Double Blockade of CD14 and Complement C5 Abolishes the Cytokine Storm and Improves Morbidity and Survival in Polymicrobial Sepsis in Mice
Double Blockade of CD14 and Complement C5 Abolishes the Cytokine Storm and Improves Morbidity and Survival in Polymicrobial Sepsis in Mice
复制标题
DOI：
10.4049/jimmunol.1400341
复制
发表时间：
2014-06-01
影响因子：
4.4
通讯作者：
Mollnes, Tom E.
中科院分区：
文献类型：
--
作者：
Huber-Lang, Markus;Barratt-Due, Andreas;Mollnes, Tom E.
由过度的全身宿主炎症反应引起的脓毒症和脓毒性休克与高发病率和死亡率相关。补体系统和TLR提供了重要的模式识别受体，通过广泛的串扰启动细胞因子风暴。我们假设，双重阻断补体C5和TLR辅助受体CD 14可以提高实验性多微生物败血症的生存率。用中和性抗CD 14 Ab biG 53、补体C5抑制剂coversin（Ornithodoros moubata C抑制剂）或其组合治疗经历盲肠结扎和穿孔（CLP）诱导的脓毒症的小鼠。炎症研究（24小时观察）显示，未治疗CLP组24种测量的血浆生物标志物中有22种统计学显著增加，包括14种促炎和抗炎细胞因子和8种趋化因子、生长因子和粒细胞活化标志物。单一CD 14或C5阻断分别显著抑制22种生物标志物中的20种和19种。与未治疗的CLP组相比，CD 14和C5联合抑制显著降低了所有22种生物标志物（平均降低85%;范围54-95%）。双重阻断比单一治疗更有效，并且需要显著抑制IL-6和CXCL 1。联合抑制显着降低发病率（运动和眼睑运动）和死亡率超过10天。在阳性对照CLP组中，中位生存期为36 h（范围24-48 h）。联合治疗将中位生存期延长至96 h（范围24-240 h）（p = 0.001），而单药治疗组的生存期未显著延长（抗CD 14和抗C5治疗的中位和范围为36 h [24-48 h]和48 h [24-96 h]）。结合标准干预治疗，特异性阻断CD 14和C5可能代表治疗多微生物脓毒症的一种有前途的新治疗策略。
Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)-induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro-and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54-95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24-48 h). Combined treatment increased median survival to 96 h (range 24-240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24-48 h] and 48 h [24-96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis.