Can we predict the effects of NF-kappaB 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-kappaB to limit inflammatory injury during sepsis. However, NF-kappaB 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-kappaB inhibitors proposed for clinical study. RESULTS:Consistent with published studies, parthenolide decreased NF-kappaB 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-kappaB 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 < or = 0.04 for each agent). CONCLUSION:While NF-kappaB inhibitors hold promise for inflammatory conditions such as sepsis, caution is necessary. Clear understanding of the net effects of NF-kappaB inhibitors on outcome will be necessary before such agents are used clinically.

authors

Li X,Su J,Cui X,Li Y,Barochia A,Eichacker PQ

doi

10.1517/13543780903018880

subject

Has Abstract

pub_date

2009-08-01 00:00:00

pages

1047-60

issue

8

eissn

1354-3784

issn

1744-7658

journal_volume

18

pub_type

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