocytes, iron induced the nuclear translo-cation of NRF2 and the expression of cytoprotective genes in an NRF2-dependent manner. Moreover, Nrf2 _ /_ hepatocytes were highly susceptible to i r o n -induced cell d e a t h . Wild-type and Nrf2 _ /_ mice fed iron-rich diet accumulated similar amounts of iron in the liver and were equally able to increase the expression of hepatic hepcidin and ferritin. Nevertheless, in Nrf2-null mice the iron loading resulted in progressive liver injury, ranging from mild confluent necrosis to s e v e r e necroinflammatory lesio ns. Hepatocytic cell death was associated with gross ul t r a s t r u c t u r a l damage to the mitochondria. Notably, liver injury was prevented in iron-fed animals that received mito-TEMPOL. Conclusions: NRF2 protects the m o u s e liver against the t o x i c i t y of dietary iron o v e r l o a d by p r e v e n t i n g hepatocytic cell d e a t h . We identify NRF2 as a potential modifier of liver disease in iron overload pathology and show the beneficial effect of the antiox-idant mito-TEMPOL in a mouse model of dietary iron-induced liver injury. ©2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 INTRODUCTIONIron is a component of several metalloproteins involved in crucial metabolic processes such as oxygen sensing and transport, energy metabolism and DNA synthesis. However, iron in excess is detrimental, as it can catalyze the formation of damaging radical species via Fenton-type reactions [1]. In normal conditions, iron toxicity is prevented by the binding of extracellular iron in the plasma to transferrin and by storage of intracellular iron in a protein with high storage capacity, ferritin [2]. In addition, plasma iron levels are tightly regulated by the action of the peptide hormone hepcidin. Hepcidin, which is mostly secreted in the liver, promotes the degradation of the iron exporter ferroportin expressed on the surface of iron-releasing cells, thus reducing intestinal iron absorption and its mobilization fr...

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Section: Discussionmentioning

confidence: 98%

“…4B). We observed both nuclear and cytoplasmic staining of swollen cells, as typically seen in cells undergoing oncotic necrosis due to the release of nucleases from infiltrating inflammatory cells [16][17][18]. We also evaluated the levels of cleaved caspase 3, a critical executioner of apoptosis [19].…”

Section: A01/00mentioning

confidence: 99%

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Silva‐Gomes

Santos

Caldas

et al. 2014

Journal of Hepatology

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“…In particular, administration of D-GalN/LPS causes TNF-a release that contributes to increased oxidative stress and formation of ROS, which are fatal to the cell and result in hepatocyte death as manifested by apoptosis and/or necrosis (Hong et al, 2009). In addition, D-galactosamine is a specific hepatotoxic agent that depletes the uridine triphosphate pool and thereby inhibits protein synthesis (Stachlewitz et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective effect ofCommiphora myrrhaagainstd-GalN/LPS-induced hepatic injury in a rat model through attenuation of pro inflammatory cytokines and related genes

Ahmad

Raish

Ganaie

et al. 2015

Pharmaceutical Biology

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(2015) Hepatoprotective effect of Commiphoramyrrha against d-GalN/LPS-induced hepatic injury in a rat model through attenuation of pro inflammatory cytokines and related genes, Pharmaceutical Biology, 53:12, 1759-1767, DOI: 10.3109/13880209.2015 Results: The administration of D-GalN/LPS increased plasma aminotransferases (174.47 ± 4.5761 and 260.96 ± 1.9839 mkat/l) and total bilirubin levels (1.012 ± 0.0288 mg/dl), which were attenuated by C. myrrha treatment. Hepatic lipid peroxidation activity and nitric oxide content also increased, while the antioxidant activity measured by GSH (0.76 nmol/g protein), SOD (81.91 U/mg protein), and CAT (15.78 U/mg protein) was reduced. Commiphora myrrha provided significant restoration of GSH (0.815 nmol/gm protein), SOD (140.57 U/mg protein), and CAT (27.02 U/mg protein) levels. Furthermore, the acute phase response elicited by D-GalN/ LPS administration enhanced mRNA expressions of TNF-a, IL-6, IL-10, iNOS-2, and HO-1, which were ameliorated by C. myrrha treatment. Discussion and conclusion: These findings indicate that C. myrrha considerably reduces the oxidative stress of D-GalN/LPS-induced hepatic injury via multiple pathways including adown regulation of inflammatory mediators and cytokines. Such a property might be sufficient to combat cellular damage caused by various conditions that resemble fulminant hepatitis and could be of a potential clinical application.

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“…Neutrophil-mediated liver injury has been widely studied using a number of experimental models, including cecal ligation and puncture (2), ischemia-reperfusion (3), alcohol (4), endotoxin (5), and other insults (6). In these situations, neutrophils can be attracted to the liver parenchyma by a variety of inflammatory mediators, including TNF-␣ and IL-1, which produce increased levels of chemokines (7).…”

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confidence: 99%

Selective Down-Regulation of Neutrophil Mac-1 in Endotoxemic Hepatic Microcirculation via IL-10

Menezes

Lee

Zhou

et al. 2009

The Journal of Immunology

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Hepatic neutrophil adhesion during endotoxemia is an integrin-independent, CD44-dependent process. Because integrins function in other endotoxemic vasculatures, we used spinning disk confocal intravital microscopy to assess whether LPS down-modulated integrin functions in sinusoids. First, we applied fMLP onto the liver surface, and compared it with systemic LPS administration. Local fMLP caused neutrophil adhesion, crawling, and emigration for at least 2 h. Surprisingly, the number of adherent and crawling neutrophils was markedly reduced in Mac-1−/− and ICAM-1−/− mice, but not in mice treated with anti-CD44 mAb. By contrast, systemic LPS injection induced a robust accumulation of neutrophils in sinusoids, which was dependent on CD44, but not on integrins. Strikingly, local fMLP could not induce any integrin-dependent adhesion in endotoxemic mice treated with anti-CD44 mAb, indicating that Mac-1-dependent neutrophil adhesion was inhibited by LPS. This response was localized to the hepatic microvasculature because neutrophils still adhered via integrins in brain microvasculature. ICAM-1/ICAM-2 levels were not decreased, but following LPS treatment, Mac-1 was down-regulated in neutrophils localized to liver, but not in the circulation. Mac-1 down-regulation in neutrophils was not observed in IL-10−/− mice. In vitro neutrophil incubation with IL-10 induced direct decrease of Mac-1 expression and adhesivity in LPS-stimulated neutrophils. Therefore, our data suggest that Mac-1 is necessary for neutrophil adhesion and crawling during local inflammatory stimuli in sinusoids, but during systemic inflammation, neutrophils are exposed to high concentrations of IL-10, leading to a CD44-dependent, integrin-independent adhesion. This may be a mechanism to keep neutrophils in sinusoids for intravascular trapping.

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Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH₂-terminal kinase activation

Cited by 61 publications

References 60 publications

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Hepatoprotective effect ofCommiphora myrrhaagainstd-GalN/LPS-induced hepatic injury in a rat model through attenuation of pro inflammatory cytokines and related genes

Selective Down-Regulation of Neutrophil Mac-1 in Endotoxemic Hepatic Microcirculation via IL-10

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Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation

Cited by 61 publications

References 60 publications

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Hepatoprotective effect ofCommiphora myrrhaagainstd-GalN/LPS-induced hepatic injury in a rat model through attenuation of pro inflammatory cytokines and related genes

Selective Down-Regulation of Neutrophil Mac-1 in Endotoxemic Hepatic Microcirculation via IL-10

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Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH₂-terminal kinase activation