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: 10456898
• 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/10456898
• 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; 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

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大问题，但它会导致孕妇的不良后果