Laube Mandy, Amann Elena, Uhlig Ulrike, Yang Yang, Fuchs Hans W, Zemlin Michael, Mercier Jean-Christophe, Maier Rolf F, Hummler Helmut D, Uhlig Stefan, Thome Ulrich H
Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, Division of Neonatology, University of Leipzig, Leipzig, Germany.
Division of Neonatology and Pediatric Critical Care, Department of Pediatrics, University of Ulm, Ulm, Germany.
PLoS One. 2017 Jan 3;12(1):e0169352. doi: 10.1371/journal.pone.0169352. eCollection 2017.
Ventilated preterm infants frequently develop bronchopulmonary dysplasia (BPD) which is associated with elevated inflammatory mediators in their tracheal aspirates (TA). In animal models of BPD, inhaled nitric oxide (iNO) has been shown to reduce lung inflammation, but data for human preterm infants is missing.
Within a European multicenter trial of NO inhalation for preterm infants to prevent BPD (EUNO), TA was collected to determine the effects of iNO on pulmonary inflammation. TA was collected from 43 premature infants randomly assigned to receive either iNO or placebo gas (birth weight 530-1230 g, median 800 g, gestational age 24 to 28 2/7 weeks, median 26 weeks). Interleukin (IL)-1β, IL-6, IL-8, transforming growth factor (TGF)-β1, interferon γ-induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, acid sphingomyelinase (ASM), neuropeptide Y and leukotriene B4 were measured in serial TA samples from postnatal day 2 to 14. Furthermore, TA levels of nitrotyrosine and nitrite were determined under iNO therapy.
The TA levels of IP-10, IL-6, IL-8, MIP-1α, IL-1β, ASM and albumin increased with advancing postnatal age in critically ill preterm infants, whereas nitrotyrosine TA levels declined in both, iNO-treated and placebo-treated infants. The iNO treatment generally increased nitrite TA levels, whereas nitrotyrosine TA levels were not affected by iNO treatment. Furthermore, iNO treatment transiently reduced early inflammatory and fibrotic markers associated with BPD development including TGF-β1, IP-10 and IL-8, but induced a delayed increase of ASM TA levels.
Treatment with iNO may have played a role in reducing several inflammatory and fibrotic mediators in TA of preterm infants compared to placebo-treated infants. However, survival without BPD was not affected in the main EUNO trial.
NCT00551642.
机械通气的早产儿经常发生支气管肺发育不良（BPD），这与他们气管吸出物（TA）中炎症介质水平升高有关。在BPD动物模型中，吸入一氧化氮（iNO）已被证明可减轻肺部炎症，但人类早产儿的数据尚缺。
在一项欧洲多中心的关于吸入NO预防早产儿BPD的试验（EUNO）中，收集TA以确定iNO对肺部炎症的影响。TA取自43例随机分配接受iNO或安慰剂气体的早产儿（出生体重530 - 1230g，中位数800g，胎龄24至28又2/7周，中位数26周）。在出生后第2天至14天的系列TA样本中检测白细胞介素（IL）-1β、IL-6、IL-8、转化生长因子（TGF）-β1、干扰素γ诱导蛋白10（IP-10）、巨噬细胞炎性蛋白（MIP）-1α、酸性鞘磷脂酶（ASM）、神经肽Y和白三烯B4。此外，在iNO治疗下测定TA中的硝基酪氨酸和亚硝酸盐水平。
危重新生儿TA中IP-10、IL-6、IL-8、MIP-1α、IL-1β、ASM和白蛋白水平随出生后年龄增长而升高，而在接受iNO治疗和安慰剂治疗的婴儿中，硝基酪氨酸TA水平均下降。iNO治疗通常会增加TA中亚硝酸盐水平，而硝基酪氨酸TA水平不受iNO治疗影响。此外，iNO治疗可短暂降低与BPD发生相关的早期炎症和纤维化标志物，包括TGF-β1、IP-10和IL-8，但会导致ASM TA水平延迟升高。
与接受安慰剂治疗的婴儿相比，iNO治疗可能在降低早产儿TA中多种炎症和纤维化介质方面发挥了作用。然而，在主要的EUNO试验中，无BPD存活情况未受影响。
NCT00551642。
