Chronic Lung Disease Of Prematurity Research Articles

Risk factors for chronic lung disease and asthma differ among children born extremely preterm.

To evaluate the hypothesis that chronic lung disease of prematurity (CLD) is a risk factor for asthma in children born extremely preterm, and the hypothesis that the risk factors for CLD are similar to those for asthma. A retrospective analysis was performed using data collected prospectively from 882 children born before the 28th week of gestation between 2002 and 2004 who returned for follow-up at ages 12 and 24 months and 10 years. We created time-oriented logistic regression models to compare risk factors for CLD, defined as need for supplemental oxygen at 36 weeks postmenstrual age, and parent-reported asthma at 10 years of age. CLD diagnosed during neonatal admission was associated with bronchodilator use at 12 months and 24 months (P < 0.001), but not with an asthma diagnosis at 10 years (Odds Ratio 1.3; 95% confidence interval 0.98-1.8). While risk factors for CLD include lower gestational age (OR 2.7; 1.5-4.7) and fetal growth restriction (OR 2.3; 1.4-3.7), risk factors for asthma include mother's eligibility for public insurance (Medicaid) (OR 1.8; 1.1-2.8), and higher weight gain velocity during the first year (OR 1.5; 1.02-2.2) and between the 2nd and 10th year (OR 1.7; 1.2-2.4). Among children born extremely preterm, the diagnosis of CLD and its antecedents were associated with transient preschool wheezing, but not with asthma. Post-NICU factors, such as growth velocity and socioeconomic disadvantage, appear to have stronger associations with asthma than exposures during NICU admission.

Paths of causal influence from prenatal inflammation and preterm gestation to childhood asthma symptoms

Introduction: Long-lasting respiratory symptoms have a huge impact on the quality of life in prematurely born children. The aim was to investigate paths of assumed causality leading from foetal inflammatory response syndrome (FIRS) to asthma symptoms in preterms. Methods: Demographic, antenatal, delivery and outcome data were collected from 262 infants with less than 32 completed weeks of gestational age over a 10-year period in a prospective cohort study. The presence of symptoms of asthma beyond the age of 5 years was the primary outcome measure. The causal effect of FIRS on childhood asthma was tested with three different logistic regression models and two structural equation models (SEM). Results: FIRS (OR = 4.7) and subsequent chronic lung disease of prematurity (OR = 7.7) and early childhood wheezing (OR = 9.5) are the most important risk factors for development of asthma symptoms in children born with less than 32 weeks of gestational age. The path analysis showed that FIRS has a large direct (0.59), medium indirect (0.11) and large overall (0.70) effect on CLD; large negative direct effect on ECW (−0.34) and a large positive indirect effect (0.74), mediated by CLD. On the occurrence of asthma symptoms, FIRS has a medium negative direct effect (−0.18) and a medium positive indirect effect (0.26), mediated by CLD and ECW. Conclusion: Prenatal inflammation plays an important role in the development of chronic respiratory disturbances in preterm infants. This influence is mainly related to structural and developmental lung abnormalities initiated in utero as consequences of FIRS, resulting in CLD of prematurity, and overcoming the protective mechanisms of chorioamnionitis.

ARE CANADIAN NEONATOLOGISTS READY FOR A STEM CELL TRIAL FOR BRONCHOPULMONARY DYSPLASIA?

Abstract BACKGROUND Pre-clinical studies support the role of stem cells in preventing bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity. We are planning the first Canadian clinical trial of stem cell therapy for BPD. OBJECTIVES To ensure successful bench-to-bedside translation, the objective of our study was to identify the barriers and enablers that may influence neonatologists’ decision to identify extremely preterm infants at risk of BPD for participation in a stem cell trial for BPD. DESIGN/METHODS Semi-structured interviews were conducted with neonatologists across Canada. We used the Theoretical Domains Framework (TDF) to develop an interview topic guide covering 14 key domains that influence behavior (e.g. knowledge, intentions, goals, social influences). Two independent researchers used directed content analysis (using qualitative software NVIVO 11) to assign utterances to TDF thematic domains. We further identified sub-themes within domains to identify key barriers and enablers to neonatologists identifying infants for the planned trial. RESULTS Sixteen interviews were conducted with neonatologists across Canada (Western Canada n=7, Central Canada n=7, Eastern Canada n=2). Seven were practicing as a neonatologist for 10 years or less, 5 for 11–20 years and 4 for &gt;20 years. Preliminary analyses demonstrated that neonatologists are eager to help identify patients for this study due to the importance they place on trying to treat BPD. Many participants had worries concerning the lack of evidence on long-term outcomes of stem cell therapy. Access to clear protocols, well defined eligibility criteria, and research assistants were brought up as key facilitators for screening patients. The most commonly reported barrier included the need for human resources (e.g. research assistants), funding, and institutional support to help screen patients. CONCLUSION Our interviews identified facilitators and barriers from a neonatologist perspective to a potential stem cells trial for BPD. Our findings will inform the design of a phase I/II clinical trial.

Polysomnography for the management of oxygen supplementation therapy in infants with chronic lung disease of prematurity

Aim: Some infants with bronchopulmonary dysplasia (BPD) may require oxygen supplementation at home but a role for overnight polysomnography (PSG) in the management of home oxygen therapy has been rarely described.Methods: Forty-one infants with BPD born at less than 30 weeks gestational age were discharged with continuous home oxygen supplementation therapy between 2010 and 2013. PSG data were recorded on oxygen supplementation versus room air at median corrected age of 2 months (range 1–5 months) (first PSG after discharge to home). Those infants who continued oxygen supplementation therapy at home had at least one more PSG before oxygen therapy was discontinued (last PSG). We also collected PSG data in 10 healthy term infants (median age 3.5 months; range 2–4 months).Results: In infants with BPD in room air, increased numbers of central apneas, hypopneas, and SaO2 desaturations were the predominant PSG features with a median apnea–hypopnea index (AHI) of 16.8 events per hour (range 0–155). On oxygen supplementation therapy, median AHI dramatically improved (2.2, range 0–22; p < .001) and was not different from control infants (2.0, range 0–3.9; p = .31). AHI on room air at the last PSG when home oxygen was ceased was 4.1 per hour (range 0–13.8) slightly higher than in healthy infants.Conclusion: Central sleep disordered breathing in infants with BPD dramatically normalizes with low flow nasal cannula home oxygen therapy and improves with age. Mild central sleep disordered breathing remains detectable, although much improved, when compared with healthy infants at the time when the decision to cease home oxygen therapy was made by the physician.

Sex-Specific Skeletal Muscle Fatigability and Decreased Mitochondrial Oxidative Capacity in Adult Rats Exposed to Postnatal Hyperoxia.

Premature birth affects more than 10% of live births, and is characterized by relative hyperoxia exposure in an immature host. Long-term consequences of preterm birth include decreased aerobic capacity, decreased muscular strength and endurance, and increased prevalence of metabolic diseases such as type 2 diabetes mellitus. Postnatal hyperoxia exposure in rodents is a well-established model of chronic lung disease of prematurity, and also recapitulates the pulmonary vascular, cardiovascular, and renal phenotype of premature birth. The objective of this study was to evaluate whether postnatal hyperoxia exposure in rats could recapitulate the skeletal and metabolic phenotype of premature birth, and to characterize the subcellular metabolic changes associated with postnatal hyperoxia exposure, with a secondary aim to evaluate sex differences in this model. Compared to control rats, male rats exposed to 14 days of postnatal hyperoxia then aged to 1 year demonstrated higher skeletal muscle fatigability, lower muscle mitochondrial oxidative capacity, more mitochondrial damage, and higher glycolytic enzyme expression. These differences were not present in female rats with the same postnatal hyperoxia exposure. This study demonstrates detrimental mitochondrial and muscular outcomes in the adult male rat exposed to postnatal hyperoxia. Given that young adults born premature also demonstrate skeletal muscle dysfunction, future studies are merited to determine whether this dysfunction as well as reduced aerobic capacity is due to reduced mitochondrial oxidative capacity and metabolic dysfunction.

Arginase and α-smooth muscle actin induction after hyperoxic exposure in a mouse model of bronchopulmonary dysplasia.

The L-arginine/NO pathway is an important regulator of pulmonary hypertension, the leading cause of mortality in patients with the chronic lung disease of prematurity, bronchopulmonary dysplasia. L-arginine can be metabolized by NO synthase (NOS) to form L-citrulline and NO, a potent vasodilator. Alternatively, L-arginine can be metabolized by arginase to form urea and L-ornithine, a precursor to collagen and proline formation important in vascular remodelling. In the current study, we hypothesized that C3H/HeN mice exposed to prolonged hyperoxia would have increased arginase expression and pulmonary vascular wall cell proliferation. C3H/HeN mice were exposed to 14days of 85% O2 or room air and lung homogenates analyzed by western blot for protein levels of arginase I, arginase II, endothelial NOS (eNOS), ornithine decarboxylase (ODC), ornithine aminotransferase (OAT), and α-smooth muscle actin (α-SMA). Hyperoxia did not change arginase I or eNOS protein levels. However, arginase II protein levels were 15-fold greater after hyperoxia exposure than in lungs exposed to room air. Greater protein levels of ODC and OAT were found in lungs following hyperoxic exposure than in room air animals. α-SMA protein levels were found to be 7-fold greater in the hyperoxia exposed lungs than in room air lungs. In the hyperoxia exposed lungs there was evidence of greater pulmonary vascular wall cell proliferation by α-SMA immunohistochemistry than in room air lungs. Taken together, these data are consistent with a more proliferative vascular phenotype, and may explain the propensity of patients with bronchopulmonary dysplasia to develop pulmonary hypertension.

LONG-TERM RESPIRATORY OUTCOMES FOLLOWING PRETERM BIRTH

Preterm birth interrupts the normal development of the respiratory system. Taken together with the lung injury that can occur antenatally such as from chorioamnionitis or postnatally by interventions such as mechanical ventilation and oxygen therapy, survivors are at risk of developing long term deficits of their respiratory system. Decrements of lung spirometry have been regularly reported in those born preterm across all gestational ages. Those who develop chronic lung disease of prematurity (also called bronchopulmonary dysplasia) are the most affected, but lung function decrements are also seen in those born at later gestation of between 33 and 36 weeks, a population that generally does not require respiratory support in the neonatal period. Besides spirometry, many other techniques have been used to assess the status of the respiratory system including measurement of static lung volumes, airway resistance and compliance, bronchial hyperresponsiveness, diffusing capacity, exhaled nitric oxide and newer imaging techniques including hyperpolarised 3-helium magnetic resonance imaging. Discussed in this review are the findings from such methods to delineate the respiratory outcomes that occur after preterm birth.

Microbial diversity within the airway microbiome in chronic pediatric lung diseases

The study of the airway microbiome in children is an area of emerging research, especially in relation to the role microbial diversity may play in acute and chronic inflammation. Three such pediatric airway diseases include cystic fibrosis, asthma, and chronic lung disease of prematurity. In cystic fibrosis, the presence of Pseudomonas spp. is associated with decreased microbial diversity. Decreasing microbial diversity is also associated with poor lung function. In asthma, early viral infections appear to drive changes in bacterial diversity which may be associated with asthma risk. Premature infants with Ureaplasma spp. are at higher risk for chronic lung disease due to inflammation. Microbiome changes due to prematurity also appear to affect the inflammatory response to viral infections post-natally. Importantly, microbial diversity can be measured using metataxonomic (e.g., 16S rRNA sequencing) and metagenomic (e.g., shotgun sequencing) approaches. A metagenomics approach may be preferable as it can provide further granularity of the sample composition, identifying the bacterial species or strain, information on additional microbial components, including fungal and viral components, information about functional genomics of the microbiome, and information about antimicrobial resistance mutations. Future studies of pediatric airway diseases incorporating these techniques may provide evidence for new treatment approaches for these vulnerable patient populations.

Trends in Utilization of Outpatient Respiratory Syncytial Virus Prophylaxis with Palivizumab among Medicaid- and Commercially Insured Infants.

IntroductionPalivizumab is indicated for the prevention of respiratory syncytial virus (RSV) infection in high-risk children. Previous palivizumab utilization studies examined prior authorization claims but did not examine utilization within insured populations as a whole. This study describes outpatient palivizumab utilization trends and characterizes high-risk infants receiving palivizumab within Medicaid- and commercially insured populations.MethodsInfants born July 1, 2003 through June 30, 2013 were identified in the MarketScan® Multistate Medicaid and Commercial claims databases. Infants with ≥ 18 months of continuous medical insurance enrollment with pharmacy benefits after birth and evidence of chronic lung disease of prematurity (CLDP), congenital heart disease (CHD), or preterm birth without CLDP or CHD were studied. Palivizumab use and demographic and clinical characteristics were measured in infant subgroups. Outpatient palivizumab utilization rates were calculated for each seasonal year (July–June) and for each infant subgroup.ResultsIn total, 29,350 (2.1%) Medicaid-insured and 9589 (2.5%) commercially insured infants received palivizumab and had CLDP, CHD, or were born at < 37 weeks gestational age (wGA). Infants with CLDP (82%) and those < 29 wGA (78%) had the highest utilization. Decreases in utilization rates between the 2003–2004 and 2012–2013 seasons were seen among Medicaid-insured infants born at 29–36 wGA (all P < .0001), and commercially insured infants born at 31–32 wGA (P < .0001), 33–34 wGA (P = .055), 35–36 wGA (P < .0001), and with CHD (P = .003). Utilization by month was consistent across subgroups among Medicaid- and commercially insured infants, with most doses administered from November to March.ConclusionPalivizumab use is targeted to a small percentage of infants who are at highest risk of hospitalization for RSV disease. Utilization declined in recent years in both Medicaid- and commercially insured infant groups. Most palivizumab doses were administered from November to March, with most infants receiving ≤ 5 doses.FundingAstraZeneca.Electronic supplementary materialThe online version of this article (10.1007/s40121-017-0178-6) contains supplementary material, which is available to authorized users.

Serum surfactant protein D as a marker for bronchopulmonary dysplasia

Background: Lung epithelial cells express surfactant protein D (SP-D), a calcium-dependent lectin that plays an important role in antibody-independent pulmonary host defense. Previous studies have shown that it is found in the peripheral circulation in patients with pulmonary disease, likely because of translocation into the blood when lung epithelial barriers are disrupted by inflammation or acute injury. In adults, serum SP-D levels are biomarkers for the progression and severity of chronic lung disease. In neonates, elevated SP-D levels in cord blood and on day 1 have been associated with prenatal risk factors and with an increased risk of respiratory distress syndrome and infections. It is not known whether serum SP-D during the first week of life is a marker for bronchopulmonary dysplasia (BPD), a form of chronic lung disease of prematurity that is associated with lung parenchymal maldevelopment and injury.Objective: The goal of this study is to determine whether serum SP-D on days 3 and 7 of life are associated with the development of BPD in preterm infants.Design/methods: Serum samples were obtained on postnatal days 3 and 7 from 106 preterm infants (500–2000 g birth weight, 23–32-week gestation). SP-D was quantified by Western blot. BPD was determined at 36 weeks PMA using NICHD criteria.Results: The mean birth weight was 1145 ± 347 g and gestational age 29.2 ± 7.4 weeks. BPD was diagnosed in 7 and “BPD or death” in 16 infants. Days 3 and 7 values tracked significantly (r = 0.648), and did not correlate with birth weight or gestational age. Contrary to expectations, serum SP-D was not associated with BPD. Significant gender differences were noted, with SP-D dropping from day 3 to day 7 in males, while increasing in females (p < .05).Conclusion: Elevated serum SP-D does not appear to be a useful marker for BPD. Decreasing serum SP-D levels in males, as compared to females, during the first week of life are likely related to gender differences in lung maturation, consistent with the higher incidence of BPD in males.

The 2014-2015 National Impact of the 2014 American Academy of Pediatrics Guidance for Respiratory Syncytial Virus Immunoprophylaxis on Preterm Infants Born in the United States.

Objective This article aims to compare respiratory syncytial virus (RSV) immunoprophylaxis (IP) use and RSV hospitalization rates (RSVH) in preterm and full-term infants without chronic lung disease of prematurity or congenital heart disease before and after the recommendation against RSV IP use in preterm infants born at 29 to 34 weeks' gestational age (wGA). Study Design Infants in commercial and Medicaid claims databases were followed from birth through first year to assess RSV IP and RSVH, as a function of infant's age and wGA. RSV IP was based on pharmacy or outpatient medical claims for palivizumab. RSVH was based on inpatient medical claims with a diagnosis of RSV. Results Commercial and Medicaid infants 29 to 34 wGA represented 2.9 to 3.5% of all births. RSV IP use in infants 29 to 34 wGA decreased 62 to 95% ( p < 0.01) in the 2014–2015 season relative to the 2013–2014 season. Compared with the 2013–2014 season, RSVH increased by 2.7-fold ( p = 0.02) and 1.4-fold ( p = 0.03) for infants aged <3 months and 29 to 34 wGA in the 2014–2015 season with commercial and Medicaid insurance, respectively. In the 2014–2015 season, RSVH for infants 29 to 34 wGA were two to seven times higher than full-term infants without high-risk conditions. Conclusion Following the 2014 RSV IP guidance change, RSV IP use declined and RSVH increased among infants born at 29 to 34 wGA and aged <3 months.

Candidatus Mycoplasma girerdii replicates, diversifies, and co-occurs with Trichomonas vaginalis in the oral cavity of a premature infant

Genital mycoplasmas, which can be vertically transmitted, have been implicated in preterm birth, neonatal infections, and chronic lung disease of prematurity. Our prior work uncovered 16S rRNA genes belonging to a novel, as-yet-uncultivated mycoplasma (lineage ‘Mnola’) in the oral cavity of a premature neonate. Here, we characterize the organism’s associated community, growth status, metabolic potential, and population diversity. Sequencing of genomic DNA from the infant’s saliva yielded 1.44 Gbp of high-quality, non-human read data, from which we recovered three essentially complete (including ‘Mnola’) and three partial draft genomes (including Trichomonas vaginalis). The completed 629,409-bp ‘Mnola’ genome (Candidatus Mycoplasma girerdii str. UC-B3) was distinct at the strain level from its closest relative, vaginally-derived Ca. M. girerdii str. VCU-M1, which is also associated with T. vaginalis. Replication rate measurements indicated growth of str. UC-B3 within the infant. Genes encoding surface-associated proteins and restriction-modification systems were especially diverse within and between strains. In UC-B3, the population genetic underpinnings of phase variable expression were evident in vivo. Unique among mycoplasmas, Ca. M. girerdii encodes pyruvate-ferredoxin oxidoreductase and may be sensitive to metronidazole. This study reveals a metabolically unique mycoplasma colonizing a premature neonate, and establishes the value of genome-resolved metagenomics in tracking phase variation.

Bronchopulmonary Dysplasia: Where Have All the Stem Cells Gone?: Origin and (Potential) Function of Resident Lung Stem Cells

Celebrating its 50th anniversary in 2017, bronchopulmonary dysplasia (BPD)-the chronic lung disease of prematurity that follows ventilator and oxygen therapy for acute respiratory failure-remains the most frequent complication of extreme prematurity. Survival of premature infants born at increasingly earlier stages of gestation has made the prevention of lung injury increasingly challenging. BPD is postulated to be a misdirection of many functions in the developing lung, including growth factor signalling and matrix as well as cellular composition, resulting in impaired alveolar and lung vascular growth. Despite improvements in understanding the mechanisms that regulate normal lung development, BPD remains without therapies. Insights into stem cell biology have identified the repair potential of stem cells. Promising preclinical studies demonstrated the lung protective effects of stem cell-based therapies in animal models mimicking BPD, leading to early-phase clinical trials. Although the time is ripe to conduct well-designed early-phase clinical trials, much more needs to be learned about the biology of these cells to develop safe, efficient, high-quality, clinical-grade cell products. Stem cells are essential for normal organ development, maintenance, and repair. It is therefore biologically plausible that exhaustion/dysfunction of resident lung stem cells contributes to the inability of the immature lung to repair itself. Understanding how normal lung stem cells function and how these cells are perturbed in BPD may prove useful in designing superior cell products with enhanced repair capabilities to ensure the successful translation of basic research into clinical practice.

Effectiveness of Palivizumab in High-risk Infants and Children: A Propensity Score Weighted Regression Analysis.

Infants with premature birth ≤35 weeks gestational age, chronic lung disease of prematurity and congenital heart disease are at an increased risk for lower respiratory tract infections and hospitalization from respiratory syncytial virus (RSV), which has been shown in randomized trials to be prevented by palivizumab. However, palivizumab effectiveness (PE) has not been studied in a large clinical setting. A multicenter study among high-risk US and Canadian children younger than 24 months hospitalized with lower respiratory tract infection and whose nasopharyngeal aspirates were tested for human metapneumovirus (HMPV) and RSV were the subjects of the trial. We conducted a test-negative case-control study in these subjects to determine PE. We used an inverse propensity score weighted (IPSW) multiple logistic regression model to adjust PE. Palivizumab was used in 434 (51%) of 849 eligible children. RSV was identified in 403 (47%) children. The unadjusted PE was 43% [95% confidence interval (CI), 34%-51%)]. After IPSW adjustment, the adjusted PE was 58% (95% CI, 43%-69%). Palivizumab prevented intensive care unit admissions (PE, 62%; 95% CI, 35%-78%). PE for 29-35 weeks gestational age and ≤6 months of chronologic age without chronic lung disease of prematurity or congenital heart disease was 74% (95% CI, 56%-85%). Using a test-negative case-control design with RSV molecular detection, palivizumab is shown to prevent RSV hospitalizations and intensive care unit admissions in high-risk infants.

Chorioamnionitis: Is a major player in the development of bronchopulmonary dysplasia?

Chorioamnionitis is an inflammation in the fetal membranes or placenta. When chorioamnionitis develops, fetal lungs are exposed to inflammatory cytokines and mediators via amniotic fluid. Because inflammation plays a pivotal role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, fetal lung inflammation induced by chorioamnionitis has been considered to be one of the major pathogenetic factors for BPD. Although there have been a number of studies that demonstrated the relationship between chorioamnionitis and BPD, there are still controversies on this issue. The controversies on the relationship between chorioamnionitis and BPD arise from not-unified definitions of chorioamnionitis and BPD, different study populations, and the proportion of contribution between inflammation and infectious microorganisms. The publication bias also contributes to the controversies. Clinical trials targeting chorioamnionitis or microorganisms that cause chorioamnionitis will answer on the actual relationship between chorioamnionitis and BPD and provide a novel prophylactic strategy against BPD based on that relationship.

Hyperpolarized Gas Magnetic Resonance Lung Imaging in Children and Young Adults.

The assessment of early pulmonary disease and its severity can be difficult in young children, as procedures such as spirometry cannot be performed on them. Computed tomography provides detailed structural images of the pulmonary parenchyma, but its major drawback is that the patient is exposed to ionizing radiation. In this context, magnetic resonance imaging (MRI) is a promising technique for the evaluation of pediatric lung disease, especially when serial imaging is needed. Traditionally, MRI played a small role in evaluating the pulmonary parenchyma. Because of its low proton density, the lungs display low signal intensity on conventional proton-based MRI. Hyperpolarized (HP) gases are inhaled contrast agents with an excellent safety profile and provide high signal within the lung, allowing for high temporal and spatial resolution imaging of the lung airspaces. Besides morphologic information, HP MR images also offer valuable information about pulmonary physiology. HP gas MRI has already made new contributions to the understanding of pediatric lung diseases and may become a clinically useful tool. In this article, we discuss the HP gas MRI technique, special considerations that need to be made when imaging children, and the role of MRI in 2 of the most common chronic pediatric lung diseases, asthma and cystic fibrosis. We also will discuss how HP gas MRI may be used to evaluate normal lung growth and development and the alterations occurring in chronic lung disease of prematurity and in patients with a congenital diaphragmatic hernia.

Mesenchymal Stromal Cell-Based Therapies for Chronic Lung Disease of Prematurity.

Advances in perinatal care allow the survival of ever more premature infants. By approaching the biological limit of viability, survival free of injury becomes more challenging. As a consequence, bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, remains one of the main complications in infants born before 28 weeks' gestation. Currently, there is no treatment for BPD. Recent progress in understanding the biology of stem cells has opened unprecedented therapeutic options to mitigate lung injury and promote lung growth. Perinatal tissue, such as the umbilical cord and the placenta, represents a rich source of potent repair cells. Thus far, mesenchymal stromal cell (MSC)-based therapies demonstrate the most potential for protecting the developing lung from injury. Preclinical evidence supporting this potential therapeutic role has provided the basis for the initiation of phase I and II clinical trials in preterm neonates. This brief review summarizes the current knowledge accumulated over the past 10 years about MSCs and their repair potential in BPD.

Glucocorticoids and erythropoietin in chronic lung disease of prematurity: Proliferative potential in lung fibroblast and epithelial cells exposed to tracheal aspirates.

We investigated the effects of glucocorticoids, erythropoietin (EPO) and spironolactone (SPL) n human fetal lung fibroblasts and human alveolar epithelial cells exposed to tracheal aspirate fluid (TAF) from extremely premature infants with chronic lung disease (CLD), characterized by fibrosis and changes in the alveolar epithelium. Fibroblasts and epithelial cells (FHs 738Lu and A549, respectively) were treated with different concentrations of hydrocortisone (HDC), dexamethasone (DEX), betamethasone (BET), SPL, and EPO in the absence or presence of TAF from infants with CLD (gestational age, 25.3 ± 0.8 weeks; birthweight, 658 ± 77 g; postnatal age, 0-28 days) and assayed for proliferation. Exposure to TAF resulted in a concentration-dependent proliferation of fibroblasts and epithelial cells. Proliferation of TAF-exposed fibroblasts was suppressed most significantly by 100 μmol/L DEX (21%, P = 0.046) and 300 mIU/mL EPO (18%, P = 0.02) and promoted most significantly by 0.4 μmol/L HDC (10%, P = 0.04). Epithelial proliferation was promoted by 4 μmol/L HDC (15%, P = 0.04), 10 μmol/L DEX (53%, P < 0.01), 0.2 μmol/L BET (56%, P < 0.01), and 300 mIU/mL EPO (35%, P < 0.01) in the presence of TAF. Treatment with glucocorticoids alone did not significantly affect fibroblast proliferation. Glucocorticoids and EPO reduced fibroproliferation while promoting epithelial cell growth in vitro within certain dose ranges. Appropriate doses of glucocorticoids and EPO may be useful in the prevention and resolution of CLD in extremely premature infants.

Palivizumab Prophylaxis for Healthy Preterm Infants: More Data Supporting American Academy of Pediatrics Guidelines.

* Abbreviations: AAP — : American Academy of Pediatrics RSV — : respiratory syncytial virus As licensed by the US Food and Drug Administration, “palivizumab is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease”.1 The American Academy of Pediatrics (AAP) Committee on Infectious Diseases has endeavored to provide pediatricians and other health care providers with guidance for determining who is at high risk for RSV disease since palivizumab was first licensed in 1998.2 Over the years, evidence has accumulated regarding the risk of RSV hospitalization and the AAP guidance for palivizumab use has become more restrictive. The most recent recommendations,3 published in 2014, removed otherwise healthy preterm infants born at or after 29 weeks of gestation from the high-risk groups recommended to receive palivizumab prophylaxis. In this issue of Pediatrics , Farber et al4 provide data from nine Medicaid managed care health programs in Texas supporting the 2014 recommendation. The investigators evaluated the effect of palivizumab administration on hospitalization for bronchiolitis with or without an RSV diagnosis among healthy preterm infants born at 29 to 36 weeks of gestation during their first RSV season occurring in 2012, 2013, or 2014.4 These infants did not have conditions known to increase hospitalization rates for RSV, specifically, chronic lung disease of prematurity or congenital heart disease. Although the recommendations to limit use of palivizumab in healthy preterm infants were released in July 2014, the Texas Medicaid program did not fully adopt them until 2015. Interestingly, even though they would have qualified under previous guidelines, the majority of the infants in the Farber study4 evaluated from 2012 to 2014, did not have paid claims for palivizumab. Overall, … Address correspondence to Carrie L. Byington, MD, HA and Edna Benning Presidential Professor of Pediatrics, Associate Vice President for Faculty and Academic Affairs, University of Utah Health Sciences Center, 26 2000 East HSEB, Suite 5515, Salt Lake City, UT. E-mail: carrie.byington{at}hsc.utah.edu

The 78-kD Glucose-Regulated Protein Regulates Endoplasmic Reticulum Homeostasis and Distal Epithelial Cell Survival during Lung Development.

Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated conditional knockout (KO) mice (cGrp78(f/f)) with lung epithelial cell-specific KO of Grp78, a gene encoding the ER chaperone 78-kD glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis, and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78(f/f) pups died immediately after birth, likely owing to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of the proapoptotic transcription factor CCAAT/enhancer-binding proteins (C/EBP) homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-β/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress, and transforming growth factor-β/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone Tauroursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78(f/f) lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress, and suggest the UPR as a potential therapeutic target in BPD.