MATERNAL ALCOHOL IMPAIRS FETAL ALVEOLAR MACROPHAGE

母体酒精会损害胎儿肺泡巨噬细胞

• 批准号: 6223946
• 负责人: THERESA Wanzor GAUTHIER
• 金额: $ 7.63万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-16 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6223946
• 关键词: alveolar macrophages; antioxidants; biological models; embryo /fetus toxicology; enzyme linked immunosorbent assay; ethanol; glutathione; guinea pigs; high performance liquid chromatography; immunomodulators; lung disorder; nitrites; oxidative stress; pregnancy; premature infant animal; respiratory epithelium; respiratory function; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION (Adapted from applicant's description): Premature newborns are at increased risk of pulmonary infection due to dysfunctional inflammatory cells including the resident alveolar macrophage (AM). The AM is the first line of defense against infection in the lung. Glutathione, (GSH) a major antioxidant in the lung is required by all cells, including the AM to maintain redox potential and optimize intracellular functioning. Levels of systemic and alveolar GSH are deficient in the premature newborn, placing the lung at increased risk for oxidant injury and cellular dysfunction. Chronic alcohol (ETOH) exposure to adults also increases systemic oxidative stress and impairs the immune function within the lung, particularly the AM. ETOH consumption has increased significantly in women of childbearing age and remains a significant health problem among pregnant women. The fetus exposed to ETOH in utero is also at risk for oxidant stress, as evidenced by decreased systemic and hepatic GSH. We postulate that the pulmonary GSH deficiency caused by prematurity is exacerbated when superimposed on oxidant stress, such as that caused by in utero ETOH exposure. Decreased GSH in the lung decreases GSH availability for the resident AM, thereby contributing to its impaired function. Although regulation of AM function is complex, we have chosen to focus on decreased GSH as one possible modulator. In a guinea pig model, preliminary studies showed that fetal ETOH exposure decreased GSH in the epithelial lining fluid, resulting in decreased AM GSH compared to gestationally matched controls. The ETOH-exposed AM demonstrated reduced cytokine release and phagocytosis when compared to gestational controls. This is clinically relevant because it suggested that the immunosuppression due to premature birth may be potentiated if chronic oxidative stress was superimposed on premature delivery. The addition of GSH in vivo or in vitro partially restored the function of ETOH-exposed AM. Therefore, we hypothesize that AM function is limited in the ETOH-exposed fetus because of decreased GSH availability, but function can be restored through GSH supplements. To further define the role of GSH availability in AM function after in utero ETOH exposure. we will: 1) determine whether the oxidant stress of in utero ETOH down-regulates immunomodulatory functions of fetal AM via GSH availability and 2) demonstrate that a maternal GSH precursor in vivo maintains the fetal AM OSH and subsequently maintains AM function during ETOH exposure in utero. Understanding the modulatory role of GSH availability in AM function will broaden our understanding of GSH supplements not only as a possible therapy for infants exposed to ETOH in utero but premature infants in general.

描述（改编自申请人的描述）：早产新生儿处于 炎症细胞功能失调导致肺部感染的风险增加 包括常驻肺泡巨噬细胞 (AM)。 AM 是第一行 防御肺部感染。 谷胱甘肽（GSH）是一种主要的抗氧化剂 肺中的所有细胞（包括 AM）都需要维持氧化还原 潜力并优化细胞内功能。 系统性和 早产儿的肺泡谷胱甘肽缺乏，使肺处于 氧化损伤和细胞功能障碍的风险增加。长期酗酒 (ETOH) 成人接触也会增加全身氧化应激并损害 肺内的免疫功能，特别是 AM。 乙醇消耗量 育龄妇女人数显着增加，并且仍然是 孕妇的严重健康问题。胎儿接触 ETOH 子宫也面临氧化应激的风险，全身系统性氧化应激下降就证明了这一点。 和肝脏谷胱甘肽。 我们推测肺部 GSH 缺乏是由 当氧化应激叠加时，早产会加剧，例如 由子宫内乙醇暴露引起。肺部 GSH 减少 居民 AM 的可用性，从而有助于其受损 功能。尽管 AM 功能的调节很复杂，但我们选择 关注减少的 GSH 作为一种可能的调节剂。在豚鼠模型中， 初步研究表明，胎儿 ETOH 暴露会降低体内的 GSH 上皮衬里液，导致 AM GSH 与 妊娠匹配对照。 暴露于 ETOH 的 AM 表现出降低的 与妊娠对照相比，细胞因子释放和吞噬作用。这 具有临床相关性，因为它表明由于 如果存在慢性氧化应激，则可能会加剧早产 叠加在早产上。体内或体外添加 GSH 部分恢复了暴露于 ETOH 的 AM 的功能。因此，我们假设 由于 GSH 减少，暴露于 ETOH 的胎儿的 AM 功能受到限制 可用性，但可以通过补充 GSH 来恢复功能。为了进一步 定义子宫内 ETOH 后 GSH 可用性在 AM 功能中的作用 接触。我们将： 1) 确定子宫内 ETOH 是否存在氧化应激 通过 GSH 的可用性下调胎儿 AM 的免疫调节功能 2) 证明母体 GSH 前体在体内维持胎儿 AM 在子宫内暴露于 ETOH 期间，OSH 并随后维持 AM 功能。 了解 GSH 可用性在 AM 功能中的调节作用将 拓宽我们对 GSH 补充剂的理解，而不仅仅是将其作为一种可能的疗法 适用于在子宫内接触 ETOH 的婴儿，但一般为早产儿。