Effect of zinc pretreatment on pulmonary endothelial cells in vitro and pulmonary function in a porcine model of endotoxemia.
BACKGROUND
During endotoxemia, the systemic inflammatory response often leads to severe pulmonary damages. Destruction of endothelial cells, interstitial edema, and interstitial alveolitis depress pulmonary circulation and raise extravascular lung water and intrapulmonary shunt. As protective effects of zinc are described in vitro as well as in vivo, this study investigates its impact on septic porcine pulmonary endothelial monolayers as well as on the pulmonary function of endotoxemic pigs.


METHODS
Cell culture: Endothelial cells were incubated with ascending doses of zinc and pooled with septic plasma. Cellular damage, metabolism, and proliferation were measured by vital stain, XTT-assay, and BrDU-ELISA. HSP70 was visualized by immunohistochemistry. Animal study: We used an established porcine model. Twenty-four hours before endotoxemia (intravenous infusion of 1.0 microg/kg Escherichia coli endotoxin WO111:B4), each animal received an intravenous pretreatment. Group I (n = 3): saline pretreatment, group II (n = 5): zinc pretreatment (5 mg/kg elementary zinc). Monitoring included blood gas analysis and the thermal dye dilution technique.


RESULTS
In vitro, zinc leads to significantly altered rates of viable cells, metabolism, and proliferation with the strongest cell-protective effect at moderate concentrations of 1 microg/ml Zn2+. This correlates with a qualitatively increased expression of HSP70. In vivo, the zinc pretreatment before LPS-induced endotoxemia grossly improves all measured hemodynamic and pulmonary parameters.


CONCLUSIONS
Zinc pretreatment of endotoxemia decreases cellular damages in vitro and improved pulmonary function in vivo. This could be mediated by the heat shock response. Further studies, particularly concerning the dose-effect relationship and the underlying mode of action, are mandatory.
Krones
Carsten Johannes
CJ
Department of Surgery, The Technical University of Aachen, Aachen, Germany. Ckrones@ukaachen.de
Klosterhalfen
Bernd
B
Butz
Nick
N
Hoelzl
Friedrich
F
Junge
Karsten
K
Stumpf
Michael
M
Peiper
Christian
C
Klinge
Uwe
U
Schumpelick
Volker
V
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects; D066298:In Vitro Techniques; D011651:Pulmonary Artery / Q000166:cytology; D034421:Sus scrofa; D015032:Zinc / Q000494:pharmacology*
D018840:HSP70 Heat-Shock Proteins; D015032:Zinc