Essential role of tumor necrosis factor α in alcohol-induced liver injury in mice

Yin, Meizhen; Wheeler, Michael D.; Kono, Hiroshi; Bradford, Blair U.; Gallucci, Randle M.; Luster, Michael I.; Thurman, Ronald G.

doi:10.1016/s0016-5085(99)70354-9

Cited by 681 publications

(516 citation statements)

References 30 publications

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“…In the intragastric model of chronic ethanol administration, the development of liver injury coincided with an increase in TNFα, associated with an increase in serum LPS (195,(197)(198)(199). The pioneering studies of Thurman and collaborators showed that anti-TNFα antibody prevented alcohol liver injury in rats (200) and mice lacking the TNFR1 receptor did not develop alcohol liver injury (133). Taken as a whole, these and other studies clearly implicate TNFα as a major risk factor for the development of alcoholic liver injury.…”

Section: Lps/tnfα-cyp2e1 Interactionsmentioning

confidence: 82%

“…On the other hand, studies by Thurman and colleagues have presented powerful support for a role for endotoxin, activation of Kupffer cells and cytokines such as TNFα in the alcoholinduced liver injury found with the intragastric infusion model (133,134). They suggested that CYP2E1 may not play a role in alcohol liver injury based upon studies with gadolinium chloride or CYP2E1 knockout mice (135,136).…”

Section: Cyp2e1 and Alcohol-induced Liver Injurymentioning

confidence: 99%

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CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

659

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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Section: Lps/tnfα-cyp2e1 Interactionsmentioning

confidence: 82%

Section: Cyp2e1 and Alcohol-induced Liver Injurymentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

659

534

View full text Add to dashboard Cite

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“…However, in this case, increased fatty acid degradation and reversal of ethanol effects on triglyceride packaging and transport also result in reduced steatosis. A significant role for oxidative stress in the elevation of TNFα following ethanol consumption and a central role for TNFα in the development of necrosis in alcoholic livers have been proposed by several investigators [4,[51][52][53][54]. However, it has also been proposed that elevation of TNFα plays a role in the development of alcoholic steatosis [4].…”

Section: Discussionmentioning

confidence: 99%

“…However, it has also been proposed that elevation of TNFα plays a role in the development of alcoholic steatosis [4]. This hypothesis is based largely on the report of Yin et al [51] demonstrating that liver damage and steatosis were completely prevented in ethanol-infused TNFR1 knockout mice and a recent report from Zhou et al [52] that NAC reverses oxidative stress, TNFα, and steatosis following acute ethanol administration to 129/ Sv mice. However, our current data with chronic ethanol administration in rats showed no correlation between TNFα expression and steatosis score and suggests that TNFα plays little or no role in the development of alcoholic steatosis.…”

Section: Discussionmentioning

confidence: 99%

Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition

Ronis

Butura

Sampey

et al. 2005

Free Radical Biology and Medicine

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The effects of the dietary antioxidant N-acetylcysteine (NAC) on alcoholic liver damage were examined in a total enteral nutrition (TEN) model of ethanol toxicity in which liver pathology occurs in the absence of endotoxemia. Ethanol treatment resulted in steatosis, inflammatory infiltrates, occasional foci of necrosis, and elevated ALT in the absence of increased expression of the endotoxin receptor CD14, a marker of Kupffer cell activation by LPS. In addition, ethanol treatment induced CYP2E1 and increased TNFα and TGFβ mRNA expression accompanied by suppressed hepatic IL-4 mRNA expression. Ethanol treatment also resulted in the hepatic accumulation of malondialdehyde (MDA) and hydroxynonenal (HNE) protein adducts, decreased antioxidant capacity, and increased antibody titers toward serum hydroxyethyl radical (HER), MDA, and HNE adducts. NAC treatment increased cytosolic antioxidant capacity, abolished ethanol-induced lipid peroxidation, and inhibited the formation of antibodies toward HNE and HER adducts without interfering with CYP2E1 induction. NAC also decreased ethanol-induced ALT release and inflammation and prevented significant loss of hepatic GSH content. However, the improvement in necrosis score and reduction of TNFα mRNA elevation did not reach statistical significance. Although a direct correlation was observed among hepatic MDA and HNE adduct content and TNFα mRNA expression, inflammation, and necrosis scores, no correlation was observed between oxidative stress markers or TNFα and steatosis score. These data suggest that ethanol-induced oxidative stress can contribute to inflammation and liver injury even in the absence of Kupffer cell activation by endotoxemia.

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“…9 Among them, tumor necrosis factor α (TNF-α) is considered one of the most important cytokines involved in the pathogenesis of alcoholic liver injury, with evidence showing that disruption of the TNF-αR1 gene or treatment with a TNF-α neutralizing antibody reduces alcoholic liver injury in mice. 10,11 In contrast, adiponectin and interleukin-6 (IL-6) have been shown to protect against alcoholic liver injury. 12-16 For example, genetic ablation of the IL-6 gene enhanced alcohol-induced liver injury, whereas IL-6 treatment ameliorated alcoholic liver injury and alcoholic fatty liver transplant.…”

Section: Introductionmentioning

confidence: 99%