Background:The health implications of in utero alcohol exposure have been difficult to study in very-low-birth-weight newborns (VLBW) because of an inability to identify maternal alcohol exposure. Fatty acid ethyl esters (FAEEs) are elevated in meconium of alcohol-exposed term newborns. We hypothesized that meconium FAEEs would be similarly elevated in alcohol-exposed VLBW premature newborns.
Methods:In a retrospective cohort study of 64 VLBW neonates, newborns were classified into Non-Exposed, Any Exposure, or Weekly Exposure groups based on an in-depth structured maternal interview. Meconium FAEE concentrations were quantified via gas chromatography mass spectrometry.
Results:Alcohol exposure during Trimester 1 (Any Exposure) occurred in ∼30% of the pregnancies, while 11% of the subjects reported drinking ≥ 1 drink/week (Weekly Exposure). Meconium ethyl linolenate was higher in Any Exposure (P = 0.01) and Weekly Exposure groups (P = 0.005) compared to the Non-Exposed VLBW group. There was a significant positive correlation between Trimester 1 drinking amounts and the concentration of meconium ethyl linolenate (P = 0.005). Adjusted receiver operating characteristic (ROC) curves evaluating ethyl linolenate to identify alcohol-exposed VLBW newborns generated areas under the curve of 88% with sensitivities of 86-89% and specificities of 83-88%.
Conclusion:Despite prematurity, meconium FAEEs hold promise to identify the alcohol-exposed VLBW newborn.
Evidence from research in humans and animals suggest that ingesting alcohol during pregnancy can disrupt the fetal immune system and result in an increased risk of infections and disease in newborns that may persist throughout life. Alcohol may have indirect effects on the immune system by increasing the risk of premature birth, which itself is a risk factor for immune-related problems. Animal studies suggest that alcohol exposure directly disrupts the developing immune system. A comprehensive knowledge of the mechanisms underlying alcohol's effects on the developing immune system only will become clear once researchers establish improved methods for identifying newborns exposed to alcohol in utero.
Alcoholic patients have an increased risk of respiratory infections, which is partially due to an impaired immune response of alveolar macrophages. The mechanisms by which alcohol impairs alveolar macrophage function are poorly understood. In this study, we demonstrated in a guinea pig model that chronic ethanol ingestion significantly impaired alveolar macrophage differentiation and function. Isolated alveolar macrophages were separated into 4 different subpopulations with varying densities and levels of maturation. Compared to control values, chronic ethanol ingestion decreased the percentage of alveolar macrophages in the mature fractions by ~60%. Alveolar macrophage function in each subpopulation was determined by measuring phagocytosis of FITC-labeled S. aureus. Alveolar macrophages from ethanol-fed animals had ~80% decrease in the phagocytic index. Western blot and immunohistochemical analysis of the differential markers GM-CSF receptor α (GM-CSFR-α), PU.1, CD11c, and CD11b verified that alcoholic macrophages displayed impaired terminal differentiation. While oral supplementation with the glutathione precursor S-adenosyl-methionine (SAM) did not alter the maturational status of control animals, SAM s supplementation shifted the distribution of macrophages to more mature fractions, normalized the phagocytic index; as well as normalized expression of CD11c, CD11b, PU.1, and GM-CSFR-α. Chronic ethanol ingestion also impaired the differentiation status of interstitial macrophages which was normalized by SAM supplementation. This improvement in the maturational status suggested that ethanol-induced oxidant stress is a central feature in impaired terminal differentiation of macrophages in the interstitial and alveolar space. Therefore, strategies targeting pulmonary oxidant stress may restore macrophage differentiation and function even after chronic ethanol ingestion.
Background: We hypothesized that maternal alcohol use occurs in pregnancies that end prematurely and that in utero alcohol exposure is associated with an increased risk of morbidities of premature newborns.
Methods: In an observational study of mothers who delivered very low birth weight newborns (VLBW) ≤1,500 g, maternal alcohol use was determined via a standardized administered questionnaire. We compared the effect of maternal drinking on the odds of developing late-onset sepsis (LOS), bronchopulmonary dysplasia (BPD), death, BPD or Death days on oxygen or any morbidity (either LOS, BPD or death). The effect of drinking amounts (light versus heavy) was also evaluated.
Results: A total of 129 subjects who delivered 143 VLBW newborns were enrolled. Approximately 1 in 3 (34%) subjects reported drinking alcohol during the first trimester ("exposed"). Within the exposed group, 15% reported drinking ≥7. drinks/week ("heavy") and 85% of the subjects reported drinking < 7. drinks/week ("light"). When controlling for maternal age, drug or tobacco use during pregnancy and neonatal gestational age, any drinking increased the odds of BPD or Death and any morbidity. Furthermore, light or heavy drinking increased the odds of BPD or Death and any morbidity, whereas heavy drinking increased the odds of LOS.
Conclusions: In utero alcohol exposure during the first trimester occurred in 34% of VLBW newborns. Maternal drinking in the first trimester was associated with significantly increased odds of neonatal morbidity. Further studies are warranted to determine the full effect of . in utero alcohol exposure on the adverse outcomes of VLBW premature newborns.
Our understanding of the intrinsic effects of cystic fibrosis (CF) transmembrane conductance regulator (cftr) deletion on resident neonatal alveolar macrophage (AM) remains limited. We previously demonstrated that diminished glutathione (GSH) or excessive AM transforming growth factor beta one (TGFβ1) contributes to AM dysfunction in a variety of disease states. In this study, using a gut-corrected cftr neonatal knockout (KO) mouse model and a siRNA-manipulated macrophage-like cell line (THP-1 cell), we hypothesized (1) that cftr mutation alone increases neonatal AM oxidant stress and cellular TGFβ1 signaling via altered GSH, thereby impairing cellular function, and (2) that exogenous GSH attenuates AM alterations and dysfunction in the KO AM In neonatal KO mice, the baseline bronchoalveolar lavage fluid demonstrated a near doubling in mixed disulfides (P ≤ 0.05) and oxidized GSSG (P ≤ 0.05) without concurrent inflammation compared to WT littermates. KO AM demonstrated diminished AM thiols (P ≤ 0.05), increased AM mitochondrial ROS (P ≤ 0.05), increased AM TGFβ1 (P ≤ 0.05) with increased TGFβ1 signaling (P ≤ 0.05), and impaired phagocytosis (P ≤ 0.05). KO AM mitochondrial ROS was modulated by exogenous GSH (P ≤ 0.05). Conversely, TGFβ1 was reduced (P ≤ 0.05) and impaired phagocytosis was rescued (P ≤ 0.05) by exogenous GSH in the KO AM These results suggest that an altered neonatal AM phenotype may contribute to the initiation of lung inflammation/infection in the CF lung. Modulation of the AM in the neonatal CF lung may potentially alter progression of disease.
Summary
Background
The effects of fetal alcohol exposure on the risks of neonatal lung injury and infection remain under investigation. The resident alveolar macrophage (AM) is the first line of immune defense against pulmonary infections. In utero ethanol (ETOH) exposure deranges the function of both premature and term guinea pig AM. We hypothesized that fetal ETOH exposure would increase the risk of pulmonary infection in vivo.
Methods
We developed a novel in vivo model of group B streptococcus (GBS) pneumonia using our established guinea pig model of fetal ETOH exposure. Timed-pregnant guinea pigs were pair fed ± ETOH and some were supplemented with the glutathione (GSH) precursor S-adenosyl-methionine (SAM-e). Term pups were given GBS intratracheally while some were pre-treated with inhaled GSH prior to the experimental GBS. Neonatal Lung and whole blood were evaluated for GBS while isolated AM were evaluated using fluorescent microscopy for GBS phagocytosis.
Results
ETOH-exposed pups demonstrated increased lung infection and sepsis while AM phagocytosis of GBS was deficient compared to control. When SAM-e was added to the maternal diet containing ETOH, neonatal lung and systemic infection from GBS was attenuated and AM phagocytosis was improved. Inhaled GSH therapy prior to GBS similarly protected the ETOH-exposed pup from lung and systemic infection.
Conclusions
In utero ETOH exposure impaired the neonatal lung’s defense against experimental GBS, while maintaining GSH availability protected the ETOH-exposed lung. This study suggested that fetal alcohol exposure deranges the neonatal lung’s defense against bacterial infection, and support further investigations into the potential therapeutic role for exogenous GSH to augment neonatal AM function.
Background
Alterations in inflammatory mediators are an important finding in neonates who develop bronchopulmonary dysplasia (BPD); however, there is a lack of research examining the relationship between multiple inflammatory mediators in premature neonates and the development of BPD.
Objective
This study investigated whether the distribution of 12 inflammatory mediators detected in the tracheal aspirate (TA) of neonates within 24 hours of birth could differentiate between neonates who did and did not develop BPD.
Study Design
TA samples were collected from 27 very low birth weight neonates (BPD+ =11) and the concentrations of 12 biomarkers associated with BPD were determined. Linear discriminate analysis (LDA) was used to classify neonates into two outcome groups.
Result
LDA based on the 12 measured biomarkers displayed a significant level of discriminant function (p=0.007).
Conclusion
Using linear discriminant analysis, predictive models of BPD can be generated. Our results suggest that multiple inflammatory mediators collected within 24 hours of birth may be used to classify neonates into who will and will not develop BPD.
Background
Analysis of exhaled breath condensates (EBC) is a non-invasive technique to evaluate biomarkers such as antioxidants in the pediatric population, but limited data exists of its use in intubated patients, particularly newborns. Currently, tracheal aspirate (TA) serves as the gold standard collection modality in critically ill newborns, but this method remains invasive. We tested the hypothesis that glutathione status would positively correlate between EBC and TA collections in intubated newborns in the Newborn Intensive Care Unit (NICU). We also hypothesized that these measurements would be associated with alveolar macrophage (AM) glutathione status in the newborn lung.
Methods
Reduced glutathione (rGSH), glutathione disulfide (GSSG), and total GSH (rGSH + (2 X GSSG)) were measured in sequential EBC and TA samples from 26 intubated newborns via high performance liquid chromatography (HPLC). Additionally, AM glutathione was evaluated via immunofluorescence. Pearson’s correlation coefficient and associated 95% confidence intervals were used to quantify the associations between raw and urea-corrected concentrations in EBC and TA samples and AM staining. Statistical significance was defined as p ≤ 0.05 using two-tailed tests. The sample size was projected to allow for a correlation coefficient of 0.5, with 0.8 power and alpha of 0.05.
Results
EBC was obtainable from intubated newborns without adverse clinical events. EBC samples demonstrated moderate to strong positive correlations with TA samples in terms of rGSH, GSSG and total GSH. Positive correlations between the two sampling sites were observed in both raw and urea-corrected concentrations of rGSH, GSSG and total GSH. AM glutathione staining moderately correlated with GSSG and total GSH status in both the TA and EBC.
Conclusions
GSH status in EBC samples of intubated newborns significantly correlated with the GSH status of the TA sample and was reflective of cellular GSH status in this cohort of neonatal patients. Non-invasive EBC sampling of intubated newborns holds promise for monitoring antioxidant status such as GSH in the premature lung. Further studies are necessary to evaluate the potential relationships between EBC biomarkers in the intubated premature newborn and respiratory morbidities.