Cytokine synthesis in the liver of endotoxin-tolerant and normal rats during hemorrhagic shock

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Abstract
In the present study the effects of endotoxin tolerance on hemorrhagic shock were investigated with particular focus on hepatic alterations. The following questions were addressed: (i) does hemorrhagic shock induce cytokine formation and heat shock response in the liver; and (ii) does endotoxin tolerance alter these reactions. Endotoxin tolerance was induced by repetitive daily injections of LPS for 5 days. Hemorrhagic shock was induced by hypovolemia (MAP 35 ± 5 mmHg). After 3 h, the animals were resuscitated by re-infusion of homologous blood. m-RNA was isolated from liver biopsies and the mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10) and heat shock protein 70 (HSP-70) were determined by RT-PCR. TNF-α was measured by ELISA in serum samples and in the supernatants of whole blood cultures. It was found that endotoxin tolerance reduced mortality caused by hemorrhagic shock from 80% to 20%. In parallel, TNF-α production in response to LPS in vivo and in vitro was significantly decreased. During hemorrhage and after resuscitation. increased mRNA levels were detected in hepatic biopsies for TNF-α, IL-6, IL-10 and HSP-70, with highest levels immediately after re-infusion. Endotoxin-tolerant rats produced significantly lower levels of TNF-α, while no differences were found for IL-10 and HSP-70. Within 30 min after reperfusion, significantly higher levels of IL-6 mRNA were found in hepatic biopsies from tolerant rats; these differences disappeared 2 h after reperfusion.