The role of tumor necrosis factor-α in acute endotoxin-induced hepatotoxicity in ethanol-fed rats

Hansen, John F.; Cherwitz, David L.; Allen, John I.

doi:10.1002/hep.1840200228

Cited by 95 publications

(38 citation statements)

References 28 publications

(35 reference statements)

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“…In alcoholic hepatitis, inflammatory cytokines, such as TNF-α, induce the liver injury [15] . After chronic ethanol feeding, Kupffer cells exhibit enhanced sensitivity to LPS-stimulated TNF-α production [16] .…”

Section: Discussionmentioning

confidence: 99%

Innate immune reactivity of the liver in rats fed a cholinedeficient L-amino-acid-defined diet

Kawaratani¹,

Tsujimoto²,

Kitazawa³

et al. 2008

WJG

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AIM:To investigate the innate immune reactivity of tumor necrosis factor-alpha (TNF-α), Toll-like receptor 4 (TLR4), and CD14 in the liver of non-alcoholic steatohepatitis (NASH) model rats. METHODS: Male F344 rats were fed a cholinedeficient L-amino-acid-defined (CDAA) diet. The rats were killed after 4 or 8 wk of the diet, and their livers were removed for immunohistochemical investigation and RNA extraction. The liver specimens were immunostained for TNF-α, TLR4, and CD14. The gene expressions of TNF-α , TLR4 , and CD14 were determined by reverse-transcriptase polymerase chain reaction (RT-PCR). Kupffer cells were isolated from the liver by Percoll gradient centrifugation, and were then cultured to measure TNF-α production. RESULTS: The serum and liver levels of TNF-α in the CDAA-fed rats increased significantly as compared with the control group, as did the immunohistochemical values and gene expressions of TNF-α, TLR4, and CD14 with the progression of steatohepatitis. TNF-α production from the isolated Kupffer cells of the CDAAfed rats was elevated by lipopolysaccharide stimulation. CONCLUSION: The expressions of TNF-α, TLR4, and CD14 increased in the NASH model, suggesting that TLR4 and CD14-mediated endotoxin liver damage may also occur in NASH.

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Section: Discussionmentioning

confidence: 99%

Innate immune reactivity of the liver in rats fed a cholinedeficient L-amino-acid-defined diet

Kawaratani¹,

Tsujimoto²,

Kitazawa³

et al. 2008

WJG

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“…47 and chronic ethanol may have a priming effect. This is suggested from studies with Kupffer cells isolated from rats chronically fed ethanol, which exhibited enhanced LPS-induced TNF-␣ release, 48 possibly as a consequence of enhanced CD14 expression. 14 The present study thus suggests that, although chronic endotoxin caused sustained expression of proinflammatory cytokines, priming of Kupffer cells or sensitization of hepatocytes was absent or insufficient for damage to develop.…”

Section: Fig 1 (A)mentioning

confidence: 99%

Effect of Chronic Coadministration of Endotoxin and Ethanol on Rat Liver Pathology and Proinflammatory and Anti–Inflammatory Cytokines

et al. 1999

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To better understand how gut-derived endotoxins influence alcohol-induced liver injury and the expression of inflammatory cytokines a new animal model was developed. After 2 weeks on a modified ethanol-containing liquid diet, some rats also were infused with endotoxin via osmotic minipumps for 4 additional weeks. Ethanol diet alone increased plasma endotoxin threefold to 9.3 pg/mL. Endotoxin infusion increased the levels to 388 and 513 pg/mL in controls and ethanol-fed animals, respectively. Panlobular macrovesicular and microvesicular steatosis and inflammatory foci were observed in livers from both ethanol-and ethanol-endotoxin-treated animals, but there was no significant potentiation by endotoxin. Only minor changes, mainly polymorphonuclear infiltration, were seen in animals treated with endotoxin alone although the messenger RNA (

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“…LPS directly causes liver injury by mechanisms involving inflammatory cells such as Kupffer cells, and chemical mediators such as superoxide, nitric oxide, and tumor necrosis factor (TNFa) and other cytokines [31,81,91]. In addition, LPS potentiates liver damage induced by hepatotoxins including ethanol [10,19,30,46,59,84]. In experimental alcoholic liver disease, the combination of LPS and chronic ethanol produces hepatic necrosis and inflammation [30,46,59,84].…”

Section: Kupffer Cells and Alcoholic Liver Diseasementioning

confidence: 99%

CYP2E1 potentiation of LPS and TNFα-induced hepatotoxicity by mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP kinases, and mitochondrial dysfunction

Cederbaum

2009

Genes Nutr

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The mechanisms by which alcohol causes cell injury are not clear. A major mechanism that is the focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a role in how alcohol induces oxidative stress. Considerable attention has been given to alcohol-elevated production of lipopolysaccharide (LPS) and TNFa and to alcohol induction of CYP2E1. These two pathways are not exclusive of each other, however, associations and interactions between them, especially in vivo, have not been extensively evaluated. We have shown that increased oxidative stress from induction of CYP2E1 in vivo sensitizes hepatocytes to LPS and TNF toxicity and that oxidants, such as peroxynitrite, activation of p38 and JNK MAP kinases, inactivation of NF-kB protective pathways and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNF potentiated hepatotoxicity. This review will summarize studies showing potentiated interactions between these two risk factors in promoting liver injury and the mechanisms involved.Keywords Alcohol Á CYP2E1 Á Lipopolysaccharide Á Oxidative stress Á Tumor necrosis factor alpha Alcohol, oxidative stress and cell injuryThe ability of acute and chronic ethanol treatment to increase production of reactive oxygen species and to enhance peroxidation of lipids, protein, and DNA has been demonstrated in a variety of systems, cells, and species, including humans [3]. Despite a tremendous growth in understanding alcohol metabolism and actions, the mechanism(s) by which alcohol causes cell injury are still not clear. A variety of leading mechanisms has been briefly summarized [13,17,67], and it is likely that many of them ultimately converge as they reflect a spectrum of the organism's response to the myriad of direct and indirect actions of alcohol. A major mechanism that is a focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a key role in how ethanol induces ''oxidative stress''. Some of these include redox state changes (decrease in the NAD ? /NADH redox ratio) produced as a result of ethanol oxidation by alcohol and aldehyde dehydrogenases; production of the reactive product acetaldehyde as a consequence of ethanol oxidation by all major oxidative pathways; damage to mitochondria which results in decreased ATP production; direct or membrane effects caused by hydrophobic ethanol interaction with either phospholipids or protein components or enzymes; ethanol-induced hypoxia, especially in the pericentral zone of the liver acinus as oxygen is consumed in order for the liver to detoxify ethanol via oxidation; ethanol effects on the immune system, and altered cytokine production; ethanol-induced increase in bacterialderived endotoxin with subsequent activation of Kupffer cells; ethanol induction of CYP2E1; ethanol mobilization of iron which results in enhanced levels of low molecular weight non-heme iron; effects...

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The role of tumor necrosis factor-α in acute endotoxin-induced hepatotoxicity in ethanol-fed rats

Cited by 95 publications

References 28 publications

Innate immune reactivity of the liver in rats fed a cholinedeficient L-amino-acid-defined diet

Innate immune reactivity of the liver in rats fed a cholinedeficient L-amino-acid-defined diet

Effect of Chronic Coadministration of Endotoxin and Ethanol on Rat Liver Pathology and Proinflammatory and Anti–Inflammatory Cytokines

CYP2E1 potentiation of LPS and TNFα-induced hepatotoxicity by mechanisms involving enhanced oxidative and nitrosative stress, activation of MAP kinases, and mitochondrial dysfunction

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