Can we predict the effects of NF-kappaB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate.
Can we predict the effects of NF-kappaB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate.
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DOI：
10.1517/13543780903018880
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发表时间：
2009-08
影响因子：
6.1
通讯作者：
Eichacker PQ
中科院分区：
文献类型：
--
作者：
Li X;Su J;Cui X;Li Y;Barochia A;Eichacker PQ
部分基于来自临床前模型的令人鼓舞的发现，对NF-κB的治疗性抑制以限制脓毒症期间的炎性损伤的兴趣已经增长。然而，NF-κB也调节保护性反应，并且预测这种抑制的净存活效应可能是困难的。为了强调这种治疗方法的必要性，我们回顾了我们在小鼠脓毒症模型中的研究，其中使用了parthenocyanate和丙酮酸乙酯，这两种NF-κB抑制剂用于临床研究。与已发表的研究一致，在体外，孤雌菊降低了脂多糖（LPS）刺激的RAW 264.7细胞的NF-κB结合活性和炎性细胞因子释放。然而，在LPS攻击小鼠（C57 BL/6 J）中，虽然两种药物在早期（1 - 3 h）降低了肺和肾NF-κB结合活性和血浆细胞因子，但这些指标在随后（6 - 12 h）以随时间显著不同的模式增加。此外，尽管研究了几种剂量的小白菊（0.25 - 4.0 mg/kg）和丙酮酸乙酯（0.1 - 100 mg/kg），但每种药物均导致存活率小幅但一致的降低，总体上具有显著性（每种药物p ≤ 0.04）。虽然NF-κB抑制剂有望治疗炎症性疾病，如脓毒症，但仍需谨慎。在临床应用NF-κB抑制剂之前，有必要清楚地了解其对预后的净效应。
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. 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. 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). 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.
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影响因子：
158.5
作者：
Abraham, E;Laterre, P;Macias, WL
通讯作者：
Macias, WL
DOI：
10.1152/ajpgi.90434.2008
发表时间：
2008-10-01
影响因子：
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作者：
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DOI：
10.1164/ajrccm.162.3.9906129
发表时间：
2000-09-01
影响因子：
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作者：
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影响因子：
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作者：
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