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-alpha (
TNF alpha) 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-PGF1 alpha,
platelet activating factor (PAF),
TNF alpha,
interleukin-1 beta (IL-1 beta), 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 Zn2+ (25 mg/kg
zinc-bis-(DL-hydrogenasparate = 5 mg/kg Zn2+). Pretreatment with Zn2+ 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
TNF alpha, IL-1 beta, 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 Zn2+ could be a practicable strategy to prevent
sepsis.