In Utero Alcohol and Alveolar Macrophage Maturation-A Risk For The Newborn

描述(申请人提供)：常驻肺泡巨噬细胞(AM)是一个异质的细胞群体，其功能是肺的第一道防线。谷胱甘肽(GSH)是肺中的一种主要抗氧化剂，AM需要它来维持氧化还原电位和优化细胞内功能。最初的临床回顾表明，宫内酒精(Etoh)暴露会增加新生儿的败血症。我们是第一个证明慢性宫内无水乙醇会加重已经脆弱的新生儿肺的氧化应激，减少谷胱甘肽的供应。乙醇损害早产儿和足月儿AM的吞噬功能和生存能力此外，体内或体外的GSH维持AM的功能。本实验室的新研究表明，在子宫内，乙醇使AM NADPH氧化酶升高，转化生长因子β1(TGFβ1)升高，AM过氧化体增殖物激活受体γ(PPAR？)降低。在胎儿AM中乙醇胺的成熟延迟，吞噬和细菌清除功能障碍，导致实验B群链球菌全身败血症和肺炎增加。此外，在摄入乙醇期间使用SAM-e的孕妇治疗可以维持AM成熟，减少乙醇诱导的功能障碍，并防止感染增加。这项修订后的应用程序将检验我们的假设，即子宫内乙醇暴露造成的慢性氧化应激延迟AM的成熟，削弱其功能并增加新生儿感染的风险。此外，我们假设，有针对性的母体或新生儿治疗将改善胎儿AM成熟和功能，最终保护接触乙醇的新生儿。使用我们的豚鼠和现在一个新的宫内和体外乙醇暴露的小鼠模型，我们将解决以下具体目标来确定：1-通过失衡增加的转化生长因子和减少的PPAR？延迟AM的成熟；2-乙醇诱导的AM成熟延迟对发育中的乙醇暴露AM的功能以及体外和体内败血症和肺炎风险的影响；3-体内摄入乙醇期间的母体治疗对AM成熟和功能的影响；4-体内乙醇暴露后新生儿治疗对AM成熟和功能的改善作用。这些新的研究将确定乙醇诱导的新生儿AM成熟延迟的机制，并探索针对高危新生儿的令人兴奋的潜在治疗措施。项目简介：该应用程序将确定宫内乙醇诱导的新生儿肺泡巨噬细胞成熟延迟的机制(S)以及新生儿肺炎/败血症的风险。这一临床前应用首次研究了对暴露于氧化应激增加的高危新生儿的潜在治疗干预措施，例如宫内酒精暴露。

DESCRIPTION (provided by applicant): The resident alveolar macrophage (AM) is a heterogenous population of cells that function as the first line of defense in the lung. Glutathione (GSH), a major antioxidant in the lung, is required by the AM to maintain redox potential and optimize intracellular functioning. Initial clinical reviews suggested that in utero alcohol (ETOH) exposure increases neonatal sepsis in the newborn. We are the first to have demonstrated that chronic in utero ETOH exaggerates oxidant stress for the already vulnerable neonatal lung, diminishing GSH availability. ETOH impaired phagocytic function and viability of the premature and term AM. Further, GSH in vivo or in vitro maintained AM function. New investigations from our laboratory suggested that in utero ETOH increased AM NADPH oxidase, increased transforming growth factor beta1 (TGF¿1) and diminished AM peroxisome proliferator-activated receptor gamma (PPAR?) in the fetal AM. The ETOH AM maturation was delayed, dysfunctional in phagocytosis and bacterial clearance, resulting in increased systemic sepsis and pneumonia from experimental group B streptococcus. Further, maternal therapy with SAM-e during ETOH ingestion maintained AM maturation, diminished ETOH-induced dysfunction and protected against increased infection. This revised application will examine our hypotheses that the chronic oxidant stress from in utero ETOH exposure delays the maturation of the AM, diminishing its function and increasing the risk of neonatal infection. Furthermore, we hypothesize that targeted maternal or neonatal therapies will improve fetal AM maturation and function, ultimately protecting the ETOH exposed neonate. Using our guinea pig and now a new mouse model of in utero and in vitro ETOH exposure, we will address the following specific aims to determine: 1-the mechanisms by which an imbalance of increased TGF¿1 and decreased PPAR? delays the maturation of the developing AM; 2-the consequences of ETOH-induced delay in AM maturation on the function of the developing ETOH-exposed AM and the risk of sepsis and pneumonia in vitro and in vivo; 3-the effects of maternal therapies during ETOH ingestion in vivo on the maturation and function of the AM; 4-a role for neonatal therapies in vivo to the newborn pups after ETOH exposure to improve AM maturation and function. These novel investigations will define the mechanism of ETOH-induced delay in the maturation of the neonatal AM, and explore exciting potential therapeutic interventions for the at-risk neonate. Project Narrative: This application will define the mechanism(s) of in utero Ethanol-induced delay in the maturation of the neonatal alveolar macrophage and the risk of pneumonia/sepsis in the newborn. This pre-clinical application is the first to investigate potential therapeutic interventions for the at-risk neonate exposed to increased oxidative stress, such as occurs with in utero alcohol exposure.