Acetaldehyde accumulation suppresses Kupffer cell release of TNF-α and modifies acute hepatic inflammation in rats

Yuji Nakamura, Hirokazu Yokoyama, Susumu Higuchi, Sachiko Hara, Shinzo Kato, Hiromasa Ishii

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12 Citations (Scopus)

Abstract

Background. Alcohol-related diseases have multiple and varied associations with acetaldehyde, a highly toxic product of ethanol oxidation that accumulates in the absence of active aldehyde dehydrogenase (ALDH). This study was designed to clarify the role of acetaldehyde in liver injury, specifically in vivo and in vitro effects on Kupffer cell release of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Methods. Rats pretreated overnight with the ALDH inhibitor disulfiram (or saline control) were ethanol loaded and challenged with lipopolysaccharide (LPS), and their blood and histological parameters were examined 3 h later. Similarly, isolated rat Kupffer cells were pretreated with disulfiram or cyanamide incubated in ethanol (1 h), then challenged with LPS and evaluated 2 h later for TNF-α and acetaldehyde levels in the culture medium. TNF-α release from Kupffer cells after LPS challenge was also evaluated following incubation in acetaldehyde and acetate for comparison with ethanol loading. Results. Higher blood acetaldehyde concentration following disulfiram pretreatment significantly attenuated acute hepatic inflammation in the ethanol-loaded, LPS-challenged rat (18 ± 2.9 vs 30 ± 3.7 polymorphonuclear cells/portal area; P = 0.01). After LPS challenge, ALDH inhibitor pretreatment attenuated Kupffer cell release of TNF-α in the presence of disulfiram at 5063 ± 151 pg/ml and cyanamide at 4390 ± 934 pg/ml, versus no inhibitor, 5869 ± 265 pg/ml (P < 0.01), but not in the absence of ethanol. Acetaldehyde significantly suppressed Kupffer cell TNF-α release (P < 0.05), but acetate treatment did not. Conclusions. Acetaldehyde accumulation suppresses macrophage function, at least suppressing TNF-α. release, which plays a role in modifying acute hepatic inflammation in rats.

Original languageEnglish
Pages (from-to)140-147
Number of pages8
JournalJournal of gastroenterology
Volume39
Issue number2
DOIs
Publication statusPublished - 2004 Feb 1

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Keywords

  • Acetaldehyde
  • Inflammation
  • Kupffer cells
  • Lipopolysaccharide
  • TNF-α

ASJC Scopus subject areas

  • Gastroenterology

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