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

Abstract

Background: Based partially on encouraging findings from preclinical models, interest has grown in therapeutic inhibition of NF-κB to limit inflammatory injury during sepsis. However, NF-κB 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-κB inhibitors proposed for clinical study. Results: Consistent with published studies, parthenolide decreased NF-κB 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-κB 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-κB inhibitors hold promise for inflammatory conditions such as sepsis, caution is necessary. Clear understanding of the net effects of NF-κB inhibitors on outcome will be necessary before such agents are used clinically.

Keywords::

• inflammation
• NF-κB
• sepsis
• therapy

Acknowledgements

This research was supported by the intramural program of the NIH Clinical Center.

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