Inhibition of necroptosis attenuates lung injury and improves survival in neonatal sepsis
Inhibition of necroptosis attenuates lung injury and improves survival in neonatal sepsis
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DOI：
10.1016/j.surg.2018.02.017
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发表时间：
2018-07-01
期刊：
影响因子：
3.8
通讯作者：
Wang, Ping
中科院分区：
文献类型：
--
作者：
Bolognese, Alexandra C.;Yang, Weng-Lang;Wang, Ping
背景：新生儿败血症是一个独特的治疗挑战，由于不成熟的免疫系统。坏死性凋亡是程序性细胞死亡的一种形式，已被确定为炎症诱导的细胞死亡的重要机制。受体相互作用蛋白激酶1在介导这一过程中起着关键作用。我们假设，受体相互作用蛋白激酶1活性的药理学阻断将在新生儿sepsis.Methods：脓毒症诱导C5 - 7 BL/6小鼠幼仔（5-7天）腹腔注射成年盲肠浆。在盲肠浆液注射后1小时，通过眶后注射给予受体相互作用蛋白激酶1抑制剂necrostatin-1（10 μ g/g体重）或溶媒（5%二甲亚砜的磷酸盐缓冲盐水溶液）。在20小时后盲肠浆液注射，血液和肺组织收集各种analysis.Results：在20小时后脓毒症诱导，溶剂处理的幼崽表现出显着增加血清白细胞介素6，白细胞介素1-β，白细胞介素18的水平相比，假手术。与溶剂相比，使用坏死抑素-1治疗时，白细胞介素6、白细胞介素1-β和白细胞介素18的血清水平分别降低了77%、81%和63%。在肺中，脓毒症诱导导致白细胞介素6、白细胞介素1-β和白细胞介素18 mRNA水平比假手术组增加232倍、10倍和2.8倍，而necrostatin-1治疗分别将这些水平降低至40倍、4倍和0.8倍。中性粒细胞趋化因子角化细胞趋化因子和巨噬细胞炎性蛋白2的表达也增加了肺脓毒症，而necrostatin-1治疗降低这些水平分别为81%和61%，相比，车辆。此外，necrostatin-1治疗显著改善了脓毒症幼崽的肺组织学损伤评分并减少了肺细胞凋亡。最后，治疗necrostatin-1增加了7天的生存率从0%的车辆处理的脓毒症幼崽到29%（P= 0.11）。结论：抑制受体相互作用蛋白激酶1的necrostatin-1减少全身和肺部炎症，减少肺损伤，并增加新生小鼠败血症的生存。靶向坏死性凋亡通路可能代表新生儿败血症的新治疗策略。(C)2018爱思唯尔公司All rights reserved.
Background: Neonatal sepsis represents a unique therapeutic challenge owing to an immature immune system. Necroptosis is a form of programmed cell death that has been identified as an important mechanism of inflammation-induced cell death. Receptor-interacting protein kinase 1 plays a key role in mediating this process. We hypothesized that pharmacologic blockade of receptor-interacting protein kinase 1 activity would be protective in neonatal sepsis.Methods: Sepsis was induced in C57BL/6 mouse pups (5-7 days old) by intraperitoneal injection of adult cecal slurry. At 1 hour after cecal slurry injection, the receptor-interacting protein kinase 1 inhibitor necrostatin-1 (10 mu g/g body weight) or vehicle (5% dimethyl sulfoxide in phosphate buffered saline) was administered via retro-orbital injection. At 20 hours after cecal slurry injection, blood and lung tissues were collected for various analyses.Results: At 20 hours after sepsis induction, vehicle-treated pups showed a marked increase in serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 compared to sham. With necrostatin-1 treatment, serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 were decreased by 77%, 81%, and 63%, respectively, compared to vehicle. In the lungs, sepsis induction resulted in a 232-, 10-, and 2.8-fold increase in interleukin 6, interleukin 1-beta, and interleukin 18 mRNA levels compared to sham, while necrostatin-1 treatment decreased these levels to 40-, 4-, and 0.8-fold, respectively. Expressions of the neutrophil chemokines keratinocyte chemoattractant and macrophage-inflammatory-protein 2 were also increased in the lungs in sepsis, while necrostatin-1 treatment decreased these levels by 81% and 61%, respectively, compared to vehicle. In addition, necrostatin-1 treatment significantly improved the lung histologic injury score and decreased lung apoptosis in septic pups. Finally, treatment with necrostatin-1 increased the 7-day survival rate from 0% in the vehicle-treated septic pups to 29% (P=.11).Conclusion: Inhibition of receptor-interacting protein kinase 1 by necrostatin-1 decreases systemic and pulmonary inflammation, decreases lung injury, and increases survival in neonatal mice with sepsis. Targeting the necroptosis pathway might represent a new therapeutic strategy for neonatal sepsis. (C) 2018 Elsevier Inc. All rights reserved.