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

• 批准号: 10671044
• 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
• 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/10671044
• 关键词: Alcohol consumption; Alcohols; Alveolar Macrophages; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Antioxidants; Attenuated; Bacteria; Biological Markers; Bronchopulmonary Dysplasia; Cells; Coupled; Data; Depressed mood; Development; Disease; Esters; Ethanol; Fatty Acids; Fetal Alcohol Exposure; Fetal alcohol effects; 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; Innate Immune Response; Intervention; Intubation; Ligands; Link; Lung; Lung diseases; Macrophage; Morbidity - disease rate; Mus; Neonatal; Newborn Infant; Oxidants; Oxidative Stress; Phenotype; Pregnancy; Reporting; Risk; Sampling; Sampling Studies; Sepsis; Signal Transduction; Societies; TLR4 gene; Term Birth; Therapeutic; Trachea; Translational Research; Very Low Birth Weight Infant; Vulnerable Populations; Zinc; adaptive immune response; adverse outcome; alcohol effect; alcohol exposure; aspirate; biomarker validation; clinically relevant; fetal; high risk population; immune depression; immune function; improved; in utero; in vivo; infection risk; inhibitor; late onset sepsis; monocyte; mouse model; neonatal human; neonatal mice; oxidant stress; phosphatidylethanol; premature; preterm newborn; programmed cell death ligand 1; programmed cell death protein 1; pup; response; translational study

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.

怀孕期间的饮酒仍然是一个重大问题，但它对不良后果的贡献 过早的新生儿仍在研究。我们以前报道说，大约三分之一非常低 每份产妇报告中，新生儿的出生体重（VLBW）过早的新生儿都暴露于子宫内。这种曝光 与晚期败血症（LOS）和支气管肺发育不良（BPD）的几率增加有关。在我们的 子宫酒精（ETOH）暴露，肺泡巨噬细胞（AM）免疫反应的动物模型 多种新生幼崽的细菌减少。这些改变包括增加氧化剂 应力和延迟的AM成熟，但通过用抗氧化剂谷胱甘肽（GSH）治疗改善。在 新生儿肺，成熟AM的个体发育仍存在争议，但胎儿单核细胞成熟到AM PU.1响应粒细胞/巨噬细胞落刺激因子（GM-CSF）。在子宫饮酒中 减少GM-CSF，但其对循环单核细胞和不同单核细胞池的影响 发育肺部未知。对于自适应免疫反应，抗原表现取决于MHC II类分子人白细胞抗原DR（HLA-DR）和免疫抑郁的特征是 在抗原呈递细胞（如单核细胞或巨噬细胞）上的HLA-DR表达降低。最近， 免疫抑郁状态（例如脓毒症）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。在新生小鼠的单核细胞和AM中，我们发现 在子宫内暴露中，通过增加氧化应激，减少锌和 GM-CSF，降低MHC-II表达，并增加PD-1/PD-L1。但是，GSH或锌治疗 阻止了这些效果。在插管VLBW婴儿的气管抽吸物中，AM中的HLA-DR从 患有LOS或BPD的婴儿的婴儿增加了LOS，而PD-L1的婴儿增加了。另外，PD- 与子宫酒精暴露的VLBW婴儿的AM相比，AM的1和PD-L1表达增加 未暴露的AM。使用在子宫ETOH小鼠模型中建立的以及VLBW新生儿的翻译研究， 我们的整体目标是：1）定义子宫ETOH对先天和适应性免疫防御的影响 单核细胞，单核细胞衍生的巨噬细胞（MDM），并反对细菌挑战； 2）确定是否 减轻氧化应激（GSH，GM-CSF和锌）的临床相关干预措施将改善先天性和 自适应反应； 3）验证乙醇代谢物脂肪酸乙酸（FAEES）和磷脂酰乙醇 （Peth）作为vlbw新生儿的子宫酒精暴露的生物标志物，4）确定表型加上先天 人类单核细胞，MDM和AM的自适应防御能力，来自胎儿的VLBW新生儿样本 酒精暴露。通过胎儿酒精暴露和 了解其免疫抑制作用叠加于与 早产对这个脆弱的人群及其对LOS和BPD的风险具有重要意义。