On study day 0, animals are time dosed at one minute intervals and then given intravenous or inter-peritoneal injections of lipopolysaccharide (LPS, 0.01 to 2 mg/kg mg/kg) at corresponding one minute intervals.
Lipopolysaccharide (LPS) injection of rats and mice results in elevated inflammatory cytokine levels, including TNF-a levels, which peak 1.5 hours post injection, and IL-6 levels, which peak 1.5 to 2.5 hours post injection.1,2 Compounds that inhibit production of inflammatory cytokines can be evaluated using experimental conditions in which compounds are given a half hour to an hour prior to the LPS challenge, depending on the pharmacokinetics of the compound.1
After 1.5 to 24 hours, animals are bled by abdominal aorta into blood collection tubes. Following blood collection and processing, serum or plasma is analyzed by ELISA or Luminex for circulation (or tissue bound) cytokines.
Treatment of rats with D-galactosamine (D-GaIN) has been shown to significantly increase the animal’s sensitivity to the lethal effects of LPS when injected together, and then decreases successively when LPS injection occurs 1, 2, or 3 hours subsequent to D-GaIN sensitization.3Although the D-GaIN/LPS model has been used as an experimental model for human septic shock, there is evidence to suggest that this model accounts for TNF-α induced caspase-dependent fulminant hepatitis rather than the systemic inflammatory response of septic shock.4 Tumor necrosis factor (TNF) has been shown to be identical to lipopolysaccharides (LPS) in its lethal effects in D-galactosamine (D-GaIN) treated mice, and represent a mediator for the initiation of the lethal toxicity of endotoxin.5
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