title: Thioredoxin is associated with endotoxin tolerance in mice.
abstract: OBJECTIVE
  Oxidative stress and subsequent lipid peroxidation appear to be central to the lethal effect of lipopolysaccharide. We hypothesized that induction of an antioxidant protein, thioredoxin, would play an important role in the development of endotoxin tolerance and reduce mortality rates in lipopolysaccharide-treated mice.
  
  
  METHODS
  Prospective, randomized, controlled study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Adult, male, ddy mice.
  
  
  METHODS
  In survival-curve experiments, mice were pre-treated intravenously with a low dose of Escherichia coli lipopolysaccharide (20 microg/mouse, pretreatment group) or saline (control group). A large dose of lipopolysaccharide (200 microg/mouse) subsequently was injected into the tail vein 16 hrs after pretreatment. In experiments to measure the expression of thioredoxin after lipopolysaccharide challenge, mice were injected intravenously with different concentrations of lipopolysaccharide (between 20 and 200 microg/mouse, designated the lipopolysaccharide group) or with saline (control group).
  
  
  RESULTS
  The survival rate during the 72-hr observation period was significantly higher in the pretreatment group (82%) than in the control group (30%; p = .025 by Mantel-Cox log rank analysis). After lipopolysaccharide challenge, thioredoxin concentrations in the lung, heart, and liver of mice in the pretreated group were about 1.5- to 2-fold higher than those in the control group. Enhancement in these organs became apparent about 6 hrs after lipopolysaccharide challenge and lasted until at least 24 hrs. The levels of accumulation of 4-hydroxy-2-nonenal modified proteins after a large dose of lipopolysaccharide challenge were lower in the pretreatment group than in the control group.
  
  
  CONCLUSIONS
  These results demonstrate that mice with an increased concentration of thioredoxin, induced by pretreatment with a low dose of lipopolysaccharide, had increased survival when given a subsequent high-dose challenge of lipopolysaccharide. Thus, thioredoxin is associated with the development of endotoxin tolerance in mice.
authors.affiliation: Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, Kita-kyusyu, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sano
authors.forename: Takeyoshi
authors.initials: T
authors.lastname: Sata
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nanri
authors.forename: Masaharu
authors.initials: M
authors.lastname: Ikeda
authors.forename: Akio
authors.initials: A
authors.lastname: Shigematsu
mesh_terms: D000818:Animals; D004361:Drug Tolerance / Q000502:physiology*; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D013879:Thioredoxins