Antenatal endotoxin disrupts lung vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase expression in the developing rat.

Vitamin D [vit D; 1,25-(OH)2D] treatment improves survival and lung alveolar and vascular growth in an experimental model of bronchopulmonary dysplasia (BPD) after antenatal exposure to endotoxin (ETX). However, little is known about lung-specific 1,25-(OH)2D3 regulation during development, especially regarding maturational changes in lung-specific expression of the vitamin D receptor (VDR), 1α-hydroxylase (1α-OHase), and CYP24A1 during late gestation and the effects of antenatal ETX exposure on 1,25-(OH)2D3 metabolism in the lung. We hypothesized that vit D regulatory proteins undergo maturation regulation in the late fetal and early neonatal lung and that prenatal exposure to ETX impairs lung growth partly through abnormal endogenous vit D metabolism.

Impaired pulmonary vascular development in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD), the chronic lung disease associated with preterm birth, results from the disruption of normal pulmonary vascular and alveolar growth. Though BPD was once described as primarily due to postnatal injury from mechanical ventilation and oxygen therapy after preterm birth, it is increasingly appreciated that BPD results from antenatal and perinatal factors that interrupt lung development in infants born at the extremes of prematurity. The lung in BPD consists of a simplified parenchymal architecture that limits gas exchange and leads to increased cardiopulmonary morbidity and mortality.

Maturational Changes in Diastolic Longitudinal Myocardial Velocity in Preterm Infants.

Background: Doppler tissue imaging (DTI) has been used to evaluate myocardial velocity during ventricular filling, a means of characterizing diastolic function. Previous studies in older children have shown age-related increases in early diastolic tissue velocities, but there are limited data in preterm infants. The aim of this study was to prospectively determine maturational changes in diastolic tissue velocities at two points in time: (1) 7 days of age and (2) 36 weeks' postmenstrual age (PMA).

Greater risk of hospitalization in children with Down syndrome and OSA at higher elevation.

Background: Children with Down syndrome (DS) are at high risk for OSA. Increasing elevation is known to exacerbate underlying respiratory disorders and worsen sleep quality in people without DS, but whether altitude modulates the severity of OSA in DS is uncertain. In this study, we evaluate the impact of elevation (≤ 1,500 m vs > 1,500 m) on the proportion of hospitalizations involving OSA in children with and without DS.

The Robyn Barst Memorial Lecture: Differences between the fetal, newborn, and adult pulmonary circulations: relevance for age-specific therapies (2013 Grover Conference series).

Pulmonary arterial hypertension (PAH) contributes to poor outcomes in diverse diseases in newborns, infants, and children. Many aspects of pediatric PAH parallel the pathophysiology and disease courses observed in adult patients; however, critical maturational differences exist that contribute to distinct outcomes and therapeutic responses in children. In comparison with adult PAH, disruption of lung vascular growth and development, or angiogenesis, plays an especially prominent role in the pathobiology of pediatric PAH.

Altered pulmonary artery endothelial-smooth muscle cell interactions in experimental congenital diaphragmatic hernia.

Background: Pulmonary hypertension (PH) secondary to vascular remodeling contributes to poor outcomes in congenital diaphragmatic hernia (CDH), however mechanisms responsible are unknown. We hypothesized that pulmonary artery endothelial cell (PAEC) dysfunction contributes to smooth muscle cell (SMC) hyperplasia in experimental CDH.

Methods: PAEC and SMC were isolated from fetal sheep with experimental CDH and controls.

Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep.

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers.

Histologic identification of prominent intrapulmonary anastomotic vessels in severe congenital diaphragmatic hernia.

Objective: To determine whether prominent intrapulmonary anastomotic vessels (IPAVs) or bronchopulmonary "shunt" vessels can be identified in lungs from infants with fatal congenital diaphragmatic hernia (CDH).

Study Design: We performed histology with immunostaining for CD31 (endothelium) and D2-40 (lymphatics), along with high-precision 3-dimensional (3D) reconstruction on lung tissue from 9 patients who died with CDH.

Results: Each patient with CDH required mechanical ventilation, cardiotonic support, and pulmonary hypertension (PH)-targeted drug therapy.

Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep.

Hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGFA) are paracrine hormones that mediate communication between pancreatic islet endothelial cells (ECs) and β-cells. Our objective was to determine the impact of intrauterine growth restriction (IUGR) on pancreatic vascularity and paracrine signaling between the EC and β-cell. Vessel density was less in IUGR pancreata than in controls.

Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns.

Objective: To assess the efficacy and safety of early, noninvasive inhaled nitric oxide (iNO) therapy in premature newborns who do not require mechanical ventilation.

Study Design: We performed a multicenter randomized trial including 124 premature newborns who required noninvasive supplemental oxygen within the first 72 hours after birth. Newborns were stratified into 3 different groups by birth weight (500-749, 750-999, 1000-1250 g) prior to randomization to iNO (10 ppm) or placebo gas (controls) until 30 weeks postmenstrual age.

Intrapulmonary vascular shunt pathways in alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a lethal neonatal lung disease characterised by severe pulmonary hypertension, abnormal vasculature and intractable hypoxaemia. Mechanisms linking abnormal lung vasculature with severe hypoxaemia in ACD/MPV are unknown. We investigated whether bronchopulmonary anastomoses form right-to-left shunt pathways in ACD/MVP.

Disrupted lung development and bronchopulmonary dysplasia: opportunities for lung repair and regeneration.

Purpose Of Review: Advances in medical therapy have increased survival of extremely premature infants and changed the pathology of bronchopulmonary dysplasia (BPD) from one of acute lung injury to a disease of disrupted lung development. With this evolution, new questions emerge regarding the molecular mechanisms that control postnatal lung development, the effect of early disruptions of postnatal lung development on long-term lung function, and the existence of endogenous mechanisms that permit lung regeneration after injury.

Recent Findings: Recent data demonstrate that a significant component of alveolarization, the final stage of lung development, occurs postnatally.

Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is a significant contributor to perinatal morbidity and mortality. Premature birth disrupts pulmonary vascular growth and initiates a cascade of events that result in impaired gas exchange, abnormal vasoreactivity, and pulmonary vascular remodeling that may ultimately lead to pulmonary hypertension (PH). Even infants who appear to have mild BPD suffer from varying degrees of pulmonary vascular disease (PVD).

Effects of early inhaled nitric oxide therapy and vitamin A supplementation on the risk for bronchopulmonary dysplasia in premature newborns with respiratory failure.

Objective: To assess whether the combination of early inhaled nitric oxide (iNO) therapy and vitamin A supplementation lowers the incidence of bronchopulmonary dysplasia (BPD) in premature newborns with respiratory failure.

Study Design: A total of 793 mechanically ventilated infants (birth weight 500-1250 g) were randomized (after stratification by birth weight) to receive placebo or iNO (5 ppm) for 21 days or until extubation (500-749, 750-999, or 1000-1250 g). A total of 398 newborns received iNO, and of these, 118 (30%) received vitamin A according to their enrollment center.

Intensive care unit readmission during childhood after preterm birth with respiratory failure.

Objective: To determine the incidence and risk factors for readmission to the intensive care unit (ICU) among preterm infants who required mechanical ventilation at birth.

Study Design: We studied preterm newborns (birth weight 500-1250 g) who required mechanical ventilation at birth and were enrolled in a multicenter trial of inhaled nitric oxide therapy. Patients were assessed up to 4.

Three-dimensional reconstruction identifies misaligned pulmonary veins as intrapulmonary shunt vessels in alveolar capillary dysplasia.

Alveolar capillary dysplasia (ACD) with misalignment of pulmonary veins (MPV) is a lethal neonatal lung disease. Death from ACD/MPV is caused by hypoxia, but the role of the MPV is unknown. Using 3-dimensional reconstruction of ACD/MPV lung tissue, we report that the veins in MPV are intrapulmonary shunt vessels, and speculate that MPV contributes to the poor prognosis.

Cord blood endothelial colony-forming cells from newborns with congenital diaphragmatic hernia.

Endothelial colony-forming cells (ECFCs) are decreased in the cord blood of preterm infants with moderate-to-severe bronchopulmonary dysplasia. We quantified ECFCs from infants with congenital diaphragmatic hernia, a neonatal disorder with severe lung hypoplasia. Unlike newborns who develop bronchopulmonary dysplasia, those with congenital diaphragmatic hernia had increased and highly-proliferative cord blood ECFCs.

Endothelial colony-forming cell conditioned media promote angiogenesis in vitro and prevent pulmonary hypertension in experimental bronchopulmonary dysplasia.

Late-outgrowth endothelial colony-forming cells (ECFCs), a type of circulating endothelial progenitor cell (EPC), may contribute to pulmonary angiogenesis during development. Cord blood ECFCs from preterm newborns proliferate more rapidly than term ECFCs but are more susceptible to the adverse effects of hyperoxia. Recent studies suggest that bone marrow-derived EPCs protect against experimental lung injury via paracrine mechanisms independent of vascular engraftment.

Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond.

Purpose Of Review: Pulmonary hypertension contributes significantly to morbidity and mortality of chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD). Advances in pulmonary vascular biology over the past few decades have led to new insights into the pathogenesis of BPD; however, many unique issues persist regarding our understanding of pulmonary vascular development and disease in preterm infants at risk for chronic lung disease.

Recent Findings: Recent studies have highlighted the important contribution of the developing pulmonary circulation to lung growth in the setting of preterm birth.

Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn.

Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. We hypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increases PVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2A receptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis.