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.
|Giliberti, Danielle; Mohan, Sowmya S; Brown, Lou Ann S et al. (2013) Perinatal exposure to alcohol: implications for lung development and disease. Paediatr Respir Rev 14:17-21|
|Gauthier, Theresa W; Ping, Xiao-Du; Gabelaia, Levan et al. (2010) Delayed neonatal lung macrophage differentiation in a mouse model of in utero ethanol exposure. Am J Physiol Lung Cell Mol Physiol 299:L8-16|