Cytokine Toxicity and Induction of NO Synthase Activity in Cultured Mouse Hepatocytes

Adamson, Gregory M.; Billings, Ruth E.

doi:10.1006/taap.1993.1048

Cited by 67 publications

(32 citation statements)

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“…The proinflammatory cytokine, interferon-␥, has been shown to exacerbate TNF-␣-induced cytotoxicity in hepatocytes (Adamson and Billings, 1993). These mediators might interact with SLD sulfide, TNF-␣, and/or hypoxia to promote liver injury.…”

Section: Tnf-␣ and Sld Sulfide In An Idiosyncratic Liver Injury Modelmentioning

confidence: 99%

Sulindac Metabolism and Synergy with Tumor Necrosis Factor-α in a Drug-Inflammation Interaction Model of Idiosyncratic Liver Injury

Zou¹,

Beggs²,

Sparkenbaugh³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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Sulindac (SLD) is a nonsteroidal anti-inflammatory drug (NSAID)that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs. In previous studies, cotreatment of rats with SLD and a modestly inflammatory dose of lipopolysaccharide (LPS) led to liver injury, whereas neither SLD nor LPS alone caused liver damage. In studies presented here, further investigation of this animal model revealed that the concentration of tumor necrosis factor-␣ (TNF-␣) in plasma was significantly increased by LPS at 1 h, and SLD enhanced this response. Etanercept, a soluble TNF-␣ receptor, reduced SLD/LPS-induced liver injury, suggesting a role for TNF-␣. SLD metabolites in plasma and liver were determined by LC/MS/MS. Cotreatment with LPS did not increase the concentrations of SLD or its metabolites, excluding the possibility that LPS contributed to liver injury through enhanced exposure to SLD or its metabolites. The cytotoxicities of SLD and its sulfide and sulfone metabolites were compared in primary rat hepatocytes and HepG2 cells; SLD sulfide was more toxic in both types of cells than SLD or SLD sulfone. TNF-␣ augmented the cytotoxicity of SLD sulfide in primary hepatocytes and HepG2 cells. These results suggest that TNF-␣ can enhance SLD sulfide-induced hepatotoxicity, thereby contributing to liver injury in SLD/LPS-cotreated rats.

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Section: Tnf-␣ and Sld Sulfide In An Idiosyncratic Liver Injury Modelmentioning

confidence: 99%

Sulindac Metabolism and Synergy with Tumor Necrosis Factor-α in a Drug-Inflammation Interaction Model of Idiosyncratic Liver Injury

Zou¹,

Beggs²,

Sparkenbaugh³

et al. 2009

The Journal of Pharmacology and Experimental Therapeutics

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“…different inflammatory mediators, including reactive oxygen species and reactive nitrogen species, which can contribute to the genesis, development and progression of hepatic fibrosis [4][5][6]. Nitric oxide (NO) is a highly reactive mediator released in the liver by endothelial cells [7], macrophages [8], hepatocytes [9][10][11], Kupffer cells [12,13] and Ito cells [14] in response to different stimuli [15]. NO is synthesized from L-arginine (ARG) by a whole family of enzymes -termed NO synthases (NOS)-in a reaction that converts arginine and oxygen into citrulline and NO [16].…”

Section: Introductionmentioning

confidence: 99%

Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation

et al. 1999

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Hepatic fibrosis or increased liver collagen contents drive functional abnormalities that, when extensive, may be life threatening. The purpose of this study was to assess the effects of the chronic stimulation or inhibition of nitric oxide synthesis in rats with hepatic fibrosis induced by permanent common bile duct ligation (3 weeks) and the role of expression of the different nitric oxide synthase isoforms. Bile duct ligation led to an important accumulation of collagen in the hepatic parenchyma, as shown both histologically and by the hydroxyproline contents of livers. Bilirubin and serum enzyme activities (measured as markers of cholestasis) increased several-fold after bile duct ligation. The area of fibrotic tissue, liver hydroxyproline content and serum markers of cholestasis were clearly related in obstructed rats. The absence of modifications in haemodynamic parameters excludes circulatory changes from being responsible for the development of liver alterations. In animals treated with NG-nitro-L-arginine methyl ester (L-NAME) the area of fibrosis was similar to that of untreated animals, the signs of cholestasis and cellular injury being more evident. In rats treated with L-arginine the area of fibrosis was almost three times larger than that found in bile duct ligated rats and in L-NAME-treated bile duct ligated rats, although the observed biochemical changes were similar to those seen in rats treated with L-NAME. Our results with inducible nitric oxide synthase, obtained by Western blots and immunohistochemistry, indicate a greater expression of the inducible enzyme in bile duct ligated and L-arginine-treated animals and a lower expression in the L-NAME and control groups. Constitutive nitric oxide synthase expression, obtained by Western blots, was very similar in all groups, except for the L-arginine-treated rats in which it was lower. These results suggest that nitric oxide production may be a key factor in the development of fibrosis in bile duct ligated rats. They also support the hypothesis of a dual role for nitric oxide; one beneficial, mediated by its circulatory effects, and the second negative, through its local toxic effects.

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“…There is ample evidence that TNF␣-mediated pathways activate PLA 2 and increase lipid peroxidation in hepatocytes causing depletion of reduced glutathione (Adamson and Billings, 1993;Adamson et al, 1994). Because of lack of modulation of inflammatory cytokine pathways in NZBW strain it is likely that FB 1 may not induce oxidative damage and consequent hepatotoxicity in these animals.…”

Section: Discussionmentioning

confidence: 99%

Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine

Sharma

Riley

2005

Toxicology

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Cytokine Toxicity and Induction of NO Synthase Activity in Cultured Mouse Hepatocytes

Cited by 67 publications

References 0 publications

Sulindac Metabolism and Synergy with Tumor Necrosis Factor-α in a Drug-Inflammation Interaction Model of Idiosyncratic Liver Injury

Sulindac Metabolism and Synergy with Tumor Necrosis Factor-α in a Drug-Inflammation Interaction Model of Idiosyncratic Liver Injury

Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation

Lupus-prone NZBWF1/J mice, defective in cytokine signaling, are resistant to fumonisin hepatotoxicity despite accumulation of liver sphinganine

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