Protective Effect of Zinc against Lipopolysaccharide/D-Galactosamine-Induced Lethality.

Abstract

Zinc is an essential and multifunctional element for all cells. Metallothionein (MT) is a low molecular weight, cystein-rich, metal-binding protein that is involved in zinc homeostasis. During the acute-phase reaction, hepatic MT production is induced and hepatic zinc accumulation is stimulated. We previously reported that MT-I and IIdeficient (MT-null) mice are highly sensitive to the lethal effects of lipopolysaccharide (LPS) plus D-galactosamine (GalN). The sensitization may relate to attenuatoin of α 1 -acid glycoprotein (AGP) expression in MT-null mice. In the present study, we hypothesized that MT-induced hepatic zinc accumulation promotes AGP expression and prevents LPS/GalN-induced lethality. To determine whether zinc reduces LPS/GalN toxicity, zinc was administered to mice. Simultaneous administration of zinc and LPS/GalN showed no effect on the lethality of LPS/GalN in mice. Zinc administration at 3 hr prior to LPS/GalN challenge reduced LPS/GalN-induced death. However, zinc pre-administration at 24 hr before LPS/GalN challenge did not reduce LPS/GalN-induced death. The expression of AGP mRNA was elevated at 3 hr after zinc administration, 24-hr pretreatment was ineffective. The protective effect of zinc was observed in both wild-type and MT-null mice. These results show that the protective effects of zinc were not caused by MT induction, but by AGP expression. We suggest that MT-induced hepatic zinc accumulation may promote AGP expression and thus prevent LPS/GalN-induced lethality.

Beryllium Alters Lipopolysaccharide-Mediated Intracellular Phosphorylation and Cytokine Release in Human Peripheral Blood Mononuclear Cells

“…(38) Zinc has a protective effect against LPS/D-galactosamine-induced lethality in mice. (39) Thus the ability of various metals to either potentiate or attenuate LPS-mediated inflammatory responses varies, suggesting differential impacts on host immunity.…”

Function of Metallothionein in Gene Expression and Signal Transduction: Newly Found Protective Role of Metallothionein

“…In this LPS/GalN model, zinc preadministration protects against lethality. 90) The effects of an MT deficiency might be dysfunction of zinc-mediated protective gene expression. MT also protects against coagu-latory and fibrinolytic disturbance and multiple organ damage induced by LPS, at least partly, via inhibition of the expression of proinflammatory proteins.…”