Leukocyte alterations do not account for hepatitis induced by endotoxin or TNFα in galactosamine-sensitized mice

Potentiation by granulocyte macrophage colony-stimulating factor of lipopolysaccharide toxicity in mice.

“…It is known that pretreatment of monocytes with GM-CSF primes these cells for endotoxin-induced TNF production (19). Like LPS shock models, the GalN/LPS-induced hepatitis is an endotoxic model where the pivotal role of TNF for inducing hepatotoxicity is documented (24,34,35). The present study demonstrates that GM-CSF is able to prime for LPSinduced TNF-production in vivo and that this priming may, in fact, have detrimental consequences for the whole organism.…”

“…Next we examined whether priming for enhanced cytokine release takes place in vivo and which consequences arise from this phenomenon in endotoxic shock models in animals. In a lethality model ofLPS toxicity, all BALB/c mice pretreated with 50 ,g/kg GM-CSF before subtoxic LPS challenge (3 mg/kg) died within 24 h, whereas all animals which had received LPS alone, survived > 72 h (n = 6). Serum TNF levels 1.5 h after challenge were significantly enhanced by GM-CSF pretreatment compared to LPS challenge alone (17.6±3.3 ng/ml vs. 0.8±0.1 ng/ml; P < 0.05).…”

“…In the alternative model, i.e., endotoxin-induced liver injury in GalN-sensitized mice, serum transaminase release 8 h after challenge allowed the quantification of septic organ failure (22). As in the case of LPS-induced mortality (23), anti-mouse TNF antiserum also protected against LPS-induced hepatic failure in GalN-sensitized mice, emphasizing the common final pathway in either model (24). The biochemical basis of the GalN model is the fact that this aminosugar depletes intracellular uridine nucleotides selectively within the liver, leading to an inhibition of hepatic transcription (25), and thereby sensitizes mice towards LPS toxicity several thousand-fold (26).…”

Importance of Kupffer Cells for T-Cell-Dependent Liver Injury in Mice

“…rmuTNF 1 hour later. This very low dose of rmuTNF, known to be nontoxic to mice when given alone, 32,33 was able to cause liver injury in otherwise resistant PEA-treated, KC-depleted mice, as determined by release of plasma transaminases 12 hours after injection of PEA (Table 1). Hence, as little as 0.5 g/kg of rmuTNF was able to overcome the protective effect of KC depletion.…”

Bacterial lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor α

“…Furthermore, LPS-induced expression of TNF-␣ has been shown to contribute to the increased susceptibility to other hepatotoxicants. [19][20][21] The purpose of this study was to gain insight into the mechanism by which LPS administration increases the susceptibility to AFB 1 hepatotoxicity. The objective was to determine the impact of TNF-␣ expression and COX-2 activity during potentiation of AFB 1 hepatotoxicity by a small dose of LPS.…”