MATERNAL ALCOHOL IMPAIRS FETAL ALVEOLAR MACROPHAGE

描述(改编自申请人的描述)：早产儿在 炎性细胞功能障碍导致肺部感染风险增加 包括常驻肺泡巨噬细胞(AM)。AM是第一行 对肺部感染的防御。谷胱甘肽(GSH)--主要的抗氧化剂 包括AM在内的所有细胞都需要在肺中维持氧化还原 潜力和优化细胞内功能。系统级别和 早产儿的肺泡GSH缺乏，使肺处于 氧化损伤和细胞功能障碍的风险增加。慢性酒精 (乙醇)暴露在成人体内也会增加全身氧化应激和损伤。 肺内的免疫功能，尤其是AM乙醇消耗量 在育龄妇女中显著增加，并仍然是 孕妇存在严重的健康问题。年暴露在乙醇中的胎儿 子宫也面临氧化应激的风险，这一点从全身性下降得到了证明。 肝脏GSH。我们推测由以下原因引起的肺GSH缺乏 当叠加氧化应激时，早产儿会加剧，比如 由宫内接触乙醇引起。肺中谷胱甘肽降低会降低谷胱甘肽 派驻AM的可用性，从而有助于其受损 功能。虽然AM函数的调节很复杂，但我们选择了 关注降低的谷胱甘肽作为一种可能的调节因素。在豚鼠模型中， 初步研究表明，胎儿接触乙醇会降低体内GSH水平 上皮衬里液体，导致AM GSH与 妊娠配对的对照组。乙醇暴露的AM表现为减少 与妊娠对照组相比，细胞因子的释放和吞噬作用。这 在临床上是相关的，因为它表明由于 如果慢性氧化应激导致早产，早产可能会加剧 叠加在早产上。谷胱甘肽在体内或体外的添加 部分恢复乙醇暴露的AM的功能因此，我们假设 由于GSH降低，接触乙醇的胎儿AM功能受到限制 但功能可以通过补充GSH来恢复。为了进一步 确定GSH在宫内无水乙醇后AM功能中的作用 曝光。我们将：1)测定宫内乙醇的氧化应激 通过GSH的可获得性下调胎儿AM的免疫调节功能 2)证明体内的母体GSH前体维持胎儿AM OSH，随后在子宫内乙醇暴露期间维持AM功能。 了解谷胱甘肽在AM功能中的调节作用 拓宽我们对GSH补充剂的理解不仅仅是作为一种可能的治疗方法 适用于宫内接触乙醇的婴儿，但一般为早产儿。

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.