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Expert Opin Investig Drugs. 2009 Aug;18(8):1047-60. doi: 10.1517/13543780903018880.

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

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  • 1Department of Nephrology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100730, China.

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.

PMID:
19555300
[PubMed - indexed for MEDLINE]
PMCID:
PMC3389994
Free PMC Article
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