title: Induction of heat shock protein 70 by zinc-bis-(DL-hydrogenaspartate) reduces cytokine liberation, apoptosis, and mortality rate in a rat model of LD100 endotoxemia.
abstract: A prospective, randomized model of LD100/24 h endotoxemia was performed in male Wistar rats (n = 26; 250-300 g). The animals were divided into four groups: Group I (n = 5; saline treatment only), Group II (n = 5; Zn2+ treatment only), Group III (n = 8; saline pretreatment, lipopolysaccharide (LPS) treatment), and Group IV (n = 8; Zn2+ pretreatment, LPS treatment). Zn2+ pretreatment was carried out by intraperitoneal injection of 50 mg/kg zinc-bis-(DL-hydrogenaspartate) (10 mg/kg Zn2+). LD100/24 h endotoxemia was induced by intraperitoneal administration of 20 mg/kg LPS of the Escherichia coli strain WO111:B4. Tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 were detected by enzyme-linked immunosorbent assay (ELISA). HSP70 expression in the lungs, the liver, and the kidneys was determined by immunohistochemistry, Western blotting, and an HSP70 ELISA. Apoptosis was also detected by an in situ apoptosis detection kit (TUNEL) and a cell death detection ELISA, respectively. This rat model of endotoxemia proves the close relationship between HSP70 expression, cytokine liberation, and development of apoptosis. The data demonstrate that: 1) Zn2+ is a potent inducer of HSP70 expression; 2) the application of Zn2+ leads to slightly increased cytokine plasma levels; and 3) the manipulation of the heat shock response by Zn2+ significantly increases the survival rate after LD100 endotoxemia. Enhanced survival rate in animals pretreated with Zn2+ may be explained by increased tissue levels of HSP70, a subsequent significantly decreased liberation of the proinflammatory cytokines after LPS challenge, and a significantly decreased rate of apoptosis.
authors.affiliation: Institute of Pathology, Technical University of Aachen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Klosterhalfen
authors.forename: S
authors.initials: S
authors.lastname: Hauptmann
authors.forename: F A
authors.initials: FA
authors.lastname: Offner
authors.forename: B
authors.initials: B
authors.lastname: Amo-Takyi
authors.forename: C
authors.initials: C
authors.lastname: Töns
authors.forename: G
authors.initials: G
authors.lastname: Winkeltau
authors.forename: M
authors.initials: M
authors.lastname: Affify
authors.forename: W
authors.initials: W
authors.lastname: Küpper
authors.forename: C J
authors.initials: CJ
authors.lastname: Kirkpatrick
authors.forename: C
authors.initials: C
authors.lastname: Mittermayer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D016207:Cytokines / Q000097:blood / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality; D004797:Enzyme-Linked Immunosorbent Assay; D018840:HSP70 Heat-Shock Proteins / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008853:Microscopy / Q000379:methods; D009942:Organometallic Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology*; D017967:Zinc Compounds
chemical_list: D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009942:Organometallic Compounds; D014409:Tumor Necrosis Factor-alpha; D017967:Zinc Compounds; C106152:zinc-bis(hydrogenaspartate); D001224:Aspartic Acid; D015032:Zinc