Fetal alcohol exposure: effects on immunity of the premature newborn

怀孕期间饮酒仍然是一个重要的问题，但它对孕妇不良结局的影响 早产儿仍未得到充分研究。我们之前报告过，大约三分之一的人非常低 根据产妇报告，出生体重(VLBW)早产儿在宫内接触酒精。这次曝光 与晚发性脓毒症(LOS)和支气管肺发育不良(BPD)的风险增加有关。在我们的 宫内酒精暴露的动物模型、肺泡巨噬细胞免疫应答 细菌在多种新生幼崽中均有减少。这些变化包括氧化剂的增加。 应激和AM成熟延迟，但经抗氧化剂谷胱甘肽(GSH)处理后得到改善。在……里面 新生的肺，成熟AM的个体发育仍然存在争议，但胎儿单核细胞通过 PU.1粒细胞/巨噬细胞集落刺激因子(GM-CSF)刺激。宫内酒精暴露 降低GM-CSF，但对循环单核细胞和体内不同的单核细胞池的影响 发育中的肺是未知的。对于获得性免疫反应，抗原提呈依赖于MHC 人类白细胞抗原-DR(人类白细胞抗原-DR)与免疫抑制 减少单核细胞或巨噬细胞等抗原提呈细胞的HLA-DR表达。最近， 免疫抑制状态，如败血症，与检查点抑制物的增加有关。 程序性细胞死亡蛋白(PD)-1及其配体PD-L1。在新生小鼠单核细胞和AM中，我们发现 子宫内乙醇暴露通过增加氧化应激，减少锌和 GM-CSF，降低MHC-II表达，升高PD-1/PD-L1。然而，GSH或锌处理 阻止了这些影响。在插管型极低出生体重儿的气管抽吸物中，AM中的人类白细胞抗原-DR从 在发生LOS或BPD的婴儿中，发生LOS而PD-L1的婴儿增加。此外，PD- 宫内酒精暴露的极低出生体重儿AM中1和PD-L1的表达增加 未曝光AM利用已建立的子宫内无水乙醇小鼠模型，加上对极低出生体重儿的翻译研究， 我们的总体目标是：1)在子宫内确定乙醇对先天性和获得性免疫防御的影响 单核细胞、单核细胞来源的巨噬细胞(MDM)和AM对抗细菌挑战；2)确定 减少氧化应激(GSH、GM-CSF和锌)的临床相关干预措施将改善先天和 适应性反应；3)验证乙醇代谢物脂肪酸乙酯(FAEE)和磷脂酰乙醇 (PEH)作为极低出生体重儿宫内酒精暴露的生物标志物和4)决定表型和先天 有/无胎儿的极低出生体重儿单核细胞、MDM和AM样本的适应性防御 酒精暴露。提高对胎儿酒精暴露的极低出生体重儿的识别能力 了解其叠加在未成熟免疫防御上的免疫抑制作用 早产对这一弱势群体及其患LOS和BPD的风险有重要影响。

Alcohol use during pregnancy continues to be a significant issue but its contribution to adverse outcomes in the premature newborn remains understudied. We previously reported that approximately one in three very low birthweight (VLBW) premature newborns were exposed to alcohol in utero per maternal report. This exposure was linked to an increased odds of late onset sepsis (LOS) and bronchopulmonary dysplasia (BPD). In our animal models of in utero alcohol (ETOH) exposure, alveolar macrophage (AM) immune responses against bacteria were decreased in multiple species of newborn pups. These alterations included increased oxidant stress and delayed AM maturation but were improved by treatment with the antioxidant glutathione (GSH). In the newborn lung, the ontogeny of the mature AM remains controversial but fetal monocytes mature to AM via PU.1 in response to Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF). In utero alcohol exposure decreases GM-CSF but its effects on circulating monocytes and different monocytic cell pools within the developing lung are unknown. For the adaptive immune response, antigen presentation depends on the MHC class II molecule human-leukocyte antigen DR (HLA-DR) and immune depression is characterized by decreased HLA-DR expression on antigen-presenting cells such as monocytes or macrophages. Recently, immune depressed states such as sepsis have been linked to increases in the check point inhibitor programmed cell death protein (PD)-1 and its ligand PD-L1. In neonatal mouse monocytes and AM, we found that in utero ETOH exposure increased immunodepression by increasing oxidant stress, diminishing zinc and GM-CSF, decreasing MHC-II expression, and increasing PD-1/PD-L1. However, GSH or Zinc treatments blocked these effects. In tracheal aspirates of intubated VLBW infants, HLA-DR was diminished in AM from babies who developed LOS while PD-L1 was increased in babies who developed LOS or BPD. In addition, PD- 1 and PD-L1 expressions were increased in AM from VLBW infants with in utero alcohol exposure compared to unexposed AM. Using established in utero ETOH mouse models plus translational studies of VLBW newborns, our overall objectives are to: 1) define in utero ETOH effects on innate and adaptive immune defenses of monocytes, monocyte-derived macrophages (MDM), and AM against bacterial challenges; 2) determine if clinically relevant interventions to diminish oxidant stress (GSH, GM-CSF and Zinc) will improve innate and adaptive responses; 3) validate ethanol metabolites Fatty Acid Ethyl Esters (FAEEs) and phosphatidylethanol (PEth) as biomarkers of in utero alcohol exposure in VLBW newborns and 4) determine phenotype plus innate and adaptive defenses of human monocyte, MDM, and AM samples from VLBW newborns with/without fetal alcohol exposure. Improving identification of VLBW newborns with fetal alcohol exposure and understanding its immunodepressive effects superimposed on immature immune defenses related to prematurity have important implications for this vulnerable population and their risk of LOS and BPD.