A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-α production

Zhanxiang Zhou, Lipeng Wang, Zhenyuan Song, Jason C. Lambert, Craig J. McClain, Yujian Kang

Research output: Contribution to journalArticle

152 Citations (Scopus)

Abstract

Tumor necrosis factor-α (TNF-α) production is a critical factor in the pathogenesis of alcoholic liver injury. Both oxidative stress and endotoxin have been implicated in the process of alcohol-induced TNF-α production. However, a cause-and-effect relationship between these factors has not been fully defined. The present study was undertaken to determine the mediators of acute alcohol-induced TNF-α production using a mouse model of acute alcohol hepatotoxicity. Alcohol administration via gavage at a dose of 6 g/kg to 129/Sv mice induced hepatic TNF-α production in Kupffer cells as demonstrated by measuring protein levels, immunohistochemical localization, and mRNA expression. Alcohol intoxication caused liver injury in association with increases in plasma endotoxin and hepatic lipid peroxidation. Treatment with an endotoxin neutralizing protein significantly suppressed alcohol-induced elevation of plasma endotoxin, hepatic lipid peroxidation, and inhibited TNF-α production. Treatment with antioxidants, N-ACETYL-L-CYSTEINE, or dimethylsulfoxide, failed to attenuate plasma endotoxin elevation, but significantly inhibited alcohol-induced hepatic lipid peroxidation, TNF-α production and steatosis. All treatments prevented alcohol-induced necrotic cell death in the liver. This study thus systemically dissected the relationship among plasma endotoxin elevation, hepatic oxidative stress, and TNF-α production following acute alcohol administration, and the results demonstrate that oxidative stress mediates endotoxin-induced hepatic TNF-α production in acute alcohol intoxication.

Original languageEnglish (US)
Pages (from-to)1137-1146
Number of pages10
JournalAmerican Journal of Pathology
Volume163
Issue number3
DOIs
StatePublished - Sep 1 2003
Externally publishedYes

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Oxidative Stress
Tumor Necrosis Factor-alpha
Endotoxins
Alcohols
Liver
Lipid Peroxidation
Alcoholic Intoxication
129 Strain Mouse
Kupffer Cells
Wounds and Injuries
Dimethyl Sulfoxide
Proteins
Cell Death
Antioxidants
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-α production. / Zhou, Zhanxiang; Wang, Lipeng; Song, Zhenyuan; Lambert, Jason C.; McClain, Craig J.; Kang, Yujian.

In: American Journal of Pathology, Vol. 163, No. 3, 01.09.2003, p. 1137-1146.

Research output: Contribution to journalArticle

Zhou, Zhanxiang ; Wang, Lipeng ; Song, Zhenyuan ; Lambert, Jason C. ; McClain, Craig J. ; Kang, Yujian. / A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-α production. In: American Journal of Pathology. 2003 ; Vol. 163, No. 3. pp. 1137-1146.
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