Inflammatory status in sepsis alters efficacy of interleukin-18 binding protein therapy.
OBJECTIVE: Sepsis remains a serious clinical problem, and multiple attempts at blocking inflammation have failed to decrease mortality rate. Interleukin-18 has been demonstrated to be an important component of the innate immune response to bacterial infections. DESIGN: Previous work demonstrated that elevated plasma concentrations of interleukin-6 obtained in the first 6 hrs of sepsis predict a worse outcome. Mice were subjected to cecal ligation and puncture and, on the basis of the plasma concentration of interleukin-6, were randomized to receive either interleukin-18 binding protein or vehicle approximately 8 hrs after the onset of sepsis. SETTING: University research laboratory. SUBJECTS: Adult, female BALB/c mice. INTERVENTIONS: We sought to determine the role of interleukin-18 in sepsis by blocking its biological activity with the interleukin-18 binding protein in the murine model of sepsis induced by cecal ligation and puncture. MEASUREMENTS AND MAIN RESULTS: In this study, elevated plasma concentrations of interleukin-6 were associated with a worse outcome. Treatment with interleukin-18 binding protein decreased inflammation as determined by lower concentrations of plasma interleukin-6 obtained 48 hrs after the onset of sepsis. In mice with increased risk of dying, interleukin-18 binding protein slightly decreased mortality rate. However, in those mice with a predicted low mortality rate, interleukin-18 binding protein significantly increased mortality rate. CONCLUSIONS: In this study, mice at low risk of death due to sepsis had decreased survival when treated with interleukin-18 binding protein. These results have potential implications for the use of interleukin-18 binding protein for treatment of chronic inflammatory conditions since it may place the host at increased risk of infectious complications.[1]References
- Inflammatory status in sepsis alters efficacy of interleukin-18 binding protein therapy. Remick, D.G., Bolgos, G.E., Siddiqui, J. Crit. Care Med. (2003) [Pubmed]
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