Influence of heat shock protein 70 and metallothionein induction by Zinc-Bis-(DL-Hydrogenaspartate) on the release of inflammatory mediators in a porcine model of recurrent endotoxemia

The manipulation of stress gene expression by heavy metals provides protection against the lethal effects of endotoxemia in murine models of septic shock. Recent in vitro studies with alveolar macrophages or monocytes show that induction of the stress response in these cells is followed by a decreased liberation of major cytokines [tumor necrosis factor-α (TNFα) and interleukin-1 (IL-1)]after endotoxin challenge. These findings suggest that the increased resistance to endotoxin in vivo after stress protein induction could be explained by an altered pattern of inflammatory mediator release. Therefore, we measured the time course of thromboxane-B2 (TxB2), 6-keto-PGF1α, platelet activating factor (PAF), TNFα, interleukin-1β (IL-1β), and interleukin-6 (IL-6) formation with and without induction of the stress response in an established porcine model of recurrent endotoxemia (Klosterhalfen et al., Biochem Pharmacol 43: 2103–2109, 1992). Induction of the stress response was done by a pretreatment with Zn 2+ (25 mg/kg zinc-bis-(DL-hydrogenasparate = 5 mg/kg Zn 2+). Pretreatment with Zn 2+ prior to lipopolysaccharide (LPS) infusion induced an increased heat shock protein 70 and metallothionein expression in the lungs, liver, and kidneys and increased plasma levels of TNFa, IL-1β, IL-6, and TxB2 as opposed to untreated controls. After LPS infusion, however, pretreated animals showed significantly decreased peak plasma levels of all mediators as opposed to the untreated group. The time course of mediator release was identical with the decreasing and increasing three peak profiles described previously. Hemodynamic data presented significantly decreased peak pulmonary artery pressures and significantly altered hypodynamic/hyperdynamic cardiac output levels in the pretreated group. In conclusion, the data show that the induction of stress proteins by Zn 2+ could be a practicable strategy to prevent sepsis.