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

描述（由申请人提供）：常驻肺泡巨噬细胞（AM）是一种异质细胞群，在肺部起第一道防线的作用。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。初步临床回顾表明，子宫内酒精（ETOH）暴露增加新生儿败血症。我们是第一个证明慢性子宫内ETOH会增加已经脆弱的新生儿肺部的氧化应激，减少谷胱甘肽的可用性。ETOH损害了早、中期AM的吞噬功能和生存能力。此外，谷胱甘肽在体内或体外维持AM功能。我们实验室的新研究表明，在子宫内，ETOH增加了AM NADPH氧化酶，增加了转化生长因子β 1 (TGF¿1)，降低了AM过氧化物酶体增殖激活受体γ (PPAR?)。ETOH AM成熟延迟，吞噬功能和细菌清除功能障碍，导致实验B组链球菌引起的全身败血症和肺炎增加。此外，在母体摄取ETOH期间，用SAM-e治疗可以维持AM成熟，减少ETOH引起的功能障碍，并防止感染增加。这一修订后的申请将检验我们的假设，即子宫内暴露于ETOH的慢性氧化应激会延迟AM的成熟，降低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亲或新生儿治疗将改善胎儿AM的成熟和功能，最终保护暴露于ETOH的新生儿。使用我们的豚鼠和现在的一个新的小鼠模型，子宫和体外ETOH暴露，我们将解决以下具体目标，以确定：1- TGF¿1增加和PPAR？延缓发育中的AM的成熟；etoh诱导的AM成熟延迟对暴露于etoh的AM发育中的功能以及脓毒症和肺炎风险的影响；3 .母体治疗在体内摄取ETOH时对AM成熟和功能的影响；4 . ETOH暴露后新生儿体内治疗对新生幼崽促进AM成熟和功能的作用。这些新的研究将确定etoh诱导的新生儿AM成熟延迟的机制，并探索对高危新生儿的潜在治疗干预。项目描述：本应用将确定胎儿内乙醇诱导的新生儿肺泡巨噬细胞成熟延迟的机制以及新生儿肺炎/败血症的风险。这项临床前应用是首次研究暴露于氧化应激增加的高危新生儿的潜在治疗干预措施，例如发生在子宫内的酒精暴露。

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.