Role of acute ethanol exposure and TLR4 in early events of sepsis in a mouse model

Alcohol. 2011 Dec;45(8):795-803. doi: 10.1016/j.alcohol.2011.07.003. Epub 2011 Aug 27.

Abstract

Sepsis is a major cause of death worldwide. The associated risks and mortality are known to significantly increase on exposure to alcohol (chronic or acute). The underlying mechanisms of the association of acute ethanol ingestion and poor prognosis of sepsis are largely unknown. The study described here was designed to determine in detail the role of ethanol and TLR4 in the pathogenesis of the sepsis syndrome. The effects of acute ethanol exposure and TLR4 on bacterial clearance, spleen cell numbers, peritoneal macrophage numbers, and cytokine production were evaluated using wild-type and TLR4 hyporesponsive mice treated with ethanol and then challenged with a nonpathogenic strain of Escherichia coli. Ethanol-treated mice exhibited a decreased clearance of bacteria and produced lesser amounts of most pro-inflammatory cytokines in both strains of mice at 2h after challenge. Neither ethanol treatment nor a hyporesponsive TLR4 had significant effects on the cell numbers in the peritoneal cavity and spleen 2h postinfection. The suppressive effect of acute ethanol exposure on cytokine and chemokine production was more pronounced in the wild-type mice, but the untreated hyporesponsive mice produced less of most cytokines than untreated wild-type mice. The major conclusion of this study is that acute ethanol exposure suppresses pro-inflammatory cytokine production and that a hyporesponsive TLR4 (in C3H/HeJ mice) decreases pro-inflammatory cytokine levels, but the cytokines and other mediators induced through other receptors are sufficient to ultimately clear the infection but not enough to induce lethal septic shock. In addition, results reported here demonstrate previously unknown effects of acute ethanol exposure on leukemia inhibitory factor and eotaxin, and provide the first evidence that interleukin (IL)-9 is induced through TLR4 in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bacterial Load
  • Cytokines / analysis
  • Cytokines / biosynthesis
  • Escherichia coli
  • Ethanol / administration & dosage*
  • Female
  • Immunity / drug effects
  • Inflammation / physiopathology
  • Macrophages, Peritoneal
  • Mice
  • Mice, Inbred C3H
  • Mice, Mutant Strains
  • Mutation
  • Peritoneal Cavity / microbiology
  • Sepsis / immunology
  • Sepsis / physiopathology*
  • Spleen / immunology
  • Spleen / microbiology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / physiology*

Substances

  • Cytokines
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Ethanol