NF-KB and P38 MAPK Inhibition Improve Survival in Endotoxin Shock and in a Cecal Ligation and Puncture Model of Sepsis in Combination With Antibiotic Therapy
NF-KB and P38 MAPK Inhibition Improve Survival in Endotoxin Shock and in a Cecal Ligation and Puncture Model of Sepsis in Combination With Antibiotic Therapy
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DOI：
10.1016/j.jss.2008.04.030
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发表时间：
2009-03-01
影响因子：
2.2
通讯作者：
Redmond, Henry P.
中科院分区：
文献类型：
--
作者：
O'Sullivan, Adrian W.;Wang, Jiang Huai;Redmond, Henry P.
背景。核因子κ B （NF-kB）和p38丝裂原活化蛋白激酶（MAPK）是介导全身性炎症反应综合征的关键细胞内信号转导途径。抗生素诱导细菌裂解，这也通过激活NF-KB和p38激酶促进细胞因子的产生和炎症反应。在这项研究中，我们着手研究p38 MAPK和NF-kB翻译在脓毒症体内模型中的抑制作用。材料和方法。脓毒症模型采用腹腔注射脂多糖（30 mg/kg）、尾静脉注射细菌（金黄色葡萄球菌+鼠伤寒沙门氏菌，5 × 10(7)菌落形成单位/kg）和盲肠结扎穿刺（CLP）加或不加抗生素（Augmentin, 100 mg/kg）。动物接受对照、SB-202190（一种p38抑制剂）或SN-50（一种NF-kB抑制剂）治疗，并通过对数秩分析评估死亡率。在不同时间点采集血液进行细胞因子分析，脾组织进行细胞质蛋白提取以评估激酶活化。SB-202190和SN-50在脂多糖模型中具有显著的生存效益（P = 0.0006），但在细菌或CLP模型中没有显著的生存效益（P = 0.9和0.3）。在CLP模型中，SB-202190和SN-50联合抗生素可获得显著的生存获益（P分别为0.0001和0.006）。肿瘤坏死因子- α和白细胞介素-6的循环水平在2小时显著降低（P分别为0.047和0.036），Western blot显示p38MAPK和SN-50抑制剂联合抗生素治疗CLP后2小时p38激酶下调。我们已经证明p-38和NF-kB抑制可改善内毒素休克患者的生存，而多微生物脓毒症患者的生存益处需要共存的抗生素治疗。(c) 2009爱思唯尔公司版权所有。
Background. Nuclear factor-kappa B (NF-kB) and p38 mitogen-activated protein kinase (MAPK) are critical intracellular signal transduction pathways that mediate the systemic inflammatory response syndrome. Antibiotics induce bacterial lysis, which also contributes to cytokine production and the inflammatory response by activating NF-KB and p38 kinase. In this study, we set out to examine the effects of inhibition of p38 MAPK and NF-kB translation in in vivo models of sepsis.Materials and methods. Intraperitoneal lipopolysaccharide (30 mg/kg), tail vein injection of bacteria (Staphylococcus aureus + Salmonella Typhimurium, 5 x 10(7) colony forming units/kg) and cecal ligation and puncture (CLP) with or without antibiotics (Augmentin, 100 mg/kg) were the septic models used. Animals received control, SB-202190 (a p38 inhibitor), or SN-50 (an NF-kB inhibitor), and mortality was assessed by log-rank analysis. Blood was collected at different time points for cytokine analysis, and splenic tissue was used for cytoplasmic protein extraction to assess kinase activation.Results. SB-202190 and SN-50 resulted in significant survival benefit in the lipopolysaccharide model (P = 0.0006) but not bacterial or CLP models (P = 0.9 and 0.3, respectively). SB-202190 and SN-50, in combination with antibiotic, resulted in a significant survival benefit in the CLP model (P = 0.0001 and 0.006, respectively). Circulating levels of both tumor necrosis factor-alpha and interleukin-6 were significantly reduced at 2 h (P = 0.047 and 0.036, respectively) and Western blot demonstrated down-regulation of p38 kinase 2 h after CLP in animals treated with p38MAPK, and SN-50 inhibitors in combination with antibiotics.Conclusions. We have demonstrated that p-38 and NF-kB inhibition improve survival in endotoxin shock, whereas the survival benefit in polymicrobial sepsis requires coexistent antibiotic treatment. (c) 2009 Elsevier Inc. All rights reserved.