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Rationale: Bronchopulmonary dysplasia (BPD) is a leading complication of preterm birth that affects infants born in the saccular stage of lung development at

A female infant is born at 38 weeks’ estimated gestational age to a 23-year-old, gravida 2, para 2 woman. Maternal history is significant for poorly controlled chronic hypertension and limited prenatal care. The woman reports she was returning home from vacation when she experienced painful, frequent contractions, prompting presentation to the nearest emergency department. Her initial blood pressure is 152/102 mm Hg. She has spontaneous rupture of membranes and undergoes repeat cesarean section 3 hours after arrival at the academic medical center. In the delivery room, Apgar scores are 7 at 1 minute (0 for skin color, and 1 for respiratory effort) and 9 at 5 minutes (1 for skin color). Growth parameters are consistent with a small-for–gestational age infant; the newborn’s head circumference, weight, and length are all less than the 1st percentile for gestational age. Initial physical examination is remarkable for upper limb abnormalities, including oligodactyly with the presence of only 2 formed digits on the left upper extremity, a single palpable forearm bone in the left upper extremity, a sacral dimple, significant hirsutism, and abnormal facial features, including synophrys and highly arched eyebrows. She is admitted to the NICU for further care. In the NICU, she is initiated on feeds of expressed breast milk and colostrum. She passes meconium on the first day after birth. The neonate initially tolerates small volumes of feeds, but by day 2, she experiences nonbilious emesis 15 to 30 minutes after each feed. Intravenous fluids are initiated and a Replogle tube is placed. An abdominal radiograph is obtained on the second day after …

Noninvasive sampling of the distal airspace in patients with acute respiratory distress syndrome (ARDS) has long eluded clinical and translational researchers. We recently reported that fluid collected from heat moisture exchange (HME) filters closely mirrors fluid directly aspirated from the distal airspace. In the current study, we sought to determine fluid yield from different HME types, optimal HME circuit dwell time, and reliability of HME fluid in reflecting the distal airspace. We studied fluid yield from four different filter types by loading increasing volumes of saline and measuring volumes of fluid recovered. We collected filters after 1, 2, and 4 h of dwell time for measurement of fluid volume and total protein from 13 subjects. After identifying 4 h as the optimal dwell time, we measured total protein and IgM in HME fluid from 42 subjects with ARDS and nine with hydrostatic pulmonary edema (HYDRO). We found that the fluid yield varies greatly by filter type. With timed sample collection, fluid recovery increased with increasing circuit dwell time with a median volume of 2.0 mL [interquartile range (IQR) 1.2–2.7] after 4 h. Total protein was higher in the 42 subjects with ARDS compared with nine with HYDRO [median 708 µg/mL (IQR 244–2017) vs. 364 µg/mL (IQR 136–578), P = 0.047], confirming that total protein concentration in HME is higher in ARDS compared with hydrostatic edema. These studies establish a standardized HME fluid collection protocol and confirm that HME fluid analysis is a novel noninvasive tool for the study of the distal airspace in ARDS.

Emerging evidence indicates that early life events can increase the risk for developing chronic obstructive pulmonary disease (COPD). Using an inducible transgenic mouse model for NF-κB activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage (P3–P5) but not alveolar stage (P10–P12) of lung development disrupted elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progressed through 24 months of age. Neutrophil depletion prevented disruption of elastic fiber assembly and restored normal lung development. Mechanistic studies uncovered a role for neutrophil elastase (NE) in downregulating expression of critical elastic fiber assembly components, particularly fibulin-5 and elastin. Further, purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation downregulated elastin and fibulin-5 expression by saccular-stage mouse lung fibroblasts. Together, our studies define a critical developmental window for assembling the elastin scaffold in the distal lung, which is required to support lung structure and function throughout the lifespan. Although neutrophils play a well-recognized role in COPD development in adults, neutrophilic inflammation may also contribute to early-life predisposition to COPD.

Integrins, the extracellular matrix receptors that facilitate cell adhesion and migration, are necessary for organ morphogenesis; however, their role in maintaining adult tissue homeostasis is poorly understood. To define the functional importance of β(1) integrin in adult mouse lung, we deleted it after completion of development in type 2 alveolar epithelial cells (AECs). Aged β(1) integrin–deficient mice exhibited chronic obstructive pulmonary disease–like (COPD-like) pathology characterized by emphysema, lymphoid aggregates, and increased macrophage infiltration. These histopathological abnormalities were preceded by β(1) integrin–deficient AEC dysfunction such as excessive ROS production and upregulation of NF-κB–dependent chemokines, including CCL2. Genetic deletion of the CCL2 receptor, Ccr2, in mice with β(1) integrin–deficient type 2 AECs impaired recruitment of monocyte-derived macrophages and resulted in accelerated inflammation and severe premature emphysematous destruction. The lungs exhibited reduced AEC efferocytosis and excessive numbers of inflamed type 2 AECs, demonstrating the requirement for recruited monocytes/macrophages in limiting lung injury and remodeling in the setting of a chronically inflamed epithelium. These studies support a critical role for β(1) integrin in alveolar homeostasis in the adult lung.

Rationale: Antenatal factors, such as chorioamnionitis, preeclampsia, and postnatal injury, are associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. IGF-1 (insulin-like growth factor-1) is markedly decreased in normal preterm infants, but whether IGF-1 treatment can prevent BPD or PH is unknown. Objectives: To evaluate whether postnatal treatment with rhIGF-1 (recombinant human IGF-1)/BP3 (binding peptide 3) improves lung growth and prevents PH in two antenatal models of BPD induced by intraamniotic exposure to endotoxin (ETX) or sFlt-1 (soluble fms-like tyrosine kinase 1), and in a postnatal model due to prolonged hyperoxia. Methods: ETX or sFlt-1 were administered into the amniotic sac of pregnant rats at Embryonic Day 20 to simulate antenatal models of chorioamnionitis and preeclampsia, respectively. Pups were delivered by cesarean section at Embryonic Day 22 and treated with rhIGF-1/BP3 (0.02–20 mg/kg/d intraperitoneal) or buffer for 2 weeks. Study endpoints included radial alveolar counts (RACs), vessel density, and right ventricular hypertrophy (RVH). Direct effects of rhIGF-1/BP3 (250 ng/ml) on fetal lung endothelial cell proliferation and tube formation and alveolar type 2 cell proliferation were studied by standard methods in vitro. Measurements and Main Results: Antenatal ETX and antenatal sFlt-1 reduced RAC and decreased RVH in infant rats. In both models, postnatal rhIGF-1/BP3 treatment restored RAC and RVH to normal values when compared with placebo injections. rhIGF-1/BP3 treatment also preserved lung structure and prevented RVH after postnatal hyperoxia. In vitro studies showed that rhIGF-1/BP3 treatment increased lung endothelial cell and alveolar type 2 cell proliferation. Conclusions: Postnatal rhIGF-1/BP3 treatment preserved lung structure and prevented RVH in antenatal and postnatal BPD models. rhIGF-1/BP3 treatment may provide a novel strategy for the prevention of BPD in preterm infants.

Hyperoxia exposure in premature infants increases the risk of subsequent lung diseases, such as asthma and bronchopulmonary dysplasia. Fibroblasts help maintain bronchial and alveolar integrity. Thus, understanding mechanisms by which hyperoxia influences fibroblasts is critical. Cellular senescence is increasingly recognized as important to the pathophysiology of multiple diseases. We hypothesized that clinically relevant moderate hyperoxia (

Background Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results. Methods We used preterm baboons, mice and humans (≤276/7 weeks gestation) to examine betamethasone’s effects on ductus gene expression and constriction both in vitro and in vivo. Results In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone’s effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally-regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone’s contractile effects were only apparent when prostaglandin signaling was inhibited, whereas, at 26-27 weeks gestation betamethasone’s contractile effects were apparent even in the absence of prostaglandin inhibitors. Conclusions We speculate that betamethasone’s contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone’s effects vary according to the infant’s developmental age at birth.

Progressive fibrosis is a complication of many chronic diseases, and collectively, organ fibrosis is the leading cause of death in the United States. Fibrosis is characterized by accumulation of activated fibroblasts and excessive deposition of extracellular matrix proteins, especially type I collagen. Extensive research has supported a role for matrix signaling in propagating fibrosis, but type I collagen itself is often considered an end product of fibrosis rather than an important regulator of continued collagen deposition. Type I collagen can activate several cell surface receptors, including α

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, lethal cause of neonatal respiratory failure and persistent pulmonary hypertension. We present a presumptive prenatal diagnosis of ACDMPV based on chorionic villus sampling of a FOXF1 mutation in a fetus with extra-pulmonary anomalies often associated with ACDMPV.

OBJECTIVE. The objective of this study was to assess the validity of parental report of influenza vaccinations. PATIENTS AND METHODS. A cross-sectional study of children who were 6 to 59 months of age and presented to a large, pediatric residency clinic from February through April 2005 was performed. A standardized, parental questionnaire ascertained the influenza vaccination status of children during the 2004–2005 influenza season and was compared with the medical chart, the criterion standard. Children were classified as being at high risk when they had a specific influenza vaccine recommendation in 2004–2005 by age (6–23 months of age) or by chronic medical condition. RESULTS. Of 218 parents approached in the pediatric residency clinic, 198 (95%) children who were 6 to 59 months of age were enrolled, and 84 (42%) were vaccinated according to the medical chart. More children who were 6 to 23 months than those who were 24 to 59 months of age were vaccinated (63% vs 21%). Children with chronic medical conditions were more likely to be vaccinated than healthy children who were 24 to 59 months of age (57% vs 11%), but no difference was observed for children who were 6 to 23 months of age (79% vs 60%). In comparison with the medical chart, parental report of influenza vaccination had a sensitivity of 88%, a specificity of 90%, and a κ coefficient of 0.78. For children who were 6 to 23 months of age or had a chronic medical condition (n = 123), parental report had a sensitivity of 89%, a specificity of 81%, and a κ coefficient of 0.71. CONCLUSIONS. Parental report of influenza vaccination among children who were 6 to 59 months of age had reasonable sensitivity, specificity, and reliability as compared with the medical chart in this study population.