Can we predict the effects of NF-κB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate

Background: Based partially on encouraging findings from preclinical models, interest has grown in therapeutic inhibition of NF-kappa B to limit inflammatory injury during sepsis. However, NF-kappa B also regulates protective responses, and predicting the net survival effects of such inhibition may be difficult. Objectives: To highlight the caution necessary with this therapeutic approach, we review our investigations in a mouse sepsis model with parthenolide and ethyl pyruvate, two NF-kappa B inhibitors proposed for clinical study. Results: Consistent with published studies, parthenolide decreased NF-kappa B binding activity and inflammatory cytokine release from lipopolysaccharide (LPS) stimulated RAW 264.7 cells in vitro. In LPS-challenged mice (C57BL/6J), however, while both agents decreased lung and kidney NF-kappa B binding activity and plasma cytokines early (1 - 3 h), these measures were increased later (6 - 12 h) in patterns differing significantly over time. Furthermore, despite studying several doses of parthenolide (0.25 - 4.0 mg/kg) and ethyl pyruvate (0.1 - 100 mg/kg), each produced small but consistent decreases in survival which overall were significant (p <= 0.04 for each agent). Conclusion: While NF-kappa B inhibitors hold promise for inflammatory conditions such as sepsis, caution is necessary. Clear understanding of the net effects of NF-kappa B inhibitors on outcome will be necessary before such agents are used clinically.