Loss of growth differentiation factor 15 exacerbates lung injury in neonatal mice.

Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-ß (TGF-ß) superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine bronchopulmonary dysplasia (BPD) models, and GDF15 loss exacerbates oxidative stress and decreases cellular viability in vitro. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal Gdf15-/- mice and wild-type (WT) controls on a similar background to room air or hyperoxia (95% [Formula: see text]) for 5 days after birth. The mice were euthanized on postnatal day 21 (PND 21). Gdf15-/- mice had higher mortality and lower body weight than WT mice after exposure to hyperoxia. Hyperoxia exposure adversely impacted alveolarization and lung vascular development, with a greater impact in Gdf15-/- mice. Interestingly, Gdf15-/- mice showed lower macrophage count in the lungs compared with WT mice both under room air and after exposure to hyperoxia. Analysis of the lung transcriptome revealed marked divergence in gene expression and enriched biological pathways in WT and Gdf15-/- mice and differed markedly by biological sex. Notably, pathways related to macrophage activation and myeloid cell homeostasis were negatively enriched in Gdf15-/- mice. Loss of Gdf15 exacerbates mortality, lung injury, and the phenotype of the arrest of alveolarization in the developing lung with loss of female-sex advantage in Gdf15-/- mice.NEW & NOTEWORTHY We show for the first time that loss of Gdf15 exacerbates mortality, lung injury, and the phenotype of the arrest of alveolarization in the developing lung with loss of female-sex advantage in Gdf15-/- mice. We also highlight the distinct pulmonary transcriptomic response in the Gdf15-/- lung including pathways related to macrophage recruitment and activation.

Unilateral neonatal pulmonary interstitial emphysema managed conservatively: A case report.

BACKGROUND: Pulmonary interstitial emphysema (PIE) is a pathological state when air escapes from ruptured alveoli and is trapped along the sheaths surrounding the bronchovascular bundle. PIE is not uncommon in infants who require mechanical ventilation and even less common in infants on noninvasive ventilatory support; however, it is extremely unusual in infants in room air. CASE PRESENTATION: A 2-week-old male infant developed worsening tachypnea in the special-care nursery. The patient was born at 33 weeks' gestation by induced vaginal delivery due to pre-eclampsia. He required positive pressure ventilation at birth and was admitted to the neonatal intensive care unit on nasal continuous positive airway pressure. On the second day of life, exogenous surfactant was administered via endotracheal tube due to increased oxygen requirement, and, soon after, he was weaned off all respiratory support. After 10 days of stability, he developed tachypnea with diminished air entry on the left side of the chest. Chest radiograph and chest computerized tomography confirmed left-sided unilateral PIE. The patient was treated conservatively with positional therapy alone. Significant clinical and radiographic improvement was noticed within 4 days; almost complete resolution by 10 days and the infant was discharged 23 days later. At follow-up at 7 months, the infant was found to be symptom-free with a normal chest radiograph. CONCLUSIONS: Traditional management of unilateral PIE generally involves a combination of invasive ventilatory support and positional therapy to break the vicious cycle pathophysiology of PIE. This report focuses on the insidious progression of PIE in nonventilated neonates and describes a nontraditional conservative management strategy for the management of unilateral PIE.

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan.

Growth Differentiation Factor 15 (GDF15) is a divergent member of transforming growth factor-beta (TGF-ß) superfamily and is ubiquitously expressed, under normal physiological conditions. GDF15 expression increases during many pathological states and serves a marker of cellular stress. GDF15 has multiple and even paradoxical roles within a pathological condition, as its effects can be dose- and time-dependent and vary based on the targeted tissues and downstream pathways. GDF15 has emerged as one of the most recognized proteins as part of the senescence associated secretory phenotype. Cellular senescence plays a major role in many lung diseases across the life-span from bronchopulmonary dysplasia in the premature neonate to COPD and idiopathic pulmonary fibrosis in aged adults. GDF15 levels have been reported to be as a useful biomarker in chronic obstructive pulmonary disease, lung fibrosis and pulmonary arterial hypertension and predict disease severity, decline in lung function and mortality. Glial-cell-line-derived neurotrophic factor family receptor alpha-like (GFRAL) in the brain stem has been identified as the only validated GDF15 receptor and mediates GDF15-mediated anorexia and wasting. The mechanisms and pathways by which GDF15 exerts its pulmonary effects are being elucidated. GDF15 may also have an impact on the lung based on the changes in circulating levels or through the central action of GDF15 activating peripheral metabolic changes. This review focuses on the role of GDF15 in different lung diseases across the lifespan and its role in cellular senescence.

High concentrations of urinary ethanol metabolites in neonatal intensive care unit infants.

BACKGROUND: Infants in the neonatal intensive care unit may be exposed to ethanol via medications that contain ethanol as an excipient and through inhalation of ethanol vapor from hand sanitizers. We hypothesized that both pathways of exposure would result in elevated urinary biomarkers of ethanol. METHODS: Urine samples were collected from infants in incubators and in open cribs. Two ethanol metabolites, ethyl sulfate (EtS) and ethyl glucuronide (EtG), were quantified in infants' urine. RESULTS: A subset of infants both in incubators and open cribs had ethanol biomarkers greater than the cutoff concentration that identifies adult alcohol consumption. These concentrations were associated with the infant having received an ethanol-containing medication on the day of urine collection. When infants who received an ethanol-containing medication were excluded from analysis, there was no difference in ethanol biomarker concentrations between the incubator and crib groups. CONCLUSIONS: Some infants who received ethanol-containing medications had concentrations of ethanol biomarkers that are indicative of adult alcohol consumption, suggesting potential exposure via ethanol excipients. IMPACT: Infants and newborns in the neonatal intensive care unit are exposed to concerning amounts of ethanol. No one has shown exposure to ethanol in these infants before this study. The impact is that better understanding of the excipients in medications given to patients in the NICU is needed. When physicians order medications in the NICU, the amount of excipient needs to be indicated.

Fetal exposure to mercury and lead from intrauterine blood transfusions.

BACKGROUND: Mercury (Hg) and lead (Pb) exposure during childhood is associated with irreversible neurodevelopmental effects. Fetal exposure to Hg and Pb from intrauterine blood transfusion (IUBT) has not been reported. METHODS: Fetal exposure was estimated based on transfusion volume and metal concentration in donor packed red blood cell (PRBCs). As biomarkers to quantify prenatal exposure are unknown, Hg and Pb in donor PRBCs were compared to estimated intravenous (IV) RfDs based on gastrointestinal absorption. RESULTS: Three pregnant women received 8 single-donor IUBTs with volumes ranging from 19 to 120 mL/kg. Hg and Pb were present in all donor PRBC units. In all, 1/8 IUBT resulted in Hg dose five times higher than the estimated IV RfD. Median Pb dose in one fetus who received 5 single-donor IUBTs between 20-32 weeks gestation was 3.4 µg/kg (range 0.5-7.9 µg/kg). One donor unit contained 12.9 µg/dL of Pb, resulting in a fetal dose of 7.9 µg/kg, 40 times higher than the estimated IV RfD at 20 weeks gestation. CONCLUSION: This is the first study documenting inadvertent exposure to Hg and Pb from IUBT and quantifying the magnitude of exposure. Screening of donor blood is warranted to prevent toxic effects from Hg and Pb to the developing fetus.