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Moderate-to-large patent ductus arteriosus (PDA) has been linked to increased risk of bronchopulmonary dysplasia (BPD), while lung ultrasound score (LUS) has been demonstrated to accurately predict BPD. We aimed to investigate the correlation of LUS as a marker of interstitial pulmonary edema and the severity of the ductal shunt in predicting future BPD development in very preterm infants. This secondary analysis of a prospective study recruited preterm infants with gestational age < 30 weeks. LUS on postnatal days 7 and 14, and echocardiographic data [PDA diameter and left atrium-to-aortic root ratio (LA/Ao)] near LUS acquisition were collected. Correlation coefficient, logistics regression analysis, and the area under the receiver operating characteristic (AUROC) procedure were used. A statistically significant and positive correlation existed between LUS and PDA diameter (ρ = 0.415, ρ = 0.581, and p < 0.001) and LA/Ao (ρ = 0.502, ρ = 0.743, and p < 0.001) at postnatal days 7 and 14, respectively, and the correlations of LUS and echocardiographic data were generally stronger in the non-BPD group. In the prediction of BPD, LUS incorporating echocardiographic data at postnatal days 7 obtained significantly higher predictive performance compared to LUS alone (AUROC 0.878 [95% CI 0.801–0.932] vs. AUROC 0.793 [95% CI 0.706–0.865]; Delong test, p = 0.013). Conclusions: There is a statistically significant correlation between LUS and echocardiographic data, suggesting their potential role as early predictors for respiratory outcomes in very preterm infants. What is Known: • Lung ultrasound score (LUS) has shown good reliability in predicting bronchopulmonary dysplasia (BPD) development. • Some echocardiographic data that characterized ventricular function was reported to be used to predict severe BPD. What is New: • There is a positive and statistically significant correlation between LUS and echocardiographic data at postnatal days 7 and 14. • The integrated use of LUS and echocardiographic data may have potential value in predicting BPD. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is fundamentally characterized by the arrest of lung development and abnormal repair mechanisms, which result in impaired development of the alveoli and microvasculature. Hepatocyte growth factor (HGF), secreted by pulmonary mesenchymal and endothelial cells, plays a pivotal role in the promotion of epithelial and endothelial cell proliferation, branching morphogenesis, angiogenesis, and alveolarization. HGF exerts its beneficial effects on pulmonary vascular development and alveolar simplification primarily through two pivotal pathways: the stimulation of neovascularization, thereby enriching the pulmonary microvascular network, and the inhibition of the epithelial-mesenchymal transition (EMT), which is crucial for maintaining the integrity of the alveolar structure. We discuss HGF and its receptor c-Met, interact with various growth factors throughout the process of lung development and BPD, and form a signaling network with HGF as a hub, which plays the pivotal role in orchestrating and integrating epithelial, endothelial and mesenchymal. [ABSTRACT FROM AUTHOR]

Infants with anterior abdominal wall defects (AWD) can suffer from pulmonary complications. Our aims were to determine if the chest radiographic thoracic areas (CRTAs) on day one differed between infants with exomphalos or gastroschisis, whether this related to differing severity of outcomes and if they were lower than those of controls indicating abnormal antenatal lung growth. A review of infants with exomphalos or gastroschisis born between January 2004 and January 2023 was conducted. The control group was term, newborn infants ventilated for poor respiratory drive at birth. Chest radiographs on day one were analysed and the highest CRTA in the first 24 h after birth for each infant included in the analysis. The 127 infants with gastroschisis had a lower gestational age and birthweight than the 62 exomphalos infants and 130 controls (all p<0.001) The CRTAs of the controls were greater than the CRTAs of the exomphalos and the gastroschisis infants (p = 0.001). The median CRTA corrected for birthweight was lower in the exomphalos infants [688, IQR 568-875 mm2/kg] than the gastroschisis infants [813, IQE 695-915 mm2/kg] No gastroschisis infant developed bronchopulmonary dysplasia (BPD). A CRTA of 1759 mm2 had a sensitivity of 81 % and specificity of 71 % in predicting BPD in infants with exomphalos. Infants with gastroschisis or exomphalos had lower CRTAs than controls suggesting both groups had abnormal antenatal lung development. The CRTA was lower in the exomphalos infants who also had worse respiratory outcomes, hence CRTA assessment may a useful prognostic aid. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is fundamentally characterized by the arrest of lung development and abnormal repair mechanisms, which result in impaired development of the alveoli and microvasculature. Hepatocyte growth factor (HGF), secreted by pulmonary mesenchymal and endothelial cells, plays a pivotal role in the promotion of epithelial and endothelial cell proliferation, branching morphogenesis, angiogenesis, and alveolarization. HGF exerts its beneficial effects on pulmonary vascular development and alveolar simplification primarily through two pivotal pathways: the stimulation of neovascularization, thereby enriching the pulmonary microvascular network, and the inhibition of the epithelial-mesenchymal transition (EMT), which is crucial for maintaining the integrity of the alveolar structure. We discuss HGF and its receptor c-Met, interact with various growth factors throughout the process of lung development and BPD, and form a signaling network with HGF as a hub, which plays the pivotal role in orchestrating and integrating epithelial, endothelial and mesenchymal.

Abstract Background Invasive mechanical ventilation contributes to bronchopulmonary dysplasia (BPD), the most common complication of prematurity and the leading respiratory cause of childhood morbidity. Non-invasive ventilation (NIV) may limit invasive ventilation exposure and can be either synchronized or non-synchronized (NS). Pooled data suggest synchronized forms may be superior. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) delivers NIV synchronized to the neural signal for breathing, which is detected with a specialized catheter. The DIVA (Diaphragmatic Initiated Ventilatory Assist) trial aims to determine in infants born 240/7–276/7 weeks’ gestation undergoing extubation whether NIV-NAVA compared to non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV) reduces the incidence of extubation failure within 5 days of extubation. Methods This is a prospective, unblinded, pragmatic, multicenter phase III randomized clinical trial. Inclusion criteria are preterm infants 24–276/7 weeks gestational age who were intubated within the first 7 days of life for at least 12 h and are undergoing extubation in the first 28 postnatal days. All sites will enter an initial run-in phase, where all infants are allocated to NIV-NAVA, and an independent technical committee assesses site performance. Subsequently, all enrolled infants are randomized to NIV-NAVA or NS-NIPPV at extubation. The primary outcome is extubation failure within 5 days of extubation, defined as any of the following: (1) rise in FiO2 at least 20% from pre-extubation for > 2 h, (2) pH ≤ 7.20 or pCO2 ≥ 70 mmHg; (3) > 1 apnea requiring positive pressure ventilation (PPV) or ≥ 6 apneas requiring stimulation within 6 h; (4) emergent intubation for cardiovascular instability or surgery. Our sample size of 478 provides 90% power to detect a 15% absolute reduction in the primary outcome. Enrolled infants will be followed for safety and secondary outcomes through 36 weeks’ postmenstrual age, discharge, death, or transfer. Discussion The DIVA trial is the first large multicenter trial designed to assess the impact of NIV-NAVA on relevant clinical outcomes for preterm infants. The DIVA trial design incorporates input from clinical NAVA experts and includes innovative features, such as a run-in phase, to ensure consistent technical performance across sites. Trial registration www.ClinicalTrials.gov , trial identifier NCT05446272 , registered July 6, 2022.

Backgroud Bronchopulmonary dysplasia (BPD) is one of the most important complications plaguing neonates and can lead to a variety of sequelae. the ability of the HIF-1α/VEGF signaling pathway to promote angiogenesis has an important role in neonatal lung development.Method Newborn rats were exposed to 85% oxygen. The effects of hyperoxia exposure on Pleomorphic Adenoma Gene like-2 (PLAGL2) and the HIF-1α/VEGF pathway in rats lung tissue were assessed through immunofluorescence and Western Blot analysis. In cell experiments, PLAGL2 was upregulated, and the effects of hyperoxia and PLAGL2 on cell viability were evaluated using scratch assays, CCK-8 assays, and EDU staining. The role of upregulated PLAGL2 in the HIF-1α/VEGF pathway was determined by Western Blot and RT–PCR. Apoptosis and ferroptosis effects were determined through flow cytometry and viability assays.Results Compared with the control group, the expression levels of PLAGL2, HIF-1α, VEGF, and SPC in lung tissues after 3, 7, and 14 days of hyperoxia exposure were all decreased. Furthermore, hyperoxia also inhibited the proliferation and motility of type II alveolar epithelial cells (AECII) and induced apoptosis in AECII. Upregulation of PLAGL2 restored the proliferation and motility of AECII and suppressed cell apoptosis and ferroptosis, while the HIF-1α/VEGF signaling pathway was also revived.Conclusions We confirmed the positive role of PLAGL2 and HIF-1α/VEGF signaling pathway in promoting BPD in hyperoxia conditions, and provided a promising therapeutic targets.

Emerging data indicate that lung macrophages (LM) may provide a novel biomarker to classify disease endotypes in bronchopulmonary dysplasia (BPD), a form of infant chronic lung disease, and that augmentation of the LM phenotype may be a potential therapeutic target. To contribute to this area of research, we first used Optical Redox Imaging (ORI) to characterize the responses to H2O2-induced oxidative stress and caffeine treatment in an in vitro model of mouse alveolar macrophages (AM). H2O2 caused a dose-dependent decrease in NADH and an increase in FAD-containing flavoproteins (Fp) and the redox ratio Fp/(NADH + Fp). Caffeine treatment did not affect Fp but significantly decreased NADH with doses of ≥50 µM, and 1000 µM caffeine treatment significantly increased the redox ratio and decreased the baseline level of mitochondrial ROS (reactive oxygen species). However, regardless of whether AM were pretreated with caffeine or not, the mitochondrial ROS levels increased to similar levels after H2O2 challenge. We then investigated the feasibility of utilizing ORI to examine macrophage redox status in tracheal aspirate (TA) samples obtained from premature infants receiving invasive ventilation. We observed significant heterogeneity in NADH, Fp, Fp/(NADH + Fp), and mitochondrial ROS of the TA macrophages. We found a possible positive correlation between gestational age and NADH and a negative correlation between mean airway pressure and NADH that provides hypotheses for future testing. Our study demonstrates that ORI is a feasible technique to characterize macrophage redox state in infant TA samples and supports further use of this method to investigate lung macrophage-mediated disease endotypes in BPD. [ABSTRACT FROM AUTHOR]

Background: Invasive mechanical ventilation contributes to bronchopulmonary dysplasia (BPD), the most common complication of prematurity and the leading respiratory cause of childhood morbidity. Non-invasive ventilation (NIV) may limit invasive ventilation exposure and can be either synchronized or non-synchronized (NS). Pooled data suggest synchronized forms may be superior. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) delivers NIV synchronized to the neural signal for breathing, which is detected with a specialized catheter. The DIVA (Diaphragmatic Initiated Ventilatory Assist) trial aims to determine in infants born 240/7–276/7 weeks’ gestation undergoing extubation whether NIV-NAVA compared to non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV) reduces the incidence of extubation failure within 5 days of extubation. Methods: This is a prospective, unblinded, pragmatic, multicenter phase III randomized clinical trial. Inclusion criteria are preterm infants 24–276/7 weeks gestational age who were intubated within the first 7 days of life for at least 12 h and are undergoing extubation in the first 28 postnatal days. All sites will enter an initial run-in phase, where all infants are allocated to NIV-NAVA, and an independent technical committee assesses site performance. Subsequently, all enrolled infants are randomized to NIV-NAVA or NS-NIPPV at extubation. The primary outcome is extubation failure within 5 days of extubation, defined as any of the following: (1) rise in FiO2 at least 20% from pre-extubation for > 2 h, (2) pH ≤ 7.20 or pCO2 ≥ 70 mmHg; (3) > 1 apnea requiring positive pressure ventilation (PPV) or ≥ 6 apneas requiring stimulation within 6 h; (4) emergent intubation for cardiovascular instability or surgery. Our sample size of 478 provides 90% power to detect a 15% absolute reduction in the primary outcome. Enrolled infants will be followed for safety and secondary outcomes through 36 weeks’ postmenstrual age, discharge, death, or transfer. Discussion: The DIVA trial is the first large multicenter trial designed to assess the impact of NIV-NAVA on relevant clinical outcomes for preterm infants. The DIVA trial design incorporates input from clinical NAVA experts and includes innovative features, such as a run-in phase, to ensure consistent technical performance across sites. Trial registration: , trial identifier , registered July 6, 2022. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate the association between different types of human milk feeds and bronchopulmonary dysplasia (BPD) in preterm infants.MethodsData on dispensed mother’s own milk (MOM) and donor human milk (DHM) from Leipzig Milk Bank for hospitalized infants with a gestational age (GA) ≤32 weeks observed from birth to 36 weeks’ postmenstrual age or prior discharge were used. BPD was assessed based on documented International Statistical Classification of Diseases and Related Health Problems (ICD) diagnosis and on electronic hospital records (EHR) of data on ventilation and oxygen supplementation. Associations of dispensed milk feed variations with BPD were investigated using logistic regressions in crude and adjusted models.Results866 infants were included with a BPD prevalence of 15.4% (EHR) and 23.2% (ICD). The mean GA was 29.1 weeks. The majority (84.4%, n = 746) of infants were nurtured with a mix of MOM, DHM supplemented by formula or parenteral (other) nutrition during hospitalization. For which, MOM comprised the highest median [Q1–Q3] percentage proportion (53[31–81] %) of this mix. Exclusive fresh milk and exclusive MOM feeds were dispensed on a mean of 40 and 34% patient-days, respectively. Statistically significant associations with lower BPD incidence were only observed for 70–80% MOM vs. DHM, and 60% fresh vs. frozen milk, in crude and adjusted models.ConclusionOur findings suggest a protective association of MOM and fresh milk with lower odds of BPD, which may be dependent on the proportion of MOM or fresh milk administered. These results highlight the importance of MOM as an ideal source of nutrition during early infancy.

This dataset offers an insight into the neurodevelopmental trajectories of preterm infants, encapsulating a wide array of neonatal and maternal factors. The data variables include demographic details alongside a detailed account of maternal health during pregnancy, encompassing aspects and other complications. Furthermore, the dataset documents neonatal health conditions. It also records critical indicators of neonatal health. The dataset is enriched with data on medical interventions and hospitalization details. It also contains information on the mother's drug usage during pregnancy and sonography results. A significant portion of the dataset is dedicated to the developmental assessment of the infants, utilizing the Bayley Scales to evaluate various domains such as cognitive, language, perceptual, fine motor, and coarse motor skills. The data are categorized to denote normal and abnormal outcomes in these domains, providing a detailed view of the developmental progress of the infants.The reuse potential of this dataset is substantial, serving as a rich resource for researchers and clinicians aiming to delve deeper into the multifaceted influences on preterm infant development. It can significantly contribute to the formulation of early intervention strategies, fostering a better understanding and enhancement of developmental outcomes in preterm infants.

This research paper provides a comprehensive review of the utilization of high-flow nasal cannula (HFNC) therapy as a means of respiratory support in extremely premature infants. The paper elucidates the underlying mechanisms of HFNC, which encompass the provision of distending pressure, reduction of respiratory effort, facilitation of carbon dioxide elimination, and optimization of gas conditioning. Noteworthy advantages of HFNC in comparison to invasive ventilation include enhanced oxygenation, improved lung compliance, and promotion of bonding, while simultaneously mitigating the occurrence of complications. Nevertheless, it is important to acknowledge potential drawbacks associated with HFNC, such as heightened morbidity, inadequate support necessitating reintubation, and an elevated risk of air leaks. Further investigations are imperative to refine HFNC protocols, conduct comparative analyses with alternative interventions, and enhance overall patient outcomes. In summation, HFNC represents an efficacious noninvasive respiratory treatment modality for premature infants, albeit with certain limitations. The optimization of benefits can be achieved through meticulous monitoring and standardization of practices.

Objective To investigate whether macrophage pyroptosis is involved in the lung injury of bronchopulmonary dysplasia （BPD）. Methods Forty full-term newborn mice were divided into room air （RA） group and hyperoxia （HO） group （n=20 for each group）. BPD mouse model was induced by chronic hyperoxia. Alveolarization was assessed by HE staining. Pulmonary vascular development was detected by CD31 immunohistochemistry. The degree of fibrosis was analyzed by Masson staining. The mRNA expression levels of pro-inflammatory cytokines and chemokines in lung tissue were quantified by qRTPCR for Il6，Il1b，Mmp12，Ccl2，Ccl5 and Il8. Concentrations of IL-1β was detected by ELISA in serum and lung homogenates. The expressions of pyroptosis-associated proteins，NLRP3, Caspase-1 p20, Ngasdermin D （GSDMD） and mature IL-1β were evaluated by Western blot. The proportion of macrophages in bronchoalveolar lavage fluid was detected by flow cytometry. Immunofluorescence colocalization of F4/80 with NLRP3/Caspase-1/IL-1β was performed. AQP5 protein expression was analyzed by immunohistochemistry. Results Compared with the RA group, alveolar block and pulmonary angiogenesis disorder were observed in the HO group, and pulmonary fibrosis was significantly increased. In lung tissue of HO group, the expression of pro-inflammatory cytokines was significantly upregulated, the expression levels of pyroptosis-associated proteins were significantly increased； the levels of IL-1β in serum and lung homogenate were significantly increased； the proportion of macrophages in bronchoalveolar lavage fluid was significantly increased, and there was a significant immunofluorescence colocalization of F4/80 with NLRP3, Caspase-1 and IL-1β in lung tissue； AQP5-positive alveolar type Ⅰ epithelial cells were severely damaged. Conclusion Hyperoxia-induced hyperactivation of the NLRP3/ Caspase-1/GSDMD mediated pyroptosis may lead to lung injury in a hyperoxia-exposed BPD mouse model. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm birth survivors characterized by inflammation, impaired alveolarization and dysmorphic vasculature. Activated IL-17A+ lymphocytes are key drivers of inflammation in preterm infants. We have shown that in immature mice chronic airway exposure to lipopolysaccharide (LPS) induces pulmonary inflammation, increased IL-17a expression, and hypoalveolarization, a BPD-like phenotype. The source of IL-17a and contribution to lung pathology is unknown. The natural-killer group 2, member D (NKG2D) receptor mediates activation and IL-17a production in γδ T cells by binding to stress molecules. LPS induces NKG2D ligand expression, including Rae-1 and MULT1. We hypothesized that IL-17a+ γδ T cells and NKG2D signaling mediate neonatal LPS-induced lung injury. Immature C57BL/6J (wild type), Nkg2d-/- or Tcrd-/- (lacking γδ T cells) mice were inoculated with 3ug/10ul of LPS from E. coli O26:B6 or 10ul of PBS intranasally on day of life 3, 5, 7, and 10. Selected mice were treated with neutralizing antibodies against IL-17a, or NKG2D intraperitoneally. Lung immune cells were assessed by flow cytometry and gene expression was analyzed by qPCR. Alveolar growth was assessed by lung morphometry. We established that anti-IL-17a antibody treatment attenuated LPS-induced hypoalveolarization. We found that LPS induced the fraction of IL-17a+NKG2D+ γδ T cells, a major source of IL-17a in the neonatal lung. LPS also induced lung mRNA expression of NKG2D, Rae-1, MULT1, and the DNA damage regulator p53. Anti-NKG2D treatment attenuated the effect of LPS on γδ T cell IL-17a expression, immune cell infiltration and hypoalveolarization. LPS-induced hypoalveolarization was also attenuated in Nkg2d-/- and Tcrd-/- mice. In tracheal aspirates of preterm infants IL-17A and its upstream regulator IL-23 were higher in infants who later developed BPD. Also, human ligands of NKG2D, MICA and MICB were present in the aspirates and MICA correlated with median FiO2. Our novel findings demonstrate a central role for activated IL-17a+ γδ T cells and NKG2D signaling in neonatal LPS-induced lung injury. Future studies will determine the role of NKG2D ligands and effectors, other NKG2D+ cells in early-life endotoxin-induced lung injury and inflammation with a long-term goal to understand how inflammation contributes to BPD pathogenesis. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm birth survivors characterized by inflammation, impaired alveolarization and dysmorphic vasculature. Activated IL-17A+ lymphocytes are key drivers of inflammation in preterm infants. We have shown that in immature mice chronic airway exposure to lipopolysaccharide (LPS) induces pulmonary inflammation, increased IL-17a expression, and hypoalveolarization, a BPD-like phenotype. The source of IL-17a and contribution to lung pathology is unknown. The natural-killer group 2, member D (NKG2D) receptor mediates activation and IL-17a production in γδ T cells by binding to stress molecules. LPS induces NKG2D ligand expression, including Rae-1 and MULT1. We hypothesized that IL-17a+ γδ T cells and NKG2D signaling mediate neonatal LPS-induced lung injury. Immature C57BL/6J (wild type), Nkg2d-/- or Tcrd-/- (lacking γδ T cells) mice were inoculated with 3ug/10ul of LPS from E. coli O26:B6 or 10ul of PBS intranasally on day of life 3, 5, 7, and 10. Selected mice were treated with neutralizing antibodies against IL-17a, or NKG2D intraperitoneally. Lung immune cells were assessed by flow cytometry and gene expression was analyzed by qPCR. Alveolar growth was assessed by lung morphometry. We established that anti-IL-17a antibody treatment attenuated LPS-induced hypoalveolarization. We found that LPS induced the fraction of IL-17a+NKG2D+ γδ T cells, a major source of IL-17a in the neonatal lung. LPS also induced lung mRNA expression of NKG2D, Rae-1, MULT1, and the DNA damage regulator p53. Anti-NKG2D treatment attenuated the effect of LPS on γδ T cell IL-17a expression, immune cell infiltration and hypoalveolarization. LPS-induced hypoalveolarization was also attenuated in Nkg2d-/- and Tcrd-/- mice. In tracheal aspirates of preterm infants IL-17A and its upstream regulator IL-23 were higher in infants who later developed BPD. Also, human ligands of NKG2D, MICA and MICB were present in the aspirates and MICA correlated with median FiO2. Our novel findings demonstrate a central role for activated IL-17a+ γδ T cells and NKG2D signaling in neonatal LPS-induced lung injury. Future studies will determine the role of NKG2D ligands and effectors, other NKG2D+ cells in early-life endotoxin-induced lung injury and inflammation with a long-term goal to understand how inflammation contributes to BPD pathogenesis.

Bronchopulmonary dysplasia (BPD) causes high morbidity and mortality in infants, but no effective preventive or therapeutic agents have been developed to combat BPD. In this study, we assessed the expression of MALAT1 and ALOX5 in peripheral blood mononuclear cells from BPD neonates, hyperoxia-induced rat models and lung epithelial cell lines. Interestingly, we found upregulated expression of MALAT1 and ALOX5 in the experimental groups, along with upregulated expression of proinflammatory cytokines. According to bioinformatics prediction, MALAT1 and ALOX5 simultaneously bind to miR-188–3p, which was downregulated in the experimental groups above. Silencing MALAT1 or ALOX5 and overexpressing miR-188–3p inhibited apoptosis and promoted the proliferation of hyperoxia-treated A549 cells. Suppressing MALAT1 or overexpressing miR-188–3p increased the expression levels of miR-188–3p but decreased the expression levels of ALOX5. Moreover, RNA immunoprecipitation (RIP) and luciferase assays showed that MALAT1 directly targeted miR-188–3p to regulate ALOX5 expression in BPD neonates. Collectively, our study demonstrates that MALAT1 regulates ALOX5 expression by binding to miR-188–3p, providing novel insights into potential therapeutics for BPD treatment. • MALAT1 and ALOX5 are highly expressed in BPD. • Silencing MALAT1 or ALOX5 promotes cell proliferation and inhibits cell apoptosis. • MALAT1 and ALOX5 directly targeted by miR-188–3p in hyperoxia-induced injury in A549 cells. • MALAT1/miR-188–3p/ALOX5 affects lung inflammatory response of BPD. [ABSTRACT FROM AUTHOR]

Introduction: Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes. Methods: Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb. Results: Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased NAMPT expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1–14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAbinduced reductions in inflammatory pathway genes. Discussion: The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPTneutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is the most common complication of extreme prematurity. Its etiology is multifactorial and is attributed to genetic susceptibility to prenatal and postnatal factors. As advancements in neonatology have led to the increased survival of premature infants, a parallel increase in the incidence of BPD has occurred. Over time, the definition and diagnostic criteria for BPD have evolved, as have management strategies. However, challenges continue to exist in the management of these infants, which is not surprising given the complexity of the disease. We summarize the key diagnostic criteria and provide insight into the challenges related to various aspects of BPD definitions, data comparisons, and clinical care implementation. [ABSTRACT FROM AUTHOR]

Background: Bronchopulmonary dysplasia (BPD) is one of the major complications of prematurity resulting in significant mortality and morbidity. Reactive oxygen species, which are highly reactive molecules that can cause oxidative damage to lung tissue and trigger inflammatory reactions, are associated with pathophysiological changes in many lung diseases, such as BPD. Hydrogen peroxide (H2O2), which is a strong oxidant, is widely used in simulating cellular oxidative damage. Whether glutamine can protect lung cells from oxidant damages is not known. Objectives: To explore the cytotoxic mechanisms of H2O2 on lung cells, including A549 and HEL299 cells, and investigate the effects of L-glutamine in the protection of oxidative damage on the lung cells. Methods: Cytotoxic effects of H2O2 and the protective effects of glutamine against H2O2 on lung cells were accessed by the cell viability assay. The underlying mechanisms for H2O2 damaging lung cells were analyzed by the flow cytometry to quantify changes in mitochondrial membrane potential before and after H2O2 and L-glutamine were added into lung cells. Pulmonary alveolar epithelial cells line, A549, and human embryonic bronchial fibroblast cell line, HEL 299, were grown in the incubator. H2O2 with and without L-glutamine was added in the lung cells, and cell viability was measured by the water-soluble tetrazolium 1 (WST-1) assay and the changes of mitochondrial membrane potential by the flow cytometry. Statistical analysis used is as follows: data comparisons from cell proliferation studies were analyzed by one-way analysis of variance. The quantification data of the mitochondrial potential assay was analyzed by Student’s t tests. A P-value of less than 0.05 was considered statistically significant. Results: A total of 100-μM H2O2 significantly decreased the viability of A549 and HEL299 cells; 8-mM L-glutamine rescued lung cell death caused by the H2O2 toxicity; and 100 μM of mitochondrial membrane potential was significantly elevated in HEL299 cells, except A549 cells in the application of H2O2 and L-glutamine. Conclusion: H2O2-induced cytotoxicity in A549 and HEL299 cells was associated with mitochondria. The different effects of L-glutamine on A549 and HEL299 cells in response to the 100 μM of H2O2-induced cytotoxicity suggest that these two cell lines may have different mechanisms against oxidative stress.

Lung ultrasound scores (LUSs) have been demonstrated to accurately predict moderate-to-severe bronchopulmonary dysplasia (msBPD). This study attempted to explore the additional value of LUSs for predicting msBPD compared to clinical multivariate models in different gestational age (GA) groups. The study prospectively recruited preterm infants with GA < 32 weeks. Lung ultrasound was performed on days 3, 7, 14, and 21 after birth. A linear mixed-effects regression model was used to evaluate LUS evolution in infants born before and after 28 weeks. The receiver operating characteristic (ROC) procedure was used to analyze the reliability of LUS and clinical multivariable models for predicting msBPD. The optimal time to predict msBPD in all infants was 7 days with a cut-off point of 5 (area under the ROC (AUROC) curve: 0.78, 95% confidence interval (CI): 0.71–0.84). In infants with GA ≥ 28 weeks, LUSs provided a moderate diagnostic accuracy for all four time points (AUROC curve: 0.74–0.78), and the AUROC curve for the clinical multivariable model on day 14 was 0.91 (95% CI: 0.84–0.96), which was significantly higher than that of LUSs (AUROC curve: 0.77, 95% CI: 0.68–0.85, P < 0.05). In infants born at 23–27 weeks, LUSs showed a low diagnostic accuracy with higher cut-off points to predict msBPD, and the AUROC curve for GA to predict msBPD was 0.75 (95% CI: 0.59–0.85), providing diagnostic accuracy similar to that of LUSs. Conclusion: The contribution of LUSs to predict msBPD in infants with different GAs remains controversial and requires further investigation. What is Known: • Lung ultrasound scores (LUSs) have been demonstrated to accurately predict moderate-to-severe bronchopulmonary dysplasia in infants with gestational age (GA)＜32 weeks. What is New: • The LUSs evolution differed between extremely preterm infants born before 28 weeks and preterm infants born at 28–32 weeks of gestation. • LUSs provided similar moderate predictive performance as GA-adjusted LUS and clinical multivariate models in infants born after 28 weeks, while LUSs seem to be less helpful in infants born before 28 weeks. [ABSTRACT FROM AUTHOR]

Objectives: Early screening and dynamic monitoring of pulmonary vascular disease (PVD) in bronchopulmonary dysplasia (BPD) high‐risk infants is of great clinical significance. Pulmonary artery acceleration time (PAAT) is a reliable and non‐invasive method for assessing PVD in children over 1 year, but to date, few studies have used PAAT to assess pulmonary hemodynamics of preterm infants, especially those with BPD. Through dynamic monitoring the main hemodynamic indicators reflected PVD after birth, this study aimed to assess the value of PAAT in evaluating early PVD in BPD infants. Methods: All 81 preterm infants at risk of BPD were divided into BPD and non‐BPD groups according to whether BPD occurred. Clinical characteristics, PAAT, right ventricular ejection time (RVET) and other main hemodynamic indicators at four different time points after birth were studied and compared. Results: PAAT and PAAT/RVET increased gradually within 72 h after birth in the BPD group (p <.05), but the curve tended to be flat over time after 72 h (p >.05). At PMA32 and 36 weeks, the PAAT (49.7 ± 4.8 vs. 54.8 ± 5.7, p =.001; 50.0 ± 5.3 vs. 57.0 ± 5.3, p =.001) and PAAT/RVET (.33 ±.04 vs..35 ±.03, p =.001;.34 ±.03 vs..37 ±.04, p =.001) in BPD group were significantly lower than those in the non‐BPD group. Conclusions: PAAT and PAAT/RVET in the BPD group infants showed different change patterns compared to non‐BPD group infants. PAAT can be used as a noninvasive and reliable screening method for screening and dynamic monitoring of PVD in BPD high‐risk infants. [ABSTRACT FROM AUTHOR]

Introduction: Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes.Methods: Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb.Results: Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased NAMPT expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1–14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAb-induced reductions in inflammatory pathway genes.Discussion: The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPT-neutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates.

IntroductionThe aim of this study is to develop an enhanced machine learning-based prediction models for bronchopulmonary dysplasia (BPD) and its severity through a two-stage approach integrated with the duration of respiratory support (RSd) using prenatal and early postnatal variables from a nationwide very low birth weight (VLBW) infant cohort.MethodsWe included 16,384 VLBW infants admitted to the neonatal intensive care unit (NICU) of the Korean Neonatal Network (KNN), a nationwide VLBW infant registry (2013–2020). Overall, 45 prenatal and early perinatal clinical variables were selected. A multilayer perceptron (MLP)-based network analysis, which was recently introduced to predict diseases in preterm infants, was used for modeling and a stepwise approach. Additionally, we applied a complementary MLP network and established new BPD prediction models (PMbpd). The performances of the models were compared using the area under the receiver operating characteristic curve (AUROC) values. The Shapley method was used to determine the contribution of each variable.ResultsWe included 11,177 VLBW infants (3,724 without BPD (BPD 0), 3,383 with mild BPD (BPD 1), 1,375 with moderate BPD (BPD 2), and 2,695 with severe BPD (BPD 3) cases). Compared to conventional machine learning (ML) models, our PMbpd and two-stage PMbpd with RSd (TS-PMbpd) model outperformed both binary (0 vs. 1,2,3; 0,1 vs. 2,3; 0,1,2 vs. 3) and each severity (0 vs. 1 vs. 2 vs. 3) prediction (AUROC = 0.895 and 0.897, 0.824 and 0.825, 0.828 and 0.823, 0.783, and 0.786, respectively). GA, birth weight, and patent ductus arteriosus (PDA) treatment were significant variables for the occurrence of BPD. Birth weight, low blood pressure, and intraventricular hemorrhage were significant for BPD ≥2, birth weight, low blood pressure, and PDA ligation for BPD ≥3. GA, birth weight, and pulmonary hypertension were the principal variables that predicted BPD severity in VLBW infants.ConclusionsWe developed a new two-stage ML model reflecting crucial BPD indicators (RSd) and found significant clinical variables for the early prediction of BPD and its severity with high predictive accuracy. Our model can be used as an adjunctive predictive model in the practical NICU field.

The impact of placental dysfunction and placental injury on the fetus and newborn infant has become a topic of growing interest in neonatal disease research. However, the use of placental pathology in directing or influencing neonatal clinical management continues to be limited for a wide range of reasons, some of which are historical and thus easily overcome today. In this review, we summarize the most recent literature linking placental function to neonatal outcomes, focusing on clinical placental pathology findings and the most common neonatal diagnoses that have been associated with placental dysfunction. We discuss how recent technological advances in neonatal and perinatal medicine may allow us to make a paradigm shift, in which valuable information provided by the placenta could be used to guide neonatal management more effectively, and to ultimately enhance neonatal care in order to improve our patient outcomes. We propose new avenues of clinical management in which the placenta could serve as a diagnostic tool toward more personalized neonatal intensive care unit management.

Bronchopulmonary dysplasia (BPD) remains the most common respiratory complication of prematurity as younger and smaller infants are surviving beyond the immediate neonatal period. The recognition that oxidative stress (OS) plays a key role in BPD pathogenesis has been widely accepted since at least the 1980s. In this article, we examine the interplay between OS and genetic regulation and review 'omics' data related to OS in BPD. Data from animal models (largely models of hyperoxic lung injury) and from human studies are presented. Epigenetic and transcriptomic analyses have demonstrated several genes related to OS to be differentially expressed in murine models that mimic BPD as well as in premature infants at risk of BPD development and infants with established lung disease. Alterations in the genetic regulation of antioxidant enzymes is a common theme in these studies. Data from metabolomics and proteomics have also demonstrated the potential involvement of OS-related pathways in BPD. A limitation of many studies includes the difficulty of obtaining timely and appropriate samples from human patients. Additional 'omics' studies could further our understanding of the role of OS in BPD pathogenesis, which may prove beneficial for prevention and timely diagnosis, and aid in the development of targeted therapies. [ABSTRACT FROM AUTHOR]

Premature infants with chronic lung disease, bronchopulmonary dysplasia (BPD), develop recurrent cough and wheezing following respiratory viral infections. The mechanisms driving the chronic respiratory symptoms are ill-defined. We have shown that hyperoxic exposure of neonatal mice (a model of BPD) increases the activated lung CD103+ dendritic cells (DCs) and these DCs are required for exaggerated proinflammatory responses to rhinovirus (RV) infection. Since CD103+ DC are essential for specific antiviral responses and their development depends on the growth factor Flt3L, we hypothesized that early-life hyperoxia stimulates Flt3L expression leading to expansion and activation of lung CD103+ DCs and this mediates inflammation. We found that hyperoxia numerically increased and induced proinflammatory transcriptional signatures in neonatal lung CD103+ DCs, as well as CD11bhi DCs. Hyperoxia also increased Flt3L expression. Anti-Flt3L antibody blocked CD103+ DC development in normoxic and hyperoxic conditions, and while it did not affect the baseline number of CD11bhi DCs, it neutralized the effect of hyperoxia on these cells. Anti-Flt3L also inhibited hyperoxia-induced proinflammatory responses to RV. In tracheal aspirates from preterm infants mechanically-ventilated for respiratory distress in the first week of life levels of FLT3L, IL-12p40, IL-12p70 and IFN-γ were higher in infants who went on to develop BPD and FLT3L levels positively correlated with proinflammatory cytokines levels. This work highlights the priming effect of early-life hyperoxia on lung DC development and function and the contribution of Flt3L in driving these effects.

Bronchopulmonary dysplasia (BPD) is one of the most common complications of premature birth. The current definition of BPD is based on the duration of oxygen therapy and/or respiratory support. Among the pitfalls of all the diagnostic definitions, the lack of a proper pathophysiologic classification makes it difficult to choose an appropriate drug strategy for BPD. In this case report, we describe the clinical course of four premature infants, admitted to the neonatal intensive care unit, for whom the use of lung and cardiac ultrasound was an integral part of the diagnostic and therapeutic process. We describe, for the first time to our knowledge, four different cardiopulmonary ultrasound patterns of evolving and established chronic lung disease of prematurity and the consequent therapeutic choices. This approach, if confirmed in prospective studies, may guide the personalized management of infants suffering from evolving and established BPD, optimizing the chances of success of the therapies and at the same time reducing the risk of exposure to inadequate and potentially harmful drugs.

Latar belakang. Bronchopulmonary dysplasia (BPD) merupakan salah satu komplikasi terbanyak pada bayi prematur dan juga merupakan prediktor penting terjadinya gangguan perkembangan. Upaya untuk mencegah BPD penting dilakukan untuk menurunkan angka mortalitas bayi prematur. Tujuan. Mengetahui efektivitas azitromisin dalam pencegahan BPD pada bayi prematur. Metode. Penelusuran pustaka dilakukan secara ekstensif melalui beberapa pangkalan data, yaitu Pubmed, Cochrane, Google scholar, dan EBSCO dengan kata kunci “neonates”, “OR” “newborn”, “AND” “preterm”, “OR” “premature”, “AND” “azithromycin”, “AND” “bronchopulmonary dysplasia”. Hasil. Penelusuran literatur diperoleh 1 artikel yang terpilih kemudian dilakukan telaah kritis, yaitu studi telaah sistematik dan meta-analisis oleh Razak dkk, dengan level of evidence 1a. Studi tersebut menunjukkan bahwa tidak terdapat perbedaan bermakna antara kedua kelompok untuk luaran BPD pada seluruh bayi prematur (RR 0,92, IK 95%, 0,71-1,19, p=0,53). Namun, terdapat perbedaan bermakna antara kelompok yang mendapat azitromisin dan kelompok yang mendapat plasebo atau tidak mendapat terapi untuk luaran angka kematian atau BPD pada bayi prematur dengan Ureaplasma positif (RR 0,83, IK 95%, 0,70-0,99, p=0,04). Durasi penggunaan suplementasi oksigen lebih rendah secara bermakna pada kelompok azitromisin dibandingkan dengan kelompok yang tidak mendapat terapi (rerata perbedaan -6,06%, IK 95%, -7,4 hingga -4,72, p

An extremely dystrophic, premature female infant, born at 25 3/7 weeks of gestational age (birth weight: 430 g) with severe pulmonary hypertension (PH), was admitted to our neonatal intensive care unit (ICU) requiring cardiorespiratory support, including mechanical ventilation and pulmonary vasodilators such as inhaled nitric oxide (iNO) and continuous intravenous sildenafil infusions. The diagnosis of bronchopulmonary dysplasia (BPD) was made. A hemodynamically relevant, persistent ductus arteriosus (PDA) was surgically ligated after failed pharmacologic PDA closure using indomethacin and ibuprofen. The patient was discharged with an estimated 2/3 systemic pulmonary artery pressure. One month after hospital discharge, on low-flow oxygen supplementation (0.5 L/min FiO2 100%), at the corrected age of 16 weeks, she was readmitted to our emergency department with signs of respiratory distress and circulatory decompensation. Echocardiography demonstrated suprasystemic PH. Severe PH persisted despite initiated invasive mechanical ventilation, triple vasodilating therapy [iNO, macitentan, and continuous intravenous (IV) sildenafil], as well as levosimendan, milrinone, and norepinephrine for recompensation from cardiac shock. Thus, we started off-label oral selexipag therapy (oral IP receptor agonist) in the smallest patient reported so far (4 kg body weight). Subsequently, RV systolic pressure decreased to half-systemic, allowing successful weaning of iNO, norepinephrine, and milrinone, and extubation of the patient over 4 days. The infant was discharged 4 weeks after pediatric intensive care unit (PICU) admission in stable cardiorespiratory condition, with an oral, specific, triple antihypertensive PAH-targeted therapy using selexipag, macitentan, and sildenafil as well as oxygen therapy at low-flow (0.5 l/min) and spironolactone. The first cardiac catheterization at the age of 9 months under aforementioned triple PAH-targeted therapy revealed mild PH with 35% systemic PA pressure (mPAP/mSAP = 0.35) and isolated pulmonary vein stenosis. A transthoracic biopsy at the age of 12 months confirmed the diagnosis of BPD and further showed pulmonary interstitial glycogenosis and severe pulmonary capillary hemangiomatosis, without involvement of the pulmonary venules (chILD A2, A3, and B4 according to the Deutsch-Classification). The patient is currently in stable cardiorespiratory condition undergoing triple PH-targeted therapy including selexipag. This report highlights the potential benefits of the oral prostacyclin mimetic selexipag as an early add-on PH-targeted drug in chronic PH of infancy (cPHi).

Disrupted neonatal lung angiogenesis and alveologenesis often give rise to bronchopulmonary dysplasia (BPD), the most common chronic lung disease in children. Hyperoxia-induced pulmonary vascular and alveolar damage in premature infants is one of the most common and frequent factors contributing to BPD. The purpose of the present study was to explore the key molecules and the underlying mechanisms in hyperoxia-induced lung injury in neonatal mice and to provide a new strategy for the treatment of BPD. In this work, we reported that hyperoxia decreased the proportion of endothelial cells (ECs) in the lungs of neonatal mice. In hyperoxic lung ECs of neonatal mice, we detected upregulated fibroblast growth factor receptor 1 (FGFR1) expression, accompanied by upregulation of the classic downstream signaling pathway of activated FGFR1, including the ERK/MAPK signaling pathway and PI3K-Akt signaling pathway. Specific deletion of Fgfr1 in the ECs of neonatal mice protected the lungs from hyperoxia-induced lung injury, with improved angiogenesis, alveologenesis and respiratory metrics. Intriguingly, the increased Fgfr1 expression was mainly attributed to aerosol capillary endothelial (aCap) cells rather than general capillary endothelial (gCap) cells. Deletion of endothelial Fgfr1 increased the expression of gCap cell markers but decreased the expression of aCap cell markers. Additionally, inhibition of FGFR1 by an FGFR1 inhibitor improved alveologenesis and respiratory metrics. In summary, this study suggests that in neonatal mice, hyperoxia increases the expression of endothelial FGFR1 in lung ECs and that deficiency of endothelial Fgfr1 can ameliorate hyperoxia-induced BPD. These data suggest that FGFR1 may be a potential therapeutic target for BPD, which will provide a new strategy for the prevention and treatment of BPD. [ABSTRACT FROM AUTHOR]

This study explores the efficacy of early systematic postnatal corticosteroids (PCS) in reducing bronchopulmonary dysplasia (BPD) and mortality among preterm infants, focusing on identifying the populations most likely to benefit. Although PCS has been extensively studied for its anti-inflammatory effects in preventing BPD, the ideal target population remains unclear. This meta-analysis included 26 randomized controlled trials (RCTs) focusing exclusively on systemic intravenous PCS. Studies were stratified by baseline BPD or mortality rates in control groups (< 50%, 50-65%, and > 65%). Results indicated that PCS effectiveness in reducing BPD or mortality was significantly associated with baseline risk, with rate differences (RD) for BPD or mortality of - 0.03 (95% CI - 0.08, 0.01) in lower-risk groups (< 50%), - 0.07 (95% CI - 0.12, - 0.01) in moderate-risk groups (50-65%), and - 0.18 (95% CI - 0.32, - 0.04) in high-risk groups (> 65%). Linear logistic analysis demonstrated a significant trend, with higher baseline event rates in control groups associated with a more substantial RD (RD ~ rates in controls, R 2  = 0.228, p = 0.014). Both dexamethasone and hydrocortisone showed similar trends., Conclusion: These findings underscore that the baseline event rates in the control group are potentially correlated with the efficacy of PCS in preventing BPD or mortality, offering more precise guidance beyond the general "high-risk" category and supporting baseline risk stratification for more targeted PCS therapy in clinical practice., What Is Known: • Early postnatal corticosteroids (PCS) have been widely studied for their anti-inflammatory effects in preventing bronchopulmonary dysplasia (BPD) in preterm infants. • Determining the optimal target population for PCS remains challenging due to varying baseline risks and associated neurodevelopmental concerns., What Is New: • Stratifying infants by baseline BPD or mortality rates reveals that PCS shows greater efficacy in high-risk groups, particularly those with baseline event rates above 50%. • Considering baseline risk stratification represents a key direction for future clinical decision-making., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Approximately 10% of all children worldwide are born preterm and respiratory consequences are amongst the most common sequelae of preterm birth. Except for a higher prevalence of respiratory symptoms and hospital admissions, preterm birth is associated with lower lung function that may track into adulthood. Lung function impairment is not restricted to extreme or very preterm-born subjects as also children born moderate-late preterm have lower Z-scores for lung function. Given the heterogeneity of prematurity-associated lung disease, phenotype-based, multidisciplinary management is needed to improve respiratory health in preterm-born subjects., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Bronchopulmonary dysplasia (BPD) is fundamentally characterized by the arrest of lung development and abnormal repair mechanisms, which result in impaired development of the alveoli and microvasculature. Hepatocyte growth factor (HGF), secreted by pulmonary mesenchymal and endothelial cells, plays a pivotal role in the promotion of epithelial and endothelial cell proliferation, branching morphogenesis, angiogenesis, and alveolarization. HGF exerts its beneficial effects on pulmonary vascular development and alveolar simplification primarily through two pivotal pathways: the stimulation of neovascularization, thereby enriching the pulmonary microvascular network, and the inhibition of the epithelial-mesenchymal transition (EMT), which is crucial for maintaining the integrity of the alveolar structure. We discuss HGF and its receptor c-Met, interact with various growth factors throughout the process of lung development and BPD, and form a signaling network with HGF as a hub, which plays the pivotal role in orchestrating and integrating epithelial, endothelial and mesenchymal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sang and Qiao.)

Left atrial hypertension (LAH) may contribute to pulmonary hypertension (PH) in premature infants with bronchopulmonary dysplasia (BPD). Primary causes of LAH in infants with BPD include left ventricular diastolic dysfunction or hemodynamically significant left to right shunt. The incidence of LAH, which is definitively diagnosed by cardiac catheterization, and its contribution to PH is unknown in patients with BPD-PH. We report the prevalence of LAH in an institutional cohort with BPD-PH with careful examination of hemodynamic contributors and impact on patient outcomes. This single-center, retrospective cohort study examined children

Abstract Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix‐, myo‐, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix‐, myo‐, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.

The newborn’s microbiota composition at birth seems to be influenced by maternal microbiota. Maternal vaginal microbiota can be a determining factor of spontaneous Preterm Birth (SPPTB), the leading cause of perinatal mortality. The aim of the study is to investigate the likelihood of a causal relationship between the maternal vaginal microbiota composition and neonatal lung and intestinal microbiota profile at birth, in cases of SPPTB. The association between the lung and/or meconium microbiota with the subsequent development of bronchopulmonary dysplasia (BPD) was also investigated. Maternal vaginal swabs, newborns’ bronchoalveolar lavage fluid (BALF) (1st, 3rd, 7th day of life) and first meconium samples were collected from 20 women and 23 preterm newborns with gestational age ≤ 30 weeks (12 = SPPTB; 11 = Medically Indicated Preterm Birth–MIPTB). All the samples were analyzed for culture examination and for microbiota profiling using metagenomic analysis based on the Next Generation Sequencing (NGS) technique of the bacterial 16S rRNA gene amplicons. No significant differences in alpha e beta diversity were found between the neonatal BALF samples of SPPTB group and the MIPTB group. The vaginal microbiota of mothers with SPPTB showed a significant difference in alpha diversity with a decrease in Lactobacillus and an increase in Proteobacteria abundance. No association was found between BALF and meconium microbiota with the development of BPD. Vaginal colonization by Ureaplasma bacteria was associated with increased risk of both SPPTB and newborns’ BPD occurrence. In conclusion, an increase in α-diversity values and a consequent fall in Lactobacillus in vaginal environment could be associated to a higher risk of SPPTB. We could identify neither a specific neonatal lung or meconium microbiota profiles in preterm infants born by SPPTB nor a microbiota at birth suggestive of subsequent BPD development. Although a strict match has not been revealed between microbiota of SPPTB mother-infant couples, a relationship cannot be excluded. To figure out the reciprocal influence of the maternal-neonatal microbiota and its potential role in the pathogenesis of SPPTB and BPD further research is needed.

IntroductionIbuprofen is one of the most common non-steroidal anti-inflammatory drugs used to close patent ductus arteriosus (PDA) in preterm infants. PDA is associated with bronchopulmonary dysplasia (BPD), while PDA closure by ibuprofen did not reduce the incidence of BPD or death. Previous studies have indicated an anti-angiogenesis effect of ibuprofen. This study investigated the change of angiogenic factors after ibuprofen treatment in preterm infants.MethodsPreterm infants with hemodynamically significant PDA (hsPDA) were included. After confirmed hsPDA by color doppler ultrasonography within 1 week after birth, infants received oral ibuprofen for three continuous days. Paired plasma before and after the ibuprofen treatment was collected and measured by ELISA to determine the concentrations of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor A (VEGF-A), and hypoxia-inducible factor-2α (HIF-2α).Results17 paired plasma from infants with hsPDA were collected. The concentration of PDGF-BB and VEGF-A significantly decreased after ibuprofen treatment (1,908 vs. 442 pg/mL for PDGF-BB, 379 vs. 174 pg/mL for VEGF-A). HIF-2α level showed a tendency to decrease after ibuprofen treatment, although the reduction was not statistically significant (p = 0.077).ConclusionThis study demonstrated decreased vascular growth factors after ibuprofen exposure in hsPDA infants.

Abstract Surfactant protein D (SP-D) is a collectin protein synthesized by alveolar type II cells in the lungs. SP-D participates in the innate immune defense of the lungs by helping to clear infectious pathogens and modulating the immune response. SP-D has shown an anti-inflammatory role by down-regulating the release of pro-inflammatory mediators in different signaling pathways such as the TLR4, decreasing the recruitment of inflammatory cells to the lung, and modulating the oxidative metabolism in the lungs. Recombinant human SP-D (rhSP-D) has been successfully produced mimicking the structure and functions of native SP-D. Several in vitro and in vivo experiments using different animal models have shown that treatment with rhSP-D reduces the lung inflammation originated by different insults, and that rhSP-D could be a potential treatment for bronchopulmonary dysplasia (BPD), a rare disease for which there is no effective therapy up to date. BPD is a complex disease in preterm infants whose incidence increases with decreasing gestational age at birth. Lung inflammation, which is caused by different prenatal and postnatal factors like infections, lung hyperoxia and mechanical ventilation, among others, is the key player in BPD. Exacerbated inflammation causes lung tissue injury that results in a deficient gas exchange in the lungs of preterm infants and frequently leads to long-term chronic lung dysfunction during childhood and adulthood. In addition, low SP-D levels and activity in the first days of life in preterm infants have been correlated with a worse pulmonary outcome in BPD. Thus, SP-D mediated functions in the innate immune response could be critical aspects of the pathogenesis in BPD and SP-D could inhibit lung tissue injury in this preterm population. Therefore, administration of rhSP-D has been proposed as promising therapy that could prevent BPD.

Abstract Introduction Association between persistency of a patent ductus arteriosus (PDA) and morbidity in preterm newborns is still controversial. We aimed to investigate the relation between PDA and morbidity in a large retrospective study. Methods A case-control study including neonates consecutively admitted to the Neonatal Intensive Care Unit (NICU), with gestational age (GA)

Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in premature infants. However, there is a lack of effective treatment. Mesenchymal stromal cells derived extracellular vesicles (MSC-EVs), as nano- and micron-sized heterogeneous vesicles secreted by MSCs, are the main medium for information exchange between MSCs and injured tissue and organ, playing an important role in repairing tissue and organ injury. EVs include exosomes, microvesicles and so on. They are rich with various proteins, nucleic acids, and lipids. Now, EVs are considered as a new way of cell-to-cell communication. EVs mainly induce regeneration and therapeutic effects in different tissues and organs through the biomolecules they carry. The surface membrane protein or loaded protein and nucleic acid molecules carried by EVs, can activate the signal transduction of target cells and regulate the biological behavior of target cells after binding and cell internalization. MSC-EVs can promote the development of pulmonary vessels and alveoli and reduce pulmonary hypertension (PH) and inflammation and play an important role in the repair of lung injury in BPD. The regeneration potential of MSC-EVs is mainly due to the regulation of cell proliferation, survival, migration, differentiation, angiogenesis, immunoregulation, anti-inflammatory, mitochondrial activity and oxidative stress. As a new type of cell-free therapy, MSC-EVs have non-immunogenic, and are small in size and go deep into most tissues. What’s more, it has good biological stability and can be modified and loaded with drugs of interest. Obviously, MSC-EVs have a good application prospect in the treatment of lung injury and BPD. However, there are still many challenges to make MSC-EVs really enter clinical application.

Backgroud: Bronchopulmonary dysplasia (BPD) is one of the most important complications plaguing neonates and can lead to a variety of sequelae. the ability of the HIF-1α/VEGF signaling pathway to promote angiogenesis has an important role in neonatal lung development., Method: Newborn rats were exposed to 85% oxygen. The effects of hyperoxia exposure on Pleomorphic Adenoma Gene like-2 (PLAGL2) and the HIF-1α/VEGF pathway in rats lung tissue were assessed through immunofluorescence and Western Blot analysis. In cell experiments, PLAGL2 was upregulated, and the effects of hyperoxia and PLAGL2 on cell viability were evaluated using scratch assays, CCK-8 assays, and EDU staining. The role of upregulated PLAGL2 in the HIF-1α/VEGF pathway was determined by Western Blot and RT-PCR. Apoptosis and ferroptosis effects were determined through flow cytometry and viability assays., Results: Compared with the control group, the expression levels of PLAGL2, HIF-1α, VEGF, and SPC in lung tissues after 3, 7, and 14 days of hyperoxia exposure were all decreased. Furthermore, hyperoxia also inhibited the proliferation and motility of type II alveolar epithelial cells (AECII) and induced apoptosis in AECII. Upregulation of PLAGL2 restored the proliferation and motility of AECII and suppressed cell apoptosis and ferroptosis, while the HIF-1α/VEGF signaling pathway was also revived., Conclusions: We confirmed the positive role of PLAGL2 and HIF-1α/VEGF signaling pathway in promoting BPD in hyperoxia conditions, and provided a promising therapeutic targets.

Invasive mechanical ventilation and oxygen toxicity are postnatal contributors to chronic lung disease of prematurity, also known as bronchopulmonary dysplasia (BPD). Cyfra 21-1 is a soluble fragment of cytokeratin 19, which belongs to the cytoskeleton stabilizing epithelial intermediate filaments. As a biomarker of structural integrity, Cyfra 21-1 might be associated with airway injury and lung hypoplasia in neonates. Serum Cyfra 21-1 concentrations for 80 preterm and 80 healthy term newborns were measured within 48 h after birth. Preterm infants with the combined endpoint BPD/mortality had significantly higher Cyfra 21-1 levels compared with those without fulfilling BPD/mortality criteria (P = 0.01). Also, severe RDS (>grade III) was associated with higher Cyfra levels (P = 0.01). Total duration of oxygen therapy was more than five times longer in neonates with high Cyfra 21-1 levels (P = 0.01). Infants with higher Cyfra 21-1 values were more likely to receive mechanical ventilation (50% vs. 17.5%). However, the duration of mechanical ventilation was similar between groups. The median Cyfra value was 1.93 ng/mL (IQR: 1.68-2.53 ng/mL) in healthy term neonates and 8.5 ng/mL (IQR: 3.6-16.0 ng/mL) in preterm infants. Using ROC analysis, we calculated a Cyfra cutoff > 8.5 ng/mL to predict BPD/death with an AUC of 0.795 (P = 0.004), a sensitivity of 88.9%, and a specificity of 55%. Mortality was predicted with a cutoff > 17.4 ng/mL (AUC: 0.94; P = 0.001), a sensitivity of 100%, and a specificity of 84%. These findings suggest that Cyfra 21-1 concentration might be useful to predict poor outcome in premature infants. [ABSTRACT FROM AUTHOR]