Fetal alcohol exposure: effects on immunity of the premature newborn

胎儿酒精暴露：对早产新生儿免疫力的影响

基本信息

批准号：
10219938
负责人：
Lou Ann S Brown
金额：
$ 50.43万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219938
关键词：
Address Alcohol consumption Alcohols Alveolar Macrophages Animal Model Antigen Presentation Antigen-Presenting Cells Antioxidants Apoptosis Aspirate substance Attenuated Bacteria Biological Markers Bronchopulmonary Dysplasia Cells Coupled Data Depressed mood Development Disease Esters Ethanol Fatty Acids Fetal Alcohol Exposure Free Radicals Glutathione Granulocyte-Macrophage Colony-Stimulating Factor Growth HLA Antigens Histocompatibility Antigens Class II Human Immune Immune System Diseases Immune response Immunity Impairment In Vitro Infant Intervention Ligands Link Low Birth Weight Infant Lung Lung diseases Morbidity - disease rate Mus Neonatal Newborn Infant Oxidants Oxidative Stress Phenotype Plague Pregnancy Proteins Reporting Risk Sampling Sampling Studies Sepsis Signal Transduction Societies TLR4 gene Term Birth Therapeutic Translational Research Very Low Birth Weight Infant Vulnerable Populations Zinc adaptive immune response adverse outcome alcohol effect alcohol exposure base clinically relevant fetal high risk population immune depression immune function improved in utero in vivo infection risk inhibitor/antagonist late onset sepsis macrophage monocyte mouse model neonatal human neonatal mice oxidant stress phosphatidylethanol premature preterm newborn programmed cell death protein 1 pup response translational study

项目摘要

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.

怀孕期间饮酒仍然是一个重要问题，但它会导致不良后果早产儿仍有待研究。我们之前报道过，大约三分之一的人非常低根据产妇报告，出生体重（VLBW）的早产儿在子宫内接触过酒精。此次曝光与迟发性败血症（LOS）和支气管肺发育不良（BPD）的几率增加有关。在我们的子宫内酒精（ETOH）暴露的动物模型，肺泡巨噬细胞（AM）免疫反应多种新生幼崽的细菌数量均减少。这些改变包括增加氧化剂应激和延迟 AM 成熟，但通过抗氧化剂谷胱甘肽 (GSH) 治疗得到改善。在在新生肺中，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 对粒细胞/巨噬细胞集落刺激因子 (GM-CSF) 的反应。子宫内酒精暴露减少 GM-CSF，但其对循环单核细胞和体内不同单核细胞池的影响肺部发育尚不清楚。对于适应性免疫反应，抗原呈递取决于 MHC II类分子人类白细胞抗原DR（HLA-DR）和免疫抑制的特点是降低抗原呈递细胞（例如单核细胞或巨噬细胞）上的 HLA-DR 表达。最近，败血症等免疫抑制状态与检查点抑制剂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 ETOH 暴露会通过增加氧化应激、减少锌和 GM-CSF，降低 MHC-II 表达，增加 PD-1/PD-L1。然而，GSH 或锌治疗阻止了这些影响。在插管 VLBW 婴儿的气管抽吸物中，HLA-DR 在 AM 中减少患有 LOS 的婴儿，而患有 LOS 或 BPD 的婴儿中 PD-L1 增加。此外，PD- 与宫内酒精暴露的 VLBW 婴儿相比，AM 中的 1 和 PD-L1 表达增加未曝光的 AM。利用建立的子宫内 ETOH 小鼠模型以及 VLBW 新生儿的转化研究，我们的总体目标是：1) 确定子宫内 ETOH 对先天性和适应性免疫防御的影响单核细胞、单核细胞源性巨噬细胞 (MDM) 和 AM 对抗细菌挑战； 2) 判断是否减少氧化应激（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 (PEth) 作为 VLBW 新生儿子宫内酒精暴露的生物标志物，4) 确定表型和先天性来自有/无胎儿的 VLBW 新生儿的人类单核细胞、MDM 和 AM 样本的适应性防御酒精暴露。改善对胎儿酒精暴露的极低出生体重新生儿的识别了解其免疫抑制作用叠加在与相关的不成熟免疫防御上早产对这一弱势群体及其患 LOS 和 BPD 的风险具有重要影响。