MATERNAL ALCOHOL IMPAIRS FETAL ALVEOLAR MACROPHAGE

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.

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.