title: 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.
abstract: 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.
authors.affiliation: Department of Surgery, Technical University of Aachen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Klosterhalfen
authors.forename: C
authors.initials: C
authors.lastname: Töns
authors.forename: S
authors.initials: S
authors.lastname: Hauptmann
authors.forename: L
authors.initials: L
authors.lastname: Tietze
authors.forename: F A
authors.initials: FA
authors.lastname: Offner
authors.forename: W
authors.initials: W
authors.lastname: Küpper
authors.forename: C J
authors.initials: CJ
authors.lastname: Kirkpatrick
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D018836:Inflammation Mediators / Q000502:physiology*; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008668:Metallothionein / Q000096:biosynthesis* / Q000235:genetics; D010972:Platelet Activating Factor / Q000096:biosynthesis; D011651:Pulmonary Artery / Q000187:drug effects; D012008:Recurrence; D013552:Swine; D013929:Thromboxane B2 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015032:Zinc / Q000494:pharmacology*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D001224:Aspartic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D008668:Metallothionein; D015032:Zinc