Neonatal Bronchopulmonary Dysplasia Research Articles

Airway microbiome in adult survivors of extremely preterm birth: the EPICure study.

Bronchopulmonary dysplasia (BPD) is a major complication of preterm birth that leads to lifelong respiratory morbidity. The EPICure study has investigated the longitudinal health outcomes of infants born extremely preterm (EP; <26 weeks gestation). Our aim was to characterise the airway microbiome in young adults born extremely preterm, with and without neonatal BPD, in comparison to matched term-born controls.Induced sputum was collected from 92 young adults aged 19 years (51 EP and 41 controls). Typical respiratory pathogens were detected using quantitative PCR. 16S rRNA gene sequencing was completed on 74 samples (29 EP with BPD; 9 EP without BPD; and 36 controls).The preterm group with BPD had the least diverse bacterial communities. The relative abundance of Bacteriodetes, particularly Prevotella melaninogenica was significantly lower in the preterm group compared to controls. This decline was balanced by a nonsignificant increase in Firmicutes. Total Prevotella relative abundance correlated with forced expiratory volume in 1 s z-score (ρ=0.272; p<0.05). Typical respiratory pathogen loads and prevalence were similar between groups.In conclusion, extremely preterm birth is associated with a significant dysbiosis in airway microbiome in young adulthood regardless of neonatal BPD status. This is characterised by a shift in the community composition away from Bacteriodetes as manifested in a significant drop in Prevotella relative abundance.

PRS6 - THE CLINICAL EFFECTIVENESS OF PROPHYLACTIC VERSUS SELECTIVE USE OF SURFACTANT IN PRETERM INFANTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Surfactant therapy is widely used to prevent or treat respiratory distress syndrome (RDS) in preterm infants. As advance with perinatal care such as antenatal steroid use and early application of nasal continuous positive airway pressure (nCPAP), there is a concern that surfactant is administrated even in infants who will not go on to develop RDS. To compare the clinical effectiveness of prophylactic and selective use of surfactant in preterm infants by a systematic review and meta-analysis. A systematic review was conducted to examine the clinical effects of selective and prophylactic surfactant use on preterm infants. The search was made in international databases (Medline, EMBASE, Cochrane library) and Korean databases up to June 2017. Primary outcomes were mortality and bronchopulmonary dysplasia (BPD). Following morbidities before discharge were analyzed; air leak disease, pulmonary hemorrhage, patent ductus arteriosus, sepsis, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, pulmonary hypertension, pneumonia. A total of 16 articles were selected. There were 12 randomized controlled trials (6,544 patients) and 4 non-randomized controlled studies (884 patients). Selective use of surfactant increased the neonatal mortality (RR 1.33, 95% CI: 1.10-1.60, P=0.008) and the combined outcome of neonatal mortality and BPD (RR 1.16, 95% CI: 1.03-1.30, P=0.01). However, there were no significant differences between prophylactic and selective use of surfactant about these outcomes by each subgroup analysis of more than 30 weeks gestation, more than 50% of antenatal steroid use, and nCPAP application. There were no significant differences of other morbidities between prophylactic and selective use of surfactant. In preterm infants at risk of RDS, prophylactic use of surfactant prevents the neonatal mortality and BPD. However, selective use of surfactant may be considered in case of more than 30 weeks gestation, antenatal steroid use and the early application of nCPAP.

Bronchopulmonary dysplasia in neonates born to mothers with preeclampsia: Impact of small for gestational age.

Background and objectivesSmall for gestational age and preeclampsia have both been described as risk factors for bronchopulmonary dysplasia in preterm neonates, but their respective role in the occurrence of bronchopulmonary dysplasia is debated. We evaluated the relation between small for gestational age and bronchopulmonary dysplasia in neonates born to mothers with preeclampsia. We hypothesized that low birth weight is still associated with bronchopulmonary dysplasia in this homogeneous population.MethodsRetrospective single-center cohort study including 141 neonates born between 24 and 30 weeks’ gestation to mothers with preeclampsia. The main outcome measure was moderate to severe bronchopulmonary dysplasia at 36 weeks’ postmenstrual age. Neonates born small for gestational age (birthweight < 10th percentile on the AUDIPOG curves) were compared to those with appropriate birthweight for gestational age by bivariable analyses and logistic regression models, estimating odds ratios (ORs) and 95% confidence intervals (CIs).ResultsBronchopulmonary dysplasia rates were 61.5% (32/52) and 27.4% (20/73) for small for gestational age and appropriate birthweight for gestational age neonates (p < .001). On adjustment for gestational age and other confounding factors, the risk of moderate to severe bronchopulmonary dysplasia was greater for small for gestational age than appropriate birthweight for gestational age neonates (adjusted OR = 5.9, 95% CI [2.2–15.4]), as was the composite outcome death or moderate to severe bronchopulmonary dysplasia (adjusted OR = 4.7, 95% CI [1.9–11.3]).ConclusionsSmall for gestational age was associated with bronchopulmonary dysplasia in very preterm neonates born to mothers with preeclampsia.Registration numberCNIL no. 1747084.

Vitamin D and IL-10 Deficiency in Preterm Neonates With Bronchopulmonary Dysplasia.

Introduction: Vitamin D deficiency and inflammation are involved with bronchopulmonary dysplasia (BPD) in preterm neonates; however, the clinical evidence still remains scarce. We hypothesized that vitamin D and inflammatory cytokines may be risk factors for BPD in infants.Methods: Preterm infants born between 28 and 31 weeks' gestation were recruited between January 2016 and 2017. Blood samples were all collected at corresponding time points. Vitamin D was measured using an automatic biochemical analyzer, and inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10) were measured using ELISA.Results: The baseline characteristics for preterm infants without BPD (non-BPD control, n = 20) or with BPD (n = 19) were similar. In the blood samples collected 24-h post birth, vitamin D was significantly reduced in the BPD neonates (non-BPD vs. BPD, 28.96 ± 3.404 vs. 17.99 ± 2.233 nmol/l, p = 0.0134). Inflammatory cytokines TNF-α, IL-1β, and IL-6 were comparable in both groups. The anti-inflammatory cytokine IL-10, however, was significantly decreased in 24-h blood samples from BPD preterm infants (non-BPD vs. BPD, 44.61 ± 10.48 vs. 11.64 ± 2.351 pg/ml, p = 0.0054). In the BPD infants with mild or moderate disease, vitamin D deficiency was quite similar. IL-10 deficiency, however, was more aggravated in the BPD infants with moderate disease. No changes in Vitamin D or cytokines (TNF-α, IL-1β, IL-6, and IL-10) were observed for blood samples collected 2 or 4 weeks after birth.Conclusion: In our pilot study, Vitamin D and IL-10 levels at 24-h of life were risk factors for the development of BPD in very preterm infants.

Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth.

Bronchopulmonary dysplasia (BPD) remains the most common and serious chronic lung disease of premature infants. Severe BPD complicated with pulmonary hypertension (PH) increases the mortality of these infants. Riociguat is an allosteric soluble guanylate cyclase stimulator and is approved by the FDA for treating PH in adults. However, it has not been approved for use in neonates due to concern for adverse effects on long bone growth. To address this concern we investigated if administration of riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without side effects on long bone growth in newborn rats. Newborn rats were randomized to normoxia (21% O2) or hyperoxia (85% O2) exposure groups within 24 hours of birth, and received riociguat or placebo by once daily intraperitoneal injections during continuous normoxia or hyperoxia exposure for 9 days. In the hyperoxia control group, radial alveolar count, mean linear intercept and vascular density were significantly decreased, the pathological hallmarks of BPD, and these were accompanied by an increased inflammatory response. There was also significantly elevated vascular muscularization of peripheral pulmonary vessels, right ventricular systolic pressure and right ventricular hypertrophy indicating PH. However, administration of riociguat significantly decreased lung inflammation, improved alveolar and vascular development, and decreased PH during hyperoxia by inducing cGMP production. Additionally, riociguat did not affect long bone growth or structure. These data indicate that riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without affecting long bone growth and structure and hence, suggests riociguat may be a potential novel agent for preventing BPD and PH in neonates.

Efficacy of atomized budesonide treating neonatal bronchopulmonary dysplasia after discharge from hospital

Objective To investigate the effects of atomized budesonide on neonatal bronchopulmonary dysplasia after discharge from hospital to 6 months of gestational age correction. Methods Analyse clinical data of fifty children with BPD, observe the effects of atomized budesonide (0.5mg inhaled q12h, at least 4weeks, course(15.4±6.16)weeks.When wheezing or dyspnea occurred: 1mg of budesonide and 1.25ml of albuterol and ipratropium bromide inhaled q12h, 2~4weeks.When respiratory frequency, heart rate and blood oxygen saturation reached normal, three concave improved obviously, lung rale disappeared, gradually reduce to no treatment)improving the clinical symptoms of children with BPD in 6 months after discharge, and observe the effects of atomized budesonide on reducing respiratory tract infection(including upper respiratory tract infection, pneumonia, wheezing and hospitalization). Results Through budesonide aerosol therapy, respiratory frequency and heart rate of children with BPD could be reduced, blood oxygen saturation could be elevated , and three concave could be improved at corrected gestational age of 3 months and 6 months.(P 0.05). Conclusion The treatment of budesonide atomization can improve the clinical symptoms of children with BPD after discharge from hospital to 6 months of gestational age correction, improve oxygen and shorten the time of oxygen inhalation after hospital, cannot reduce the incidence of respiratory infection. Key words: Preterm infant; Bronchopulmonary dysplasia; Budesonide; Efficacy

Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6

BackgroundMesenchymal stem cells (MSCs) are promising tools for the treatment of human lung disease and other pathologies relevant to newborn medicine. Recent studies have established MSC exosomes (EXO), as one of the main therapeutic vectors of MSCs in mouse models of multifactorial chronic lung disease of preterm infants, bronchopulmonary dysplasia (BPD). However, the mechanisms underlying MSC-EXO therapeutic action are not completely understood. Using a neonatal mouse model of human BPD, we evaluated the therapeutic efficiency of early gestational age (GA) human umbilical cord (hUC)-derived MSC EXO fraction and its exosomal factor, tumor necrosis factor alpha-stimulated gene-6 (TSG-6).MethodsConditioned media (CM) and EXO fractions were isolated from 25 and 30 weeks GA hUC-MSC cultures grown in serum-free media (SFM) for 24 h. Newborn mice were exposed to hyperoxia (> 95% oxygen) and were given intraperitoneal injections of MSC-CM or MSC-CM EXO fractions at postnatal (PN) day 2 and PN4. They were then returned to room air until PN14 (in a mouse model of severe BPD). The treatment regime was followed with (rh)TSG-6, TSG-6-neutralizing antibody (NAb), TSG-6 (si)RNA-transfected MSC-CM EXO and their appropriate controls. Echocardiography was done at PN14 followed by harvesting of lung, heart and brain for assessment of pathology parameters.ResultsSystemic administration of CM or EXO in the neonatal BPD mouse model resulted in robust improvement in lung, cardiac and brain pathology. Hyperoxia-exposed BPD mice exhibited pulmonary inflammation accompanied by alveolar-capillary leakage, increased chord length, and alveolar simplification, which was ameliorated by MSC CM/EXO treatment. Pulmonary hypertension and right ventricular hypertrophy was also corrected. Cell death in brain was decreased and the hypomyelination reversed. Importantly, we detected TSG-6, an immunomodulatory glycoprotein, in EXO. Administration of TSG-6 attenuated BPD and its associated pathologies, in lung, heart and brain. Knockdown of TSG-6 by NAb or by siRNA in EXO abrogated the therapeutic effects of EXO, suggesting TSG-6 as an important therapeutic molecule.ConclusionsPreterm hUC-derived MSC-CM EXO alleviates hyperoxia-induced BPD and its associated pathologies, in part, via exosomal factor TSG-6. The work indicates early systemic intervention with TSG-6 as a robust option for cell-free therapy, particularly for treating BPD.

Bronchopulmonary dysplasia: effect of altitude correction and role for the Neonatal Research Network Prediction Algorithm.

To determine the effect of altitude correction on bronchopulmonary dysplasia (BPD) rates and to assess validity of the NICHD "Neonatal BPD Outcome Estimator" for predicting BPD with and without altitude correction. Retrospective analysis included neonates born <30 weeks gestational age (GA) between 2010 and 2016. "Effective" FiO2 requirements were determined at 36 weeks corrected GA. Altitude correction performed via ratio of barometric pressure (BP) in our unit to sea level BP. Probability of death and/or moderate-to-severe BPD was calculated using the NICHD BPD Outcome Estimator. Five hundred and sixty-one infants were included. Rate of moderate-to-severe BPD decreased from 71 to 40% following altitude correction. Receiver-operating characteristic curves indicated high predictability of BPD Outcome Estimator for altitude-corrected moderate-to-severe BPD diagnosis. Correction for altitude reduced moderate-to-severe BPD rate by almost 50%, to a rate consistent with recent published values. NICHD BPD Outcome Estimator is a valid tool for predicting the risk of moderate-to-severe BPD following altitude correction.

Respiratory morbidity through the first decade of life in a national cohort of children born extremely preterm

BackgroundAdvances in perinatal care have markedly increased the prospects of survival for infants born extremely preterm (EP). The aim of this study was to investigate hospitalisation rates and respiratory morbidity from five to 11 years of age in a prospective national cohort of EP children born in the surfactant era.MethodsThis was a national prospective cohort study of all children born in Norway during 1999 and 2000 with gestational age (GA) < 28 weeks or birth weight < 1000 grams, and of individually matched term-born controls recruited for a regional subsample. Data on hospital admissions, respiratory symptoms, and use of asthma medication was obtained by parental questionnaires at 11 years of age.ResultsQuestionnaires were returned for 232/372 (62%) EP-born and 57/61 (93%) regional term-born controls. Throughout the study period, 67 (29%) EP-born and seven (13%) term-born controls were admitted to hospital (odds ratio (OR) 2.90, 95% confidence interval (CI): 1.25, 6.72). Admissions were mainly due to surgical procedures, with only 12% due to respiratory causes, and were not influenced by neonatal bronchopulmonary dysplasia (BPD) or low GA(≤ 25 weeks). Respiratory symptoms, asthma and use of asthma medication tended to be more common for EP-born, significantly so for medication use and wheeze on exercise. Neonatal BPD was a risk factor for medication use, but not for current wheeze. In multivariate regression models, home oxygen after discharge (OR 4.84, 95% CI: 1.38, 17.06) and parental asthma (OR 4.38, 95% CI: 1.69, 11.38) predicted current asthma, but neither BPD nor low GA were associated with respiratory symptoms at 11 years of age.ConclusionsHospitalisation rates five to 11 years after EP birth were low, but twice those of term-born controls, and unrelated to neonatal BPD and low GA. Respiratory causes were rare. Respiratory complaints were more common in children born EP, but the burden of symptoms had declined since early childhood.

Characterising the Maturation of T Cell Polarisation in Preterm and Term Infants and in the Neonatal Chronic Lung Disease Bronchopulmonary Dysplasia

Characterising the Maturation of T Cell Polarisation in Preterm and Term Infants and in the Neonatal Chronic Lung Disease Bronchopulmonary Dysplasia

Brainstem auditory abnormality in extremely premature babies and the impact of neonatal bronchopulmonary dysplasia.

Extremely premature babies, particularly those who have neonatal bronchopulmonary dysplasia, are at risk of brain damage and neurodevelopmental impairment. This study aimed to examine functional status of the brainstem auditory pathway in extremely premature babies and assess the impact of bronchopulmonary dysplasia on function. Brainstem auditory evoked response was studied at term in babies born at ≤27 weeks of gestation with or without neonatal bronchopulmonary dysplasia. The normal controls were term babies without perinatal problems. Compared with the normal controls, the extremely premature babies showed an elevated response threshold, increased latencies of waves I, III and particularly V. They also showed significantly increased I-V and III-V intervals. The amplitudes of waves I and V were moderately reduced. These abnormalities were clearly more significant in those with bronchopulmonary dysplasia than those without bronchopulmonary dysplasia. A direct comparison between the two groups of extremely premature babies revealed that wave V latency, and I-V and particularly III-V intervals were significantly longer in the babies with bronchopulmonary dysplasia than those without bronchopulmonary dysplasia. Extremely premature babies have functional impairment of the brainstem auditory pathway. The impairment is clearly more significant in those with bronchopulmonary dysplasia than those without bronchopulmonary dysplasia. Neonatal bronchopulmonary dysplasia and associated unfavorable conditions are major contributors to brainstem auditory impairment in extremely premature babies.

Ventilator flow data predict bronchopulmonary dysplasia in extremely premature neonates.

Early prediction of bronchopulmonary dysplasia (BPD) may facilitate tailored management for neonates at risk. We investigated whether easily accessible flow data from a mechanical ventilator can predict BPD in neonates born extremely premature (EP).In a prospective population-based study of EP-born neonates, flow data were obtained from the ventilator during the first 48 h of life. Data were logged for >10 min and then converted to flow–volume loops using custom-made software. Tidal breathing parameters were calculated and averaged from ≥200 breath cycles, and data were compared between those who later developed moderate/severe and no/mild BPD.Of 33 neonates, 18 developed moderate/severe and 15 no/mild BPD. The groups did not differ in gestational age, surfactant treatment or ventilator settings. The infants who developed moderate/severe BPD had evidence of less airflow obstruction, significantly so for tidal expiratory flow at 50% of tidal expiratory volume (TEF50) expressed as a ratio of peak tidal expiratory flow (PTEF) (p=0.007). A compound model estimated by multiple logistic regression incorporating TEF50/PTEF, birthweight z-score and sex predicted moderate/severe BPD with good accuracy (area under the curve 0.893, 95% CI 0.735–0.973).This study suggests that flow data obtained from ventilators during the first hours of life may predict later BPD in premature neonates. Future and larger studies are needed to validate these findings and to determine their clinical usefulness.

The Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Lung Architecture Remodeling.

Chronic lung disorders, such as pulmonary artery hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma and neonatal bronchopulmonary dysplasia (BPD), are characterized by airway and/or vascular remodeling. Despite differences in the pathology, reactive oxygen species (ROS) have been highlighted as a critical contributor to the initiation and development of airway and vascular remodeling. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) appear to play a pivotal role in lung signaling, leading to marked changes in pulmonary airway and vascular cell phenotypes, including proliferation, hypertrophy and apoptosis. In this review, we summarized the current literature regarding the role of Nox in the airway and vascular remodeling.

Morphométrie du tissu pulmonaire : de la méthode manuelle à l’automatisation à haut débit

Weibel's research has shown that any alteration of the pulmonary structure has effects on function. This demonstration required a quantitative analysis of lung structures called morphometry. This is possible thanks to stereology, a set of methods based on principles of geometry and statistics. His work has helped to better understand the morphological harmony of the lung, which is essential for its proper functioning. An imbalance leads to pathophysiology such as chronic obstructive pulmonary disease in adults and bronchopulmonary dysplasia in neonates. It is by studying this imbalance that new therapeutic approaches can be developed. These advances are achievable only through morphometric analytical methods, which are increasingly precise and focused, in particular thanks to the high-throughput automation of these methods. This review makes a comparison between an automated method that we developed in the laboratory and semi-manual methods of morphometric analyzes. The automation of morphometric measurements is a fundamental asset in the study of pulmonary pathophysiology because it is an assurance of robustness, reproducibility and speed. This tool will thus contribute significantly to the acceleration of the race for the development of new drugs.

Abstract P138: Alterations in Cardiac Structure and Function in Young Adults Born Extremely Preterm: Impact of Neonatal Bronchopulmonary Dysplasia

Objective: Studies support a causal association between preterm birth and increased risk of cardiovascular diseases. Increased left and right ventricular mass and impaired systolic and diastolic function has been reported in young adults born preterm. However, the impact of extreme preterm birth and prematurity-specific complications on adult cardiac structure and function has not been evaluated. We assessed cardiac structure and function in young adults born extremely preterm (EPT) versus term, and correlated long term cardiac remodeling with neonatal bronchopulmonary dysplasia (BPD). Methods: Eighty five EPT (gest. age = 27.1±1.4 weeks) were recruited along with term-born controls matched for age, sex and socioeconomic status. Birth and neonatal data (gestational age, birth weight, BPD indicated by O 2 requirements at 36 weeks postmenstrual age) was collected. Ambulatory blood pressure (Spacelabs) and echocardiographic measurements (Phillips) were taken. Comparisons were performed using ANOVA or T-test. Results: EPT presented with increased systolic (119±9 vs 116±8 mmHg, P&lt;0.05) and diastolic (68±5 vs 66±6 mmHg, P&lt;0.05) blood pressures. EPT exhibited reduced septal thickness (IVS, 6.8±0.8 vs 7.1±1.1 mm, P&lt;0.05), left ventricular internal dimension (LVID, 46±4 vs 48±5 mm, P&lt;0.05), LV end-diastolic (98±20 vs 106±24 ml, P&lt;0.05) and end-systolic (36±9 vs 40±11 ml, P&lt;0.01) volumes, right ventricular internal dimension (RVID, 22±3 vs 24±4 mm, P&lt;0.05), and LV mass (104±27 vs 115±30 g, P&lt;0.05), but similar LV mass and volume indexes. EPT exhibited increased LV myocardial performance index (0.41±0.04 vs 0.39±0.04, P&lt;0.01), reduced mitral lateral e’ (17.6±2.8 vs 19.1±2.6 cm/s, P&lt;0.01), mitral s’ (10.7±2.3 vs 11.6±2.3 cm/s, P&lt;0.01), tricuspid E’ (15.8±2.7 vs 16.8±2.1 cm/s, P&lt;0.05), and tricuspid S’ (13.1±2.0 vs 14.0±2.0 cm/s, P&lt;0.01) waves, and a trend in reduced mitral E wave (81±14 vs 85±15 cm/s, P=0.09). EPT with neonatal BPD exhibited greater reduction in IVS (6.5±0.8 mm, P&lt;0.05 vs terms), LVID (45±4 mm, P&lt;0.05), LV Mass (98±22 g, P&lt;0.05), and RVID (20±3 mm, P&lt;0.01). Conclusions: EPT exhibit cardiac structural and functional alterations compared to term-born individuals. Neonatal BPD in EPT is a key contributor to long term cardiac remodeling.

Expression profiling of genes regulated by sphingosine kinase1 signaling in a murine model of hyperoxia induced neonatal bronchopulmonary dysplasia

BackgroundSphingosine- 1-Phosphate (S1P) is a bioactive lipid and an intracellular as well as an extracellular signaling molecule. S1P ligand specifically binds to five related cell surface G-protein-coupled receptors (S1P1-5). S1P levels are tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and catabolism by S1P phosphatases, lipid phosphate phosphatases and S1P lyase. We previously reported that knock down of SphK1 (Sphk1−/−) in a neonatal mouse BPD model conferred significant protection against hyperoxia induced lung injury. To better understand the underlying molecular mechanisms, genome-wide gene expression profiling was performed on mouse lung tissue using Affymetrix MoGene 2.0 array.ResultsTwo-way ANOVA analysis was performed and differentially expressed genes under hyperoxia were identified using Sphk1−/− mice and their wild type (WT) equivalents. Pathway (PW) enrichment analyses identified several signaling pathways that are likely to play a key role in hyperoxia induced lung injury in the neonates. These included signaling pathways that were anticipated such as those involved in lipid signaling, cell cycle regulation, DNA damage/apoptosis, inflammation/immune response, and cell adhesion/extracellular matrix (ECM) remodeling. We noted hyperoxia induced downregulation of the expression of genes related to mitotic spindle formation in the WT which was not observed in Sphk1−/− neonates. Our data clearly suggests a role for SphK1 in neonatal hyperoxic lung injury through elevated inflammation and apoptosis in lung tissue. Further, validation by RT-PCR on 24 differentially expressed genes showed 83% concordance both in terms of fold change and vectorial changes. Our findings are in agreement with previously reported human BPD microarray data and completely support our published in vivo findings. In addition, the data also revealed a significant role for additional unanticipitated signaling pathways involving Wnt and GADD45.ConclusionUsing SphK1 knockout mice and differential gene expression analysis, we have shown here that S1P/SphK1 signaling plays a key role in promoting hyperoxia induced DNA damage, inflammation, apoptosis and ECM remodeling in neonatal lungs. It also appears to suppress pro-survival cellular responses involved in normal lung development. We therefore propose SphK1 as a therapeutic target for the development drugs to combat BPD.

Lipoxin A4 Attenuates Bronchopulmonary Dysplasia via Upregulation of Let-7c and Downregulation of TGF-β1 Signaling Pathway.

Transforming growth factor-β (TGF-β) superfamily members are key regulators for lung development and progress of bronchopulmonary dysplasia (BPD). The mechanisms by which lipoxin A4 (LXA4) attenuates development of BPD have not been clarified. Neonatal murine BPD models were inducted by hyperoxia treatment. Neonatal mice were exposed to room air or 85% O2 hyperoxia with or without treatment with 5S,6R-methyl-LXA4 or anti-TGF-β antibodies. Mouse lung epithelial cells (MLE-12 cells) and mouse embryonic fibroblasts (NIH/3T3 cells) were cultured in room air or 85% O2 followed by treatment of LXA4, anti-TGF-β antibodies, and let-7c mimic/anti-microRNA transfections. Treatment with 5S,6R-methyl-LXA4 and anti-TGF-β antibodies both attenuated the mice alveolar simplification induced by hyperoxia. Hyperoxia treatment significantly altered pulmonary basal mRNA and protein expressions of several important extracellular matrix (ECM) and ECM remodeling proteins including fibronectin, α-smooth muscle actin (α-SMA), tissue inhibitor of metalloproteinase-1 (TIMP-1), elastin, tenascin C, collagen I, and matrix metalloproteinase-1 (MMP-1). 5S,6R-methyl-LXA4 and anti-TGF-β antibodies suppressed the mRNA and protein expressions of TGF-β1 and TGF-βR1 but not TGF-βR2 in the lungs exposed to hyperoxia. Treatment with LXA4 and anti-TGF-β antibodies alleviated hyperoxia-induced injury of the NIH/3T3 cells identified by morphologic observation and flow cytometry, and expressions of ECM, ECM remodeling proteins, and TGF-β1 signaling pathway, but reversed by transfection with let-7c anti-miRNA. LXA4 upregulated the let-7c expression in MLE-12 cells, transfection with let-7c anti-miRNA, inhibited the LXA4-induced let-7c expression in MLE-12 cells exposed to hyperoxia and reduced the relative luciferase activity of let-7c binding with let-7c binding sites of the TGF-βR1 3' UTR. Treatment with 5S,6R-methyl-LXA4 and anti-TGF-β antibodies significantly improved histology, ECM, and ECM remodeling proteins in the lungs isolated from the murine BPD model induced by hyperoxia. The LXA4-imparted protective effects on hyperoxia-induced lung injury are mediated by upregulation of let-7c and inhibition of TGF-β1 and subsequent downregulation of TGF-β1 signaling pathway.

Assessment of corticosteroids in prevention and treatment of neonatal bronchopulmonary dysplasia

There is a great controversy over the application of corticosteroids in preventing and treating bronchopulmonary dysplasia(BPD). Prenatal use of corticosteroids may reduce the occurrence of BPD.Intravenous corticosteroids within 1 week after birth can reduce the incidence of BPD.However, in light of the short and long-term adverse reactions, it is not recommended.For premature infants with BPD in high risk, clinicians should weigh the pros and cons and may apply a small dose, short course of corticosteroids for intervention in 1 week after birth.Early inhalation or instilling of corticosteroids may be an effective and safe way to reduce the occurrence of BPD. Key words: Bronchopulmonary dysplasia; Corticosteroids; Infant, premature

Bone Morphogenetic Protein 9 Protects against Neonatal Hyperoxia-Induced Impairment of Alveolarization and Pulmonary Inflammation.

Aim: Effective treatment of premature infants with bronchopulmonary dysplasia (BPD) is lacking. We hypothesize that bone morphogenetic protein 9 (BMP9), a ligand of the TGF-β family that binds to the activin receptor-like kinase 1 (ALK1)-BMP receptor type 2 (BMPR2) receptor complex, may be a novel therapeutic option for BPD. Therefore, we investigated the cardiopulmonary effects of BMP9 in neonatal Wistar rats with hyperoxia-induced BPD.Methods: Directly after birth Wistar rat pups were exposed to 100% oxygen for 10 days. From day 2 rat pups received BMP9 (2.5 μg/kg, twice a day) or 0.9% NaCl by subcutaneous injection. Beneficial effects of BMP9 on aberrant alveolar development, lung inflammation and fibrosis, and right ventricular hypertrophy (RVH) were investigated by morphometric analysis and cytokine production. In addition, differential mRNA expression of BMP9 and its receptor complex: ALK1, BMPR2, and Endoglin, and of the ALK1 downstream target transmembrane protein 100 (TMEM100) were studied during the development of experimental BPD. Expression of the BMP9 receptor complex and TMEM100 was studied in human endothelial and epithelial cell cultures and the effect of BMP9 on inflammatory cytokine production and TMEM100 expression was studied in endothelial cell cultures.Results: ALK1, ALK2, BMPRII, TMEM100, and Endoglin were differentially expressed in experimental BPD, suggesting a role for BMP9-dependent signaling in the development of (experimental) BPD. TMEM100 was expressed in the wall of blood vessels, showing an elastin-like expression pattern in arterioles. Expression of TMEM100 mRNA and protein was decreased after exposure to hyperoxia. BMP9 treatment of rat pups with hyperoxia-induced experimental BPD reduced alveolar enlargement, lung septal thickness and fibrosis, and prevented inflammation, but did not attenuate vascular remodeling and RVH. The anti-inflammatory effect of BMP9 was confirmed in vitro. Highest expression of ALK1, BMPR2, and TMEM100 was observed in human endothelial cell cultures. Stimulation of human endothelial cell cultures with BMP9 reduced their pro-inflammatory cytokine response and induced TMEM100 expression in pulmonary arterial endothelial cells.Conclusion: BMP9 protects against neonatal hyperoxia-induced BPD by improving aberrant alveolar development, inflammation and fibrosis, demonstrating its therapeutic potential for premature infants with severe BPD.

Reevaluating Postnatal Steroids for Extremely Preterm Infants to Prevent Lung Disease

Compared with the universal acceptance of antenatal steroids as an inexpensive, safe, and highly effective way of enhancing neonatal survival and reducing morbidity in preterm infants, the use of steroids after birth has been more controversial,1 and there remains uncertainty about which steroid to use, indications, safety, and dosage. Neonatal bronchopulmonary dysplasia or chronic lung disease is the most common neonatal complication following extremely preterm birth (gestational age of <28 weeks) or in extremely low-birth-weight infants (<1000 g), and approximately half of these infants will require supplemental oxygen at 36 weeks of postmenstrual age. Chronic respiratory morbidity remains with the child throughout life. Children with more severe neonatal lung disease have poorer respiratory function in early adolescence2 and are likely also to have respiratory morbidity in adult life.