title: Acetaldehyde accumulation suppresses Kupffer cell release of TNF-Alpha and modifies acute hepatic inflammation in rats.
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-Alpha).
  
  
  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-Alpha and acetaldehyde levels in the culture medium. TNF-Alpha 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-Alpha 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-Alpha release ( P < 0.05), but acetate treatment did not.
  
  
  CONCLUSIONS
  Acetaldehyde accumulation suppresses macrophage function, at least suppressing TNF-Alpha release, which plays a role in modifying acute hepatic inflammation in rats.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Susumu
authors.initials: S
authors.lastname: Higuchi
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hara
authors.forename: Shinzo
authors.initials: S
authors.lastname: Kato
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Ishii
mesh_terms: D000079:Acetaldehyde / Q000037:antagonists & inhibitors / Q000097:blood*; D000818:Animals; D015152:Blotting, Northern; D018929:Cell Culture Techniques; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000378:metabolism*; D003484:Cyanamide / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D000431:Ethanol / Q000009:adverse effects / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D003484:Cyanamide; D000079:Acetaldehyde; D004221:Disulfiram