Pirr Sabine, Richter Manuela, Fehlhaber Beate, Pagel Julia, Härtel Christoph, Roth Johannes, Vogl Thomas, Viemann Dorothee
Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
Children's Hospital "Auf der Bult", Hannover, Germany.
Front Immunol. 2017 Dec 13;8:1822. doi: 10.3389/fimmu.2017.01822. eCollection 2017.
Sepsis is a leading cause of perinatal mortality worldwide. Breast milk (BM) feeding is protective against neonatal sepsis, but the molecular mechanisms remain unexplained. Despite various supplementations with potential bioactive components from BM formula feeding cannot protect from sepsis. S100-alarmins are important immunoregulators in newborns preventing excessive inflammation. At high concentrations, the S100A8/A9 protein complex also has antimicrobial properties due to its metal ion chelation capacity. To assess whether BM contains S100-alarmins that might mediate the sepsis-protective effect of BM 97 human BM samples stratified for gestational age, mode of delivery and sampling after birth were collected and analyzed. S100A8/A9 levels were massively elevated after birth ( < 0.0005). They slowly decreased during the first month of life, then reaching levels comparable to normal values in adult serum. The concentration of S100A8/A9 in BM was significantly higher after term compared with preterm birth (extremely preterm, < 0.005; moderate preterm, < 0.05) and after vaginal delivery compared with cesarean section ( < 0.0005). In newborn mice, enterally supplied S100-alarmins could be retrieved systemically in the plasma. To explore the antimicrobial activity against common causal pathogens of neonatal sepsis, purified S100-alarmins and unmodified as well as S100A8/A9-depleted BM were used in growth inhibition tests. The high amount of S100A8/A9 proved to be an important mediator of the antimicrobial activity of BM, especially inhibiting the growth of manganese (Mn) sensitive bacteria such as ( < 0.00005) and group B streptococci ( < 0.005). Depletion of S100A8/A9 significantly reduced this effect ( < 0.05, respectively). The growth of was also inhibited by BM ( < 0.00005) as well as by S100A8/A9 in culture assays ( < 0.05). But its growth in BM remained unaffected by the removal of S100A8/A9 and was neither dependent on Mn suggesting that the antimicrobial effects of S100A8/A9 in BM are primarily mediated by its Mn chelating capacity. In summary, the enteral supply of bioavailable, antimicrobially active amounts of S100-alarmins might be a promising option to protect newborns at high risk from infections and sepsis.
脓毒症是全球围产期死亡的主要原因。母乳喂养对新生儿脓毒症具有保护作用，但其分子机制仍不清楚。尽管在母乳配方奶中添加了各种潜在的生物活性成分，但配方奶喂养并不能预防脓毒症。S100警报素是新生儿重要的免疫调节因子，可预防过度炎症反应。在高浓度时，S100A8/A9蛋白复合物因其金属离子螯合能力也具有抗菌特性。为了评估母乳中是否含有可能介导母乳对脓毒症保护作用的S100警报素，收集并分析了97份根据胎龄、分娩方式和出生后采样分层的人母乳样本。出生后S100A8/A9水平大幅升高（<0.0005）。在生命的第一个月内它们缓慢下降，然后达到与成人血清正常值相当的水平。与早产（极早产，<0.005；中度早产，<0.05）相比，足月后母乳中S100A8/A9的浓度显著更高，与剖宫产相比，阴道分娩后母乳中S100A8/A9的浓度显著更高（<0.0005）。在新生小鼠中，经肠道供应的S100警报素可在血浆中全身检测到。为了探索对新生儿脓毒症常见致病病原体的抗菌活性，在生长抑制试验中使用了纯化的S100警报素以及未修饰的和S100A8/A9缺失的母乳。结果证明，大量的S100A8/A9是母乳抗菌活性的重要介质，尤其能抑制对锰（Mn）敏感的细菌如……（<0.00005）和B族链球菌（<0.005）的生长。去除S100A8/A9显著降低了这种作用（分别为<0.05）。在培养试验中，……（<0.00005）以及S100A8/A9也抑制了……的生长（<0.05）。但其在母乳中的生长不受去除S100A8/A9的影响，也不依赖于锰，这表明母乳中S100A8/A9的抗菌作用主要由其锰螯合能力介导。总之，经肠道供应生物可利用的、具有抗菌活性量的S100警报素可能是保护高危新生儿免受感染和脓毒症的一个有前景的选择。
