Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species

Michael, Sherryll L.; Pumford, Neil R.; Mayeux, Philip R.; Niesman, Michael R.; Hinson, Jack

doi:10.1002/hep.510300104

Cited by 312 publications

(271 citation statements)

References 33 publications

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“…Increased reactive oxygen formation has been implicated in APAP hepatotoxicity. 6,9,25 Our results indicate that neutrophils are important cellular sources of reactive oxygen intermediates in the liver (Fig. 6), which might be involved in mediating hepatocyte death.…”

Section: Discussionmentioning

confidence: 66%

“…4,6,9 Activated phagocytes undergo respiratory burst to generate superoxide and hydrogen peroxide, which are important in killing invading organisms, and are also capable of inflicting damage to surrounding tissues. Respiratory burst was measured in isolated hepatic leukocytes stimulated by PMA to examine whether neutrophils contribute to oxidative stress in the liver.…”

Section: Respiratory Burst In Hepatic Leukocytesmentioning

confidence: 99%

“…[5][6][7][8][9][10][11] The inflammatory mediators such as cytokines, chemokines, reactive oxygen, and nitrogen species released by Kupffer cells/macrophages have been implicated in APAP hepatotoxicity. [5][6][7][8][9][10] We have previously reported that natural killer (NK) and NKT cells, a major component of liver innate immune system, play a critical role in the severity and progression of APAP-induced liver injury by secreting cytokine interferon gamma (IFN-␥), modulating chemokine production and recruitment of inflammatory cells into the liver. 11 Our previous study also identified neutrophils as a major fraction of inflammatory cells in the liver from APAP-challenged mice.…”

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confidence: 99%

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Neutrophil depletion protects against murine acetaminophen hepatotoxicity†‡

et al. 2006

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We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-␥) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP hepatotoxicity. C57BL/6 mice were given an intraperitoneal toxic dose of APAP (500 mg/kg), which caused severe acute liver injury characterized by significant elevation of serum ALT, centrilobular hepatic necrosis, and increased hepatic inflammatory cell accumulation. Flow cytometric analysis of isolated hepatic leukocytes demonstrated that the major fraction of increased hepatic leukocytes at 6 and 24 hours after APAP was neutrophils (Mac-1 ؉ Gr-1 ؉ ). Depletion of neutrophils by in vivo treatment with anti-Gr-1 antibody (RB6-8C5) significantly protected mice against APAP-induced liver injury, as evidenced by markedly reduced serum ALT levels, centrilobular hepatic necrosis, and improved mouse survival. The protection was associated with decreased FasL-expressing cells, cytotoxicity against hepatocytes, and respiratory burst in hepatic leukocytes. In intracellular adhesion molecule (ICAM)-1-deficient mice, APAP caused markedly reduced liver injury when compared with wild-type mice. The marked protection in ICAM-1-deficient mice was associated with decreased accumulation of neutrophils in the liver. Hepatic GSH depletion and APAP-adducts showed no differences among the antibody-treated, ICAM-1-deficient, and normal mice. In conclusion, accumulated neutrophils in the liver contribute to the progression and severity of APAP-induced liver injury. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

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Section: Discussionmentioning

confidence: 66%

Section: Respiratory Burst In Hepatic Leukocytesmentioning

confidence: 99%

mentioning

confidence: 99%

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Neutrophil depletion protects against murine acetaminophen hepatotoxicity†‡

et al. 2006

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“…6 Suppression of KCs function by pretreatment with GD has been shown to ameliorate or even prevent chemically induced liver damage in rats and mice. 7,8 Although it is known that GD selectively reduces the capacity of KCs to ingest cellular matter and reduces both cytokine and free radical production in response to hepatic injury, 9-11 the precise effects of GD administration on KCs are not well defined. Zymosan is a substance derived from the cell wall of the yeast Saccharomyces cerevisiae.…”

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confidence: 99%

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Moriconi

Ahmad

Ramadori

et al. 2009

Laboratory Investigation

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The liver and the spleen are the organs in which cellular material and aged erythrocytes are eliminated from the blood. Within the liver, Kupffer cells (KCs) are mainly responsible for this task, as such KCs have a pivotal role in iron metabolism. The aim of this study is to investigate the changes of hepatic gene expression in two models of KC phagocytosis. Gadolinium chloride (GD) or zymosan was injected intraperitoneally into rats and to endotoxin-resistant mice (C3H/HeJ). The animals were killed at different time points and their livers were immediately frozen in liquid nitrogen for RNA isolation and immunohistological studies. RNA was analyzed by real-time PCR and northern blot. Sera were used to measure transaminases, hepcidin and iron levels. The expression of iron metabolism genes, hepcidin, hemojuvelin (Hjv), ferroportin-1 (Fpn-1) and of the inflammatory cytokines IL-6, IL-1b, TNF-a and IFN-g was determined. Although phagocytosed material was detected in ED-1-and C1q-positive cells, no inflammatory cells were identified within the liver parenchyma. Serum levels of hepcidin, iron and transaminases did not differ from those of control animals. Both GD and zymosan induced an upregulation of hepcidin-gene expression in rat liver as early as 3 h, reaching a maximum 6 h after treatment. Hjv-and Fpn-1-gene expression was downregulated at the same time. IL-6 was by far the most induced acute-phase-cytokine in GD-and zymosan-treated livers, although IL-1b and TNF-a were also strongly upregulated by zymosan and to a lesser extent by GD. Similar results were obtained in the C3H/HeJ mouse strain excluding the possible role of contaminating endotoxin. This study shows that phagocytosis upregulates hepcidin-gene expression and downregulates Hjv-and Fpn-1-gene expression within the liver. These changes in iron-regulating-gene expression may be mediated by the locally produced acute-phase-cytokines.

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“…Several studies have shown that pre-treatment with Gadolinium (Gd), a lanthanide rare earth element, alleviates acetaminophen-, CCl 4 -and ethanolinduced liver injury in rats (9,13,15). Badger et al (1) suggested that Gd serves as an alleviator of P450 induction.…”

mentioning

confidence: 99%

Gadolinium chloride suppresses styrene-induced cytochrome P450s expression in rat liver

Hirasawa¹,

Kawagoe²,

Wang³

et al. 2007

Biomed. Res.

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To assess the effect of gadolinium (Gd) on the expression of several forms of cytochrome P450 (P450s) and antioxidant enzymes, we treated rats with gadolinium chloride (25 mg as Gd/kg body weight) 4 h after styrene (a multiple P450 inducer) treatment (600 mg/kg). Gd treatment significantly suppressed styrene-inducible cytochrome P4502B1 (CYP2B1), CYP2B2, CYP2E1, and CYP3A2 mRNA expressions to 48.6%, 69.8%, 61.1%, and 38.5%, accompanying with the reduction of proteins expression to 1.42%, 31.2%, 21.1% and 21.1%, respectively, compared with styrene alone treatment. Gd suppressed styrene-inducible CYP1A2 expression, but only at the protein level. On the other hand, styrene treatment caused a decrease in reduced form of glutathione (GSH), as well as increases in lipid peroxide and serum ALT and AST activities, suggesting the occurrence of hepatic damage probably due to styrene-induced oxidative stress in rat liver. Post-treatment of Gd attenuated this styrene-caused hepatic damage. Moreover, mRNA expressions of cellular antioxidant enzymes such as catalase, CuZn-superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPX) were hardly changed by styrene and/or Gd treatment. In summary, Gd suppressed styrene-inducible expression of not only CYP2B1 but also several forms of P450 at both the mRNA and protein levels, along with attenuation of styrene-caused liver damage. These findings suggested that Gd is a chemo-preventive agent against hepatic damage caused by xenobiotics requiring biotransformation.

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Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species

Cited by 312 publications

References 33 publications

Neutrophil depletion protects against murine acetaminophen hepatotoxicity†‡

Neutrophil depletion protects against murine acetaminophen hepatotoxicity†‡

Phagocytosis of gadolinium chloride or zymosan induces simultaneous upregulation of hepcidin- and downregulation of hemojuvelin- and Fpn-1-gene expression in murine liver

Gadolinium chloride suppresses styrene-induced cytochrome P450s expression in rat liver

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