Soluble TNFR II/IgG1 Fc fusion protein treatment in the LPS-mediated septic shock of rats

Tumor necrosis factor-alpha (TNF-alpha) is thought to play a major role in systemic inflammation associated with sepsis. A potent TNF antagonist, a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (sTNFR II/IgG1 Fc fusion protein, sTNFR:Fc), has been shown to provide rapid and sustained improvement in local inflammation diseases by binding TNF-alpha and preventing its proinflammatory activities. To explore the potential therapeutic efficacy for septic shock of sTNFR:Fc, we investigate the effect of this molecule on the survival rate, blood pressure, serum TNF-alpha bioactivity as well as the expression of TNF-alpha at mRNA level in the liver in a LPS-induced rat septic shock model. Blood pressure of the rats was monitored by multi-channel creature signal analysis system. Serum TNF-alpha level and bioactivity was assessed using an enzyme-linked immunoassay and a L929 cytotoxicity assay, respectively. The expression of TNF-alpha mRNA in liver was examined by semi-quantitativc RT-PCR. sTNFR:Fc administered to rats 24 h before LPS challenge ablated the rise in serum TNF-alpha bioactivity that occurs in response to LPS and protected against hypotension and death. These results indicate that TNF-alpha is a mediator of fatal septic shock, and suggest that sTNFR:Fc offer a potential therapy of systemic infection. (C) 2008 Elsevier Masson SAS. All rights reserved.