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 pr otection against the lethal effects of endotoxemia in murine models of septic shock. Recent in vitro studies with alveolar macrophages or mo nocytes show that induction of the stress response in these cells is f ollowed by a decreased liberation of major cytokines [tumor necrosis f actor-alpha (TNF alpha) and interleukin-1 (IL-1)] after endotoxin chal lenge. These findings suggest that the increased resistance to endotox in in vivo after stress protein induction could be explained by an alt ered 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), an d interleukin-6 (IL-6) formation with and without induction of the str ess response in an established porcine model of recurrent endotoxemia (Klosterhalfen et al., Biochem Pharmacol 43: 2103-2109, 1992). Inducti on of the stress response was done by a pretreatment with Zn2+ (25 mg/ kg zinc-bis-(DL-hydrogenasparate = 5 mg/kg Zn2+). Pretreatment with Zn 2+ prior to lipopolysaccharide (LPS) infusion induced an increased hea t 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, howev er, pretreated animals showed significantly decreased peak plasma leve ls 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 s ignificantly decreased peak pulmonary artery pressures and significant ly altered hypodynamic/hyperdynamic cardiac output levels in the pretr eated group. In conclusion, the data show that the induction of stress proteins by Zn2+ could be a practicable strategy to prevent sepsis.