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Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in interorgan communication in diverse pathological processes. ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of the alveolar macrophage (AM) markers CD11b, CD11c, and CD206 as well as ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction of inspired oxygen therapy (HO2⩾30%) had increased concentrations of AM-derived EV-ASC compared with infants on lower fraction of inspired oxygen (LO2<30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood–brain barrier, and the EVs from infants on HO2 caused inflammation, reduced cell survival, and increased cell death, with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain cross-talk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Hospital‐level and international variations exist in the management strategies of bronchopulmonary dysplasia (BPD). However, studies evaluating hospital‐level variations in the respiratory outcomes of pre‐term infants associated with differing management strategies of BPD are lacking.Herein, we aimed to assess inter‐hospital variations in the respiratory outcomes of BPD in very pre‐term and extremely pre‐term infants.In this cohort study, the administrative claims and discharge summary data were extracted from 276 hospitals in Japan between April 2014 and March 2016. This study assessed neonates of a gestational age of 22–31 weeks old, who had been hospitalised for ≥7 days.The primary outcome was a BPD defined using any respiratory support, such as supplemental oxygen, high‐flow nasal cannula, CPAP, or mechanical ventilation at 36 weeks PMA. The median odds ratio (MOR) was calculated using a multilevel logistic regression model, including baseline characteristics, comorbidities, and treatment as covariates, to evaluate the inter‐hospital variation of the outcome.Of the 8143 neonates from across 132 hospitals, 53.7% were male, with a mean gestational age (standard deviation) of 28.0 (2.5)‐weeks‐old and birthweight of 1086 (386) g. Among these patients, BPD occurred in 2737 (33.6%). The MOR was 2.49, representing the median value of odds ratios when comparing two neonates with identical covariates from hospitals with high and low propensity for the outcomes to occur.Outcome variations in the BPD were observed among hospitals in Japan, even after adjusting for individual factors, including gestational age, birthweight, comorbidities, and treatments. Thus, in Japan, developing strategies is essential to decrease the BPD rates, while minimising inter‐hospital heterogeneity, to improve the healthcare quality for pre‐term neonates. [ABSTRACT FROM AUTHOR]

Background: Antenatal corticosteroids (ACS) are administered to prevent neonatal complications and death in women at risk of imminent preterm birth. Internationally, the optimal interval from ACS to delivery (ACS-to-delivery interval) is within seven days; however, evidence in Asian populations specifically is limited. This study aimed to investigate the association between ACS-to-delivery interval and the incidence of neonatal complications in Japan. Methods: This retrospective observational study enrolled singleton neonates born preterm at < 32 weeks of gestational age between 2012 and 2020 at two tertiary centers. A total of 625 neonates were divided into the following four groups according to the timing of ACS (measured in days): no ACS (n = 145), partial ACS (n = 85), ACS 1–7 (n = 307), and ACS ≥ 8 (n = 88). The following outcomes were compared between the groups: treated respiratory distress syndrome (RDS), severe intraventricular hemorrhage (IVH), treated patent ductus arteriosus (PDA), necrotizing enterocolitis, sepsis, bronchopulmonary dysplasia (BPD), treated retinopathy of prematurity (ROP), periventricular leukomalacia, and death discharge. Results: The ACS 1–7 group had significantly decreased adjusted odds ratios (ORs) for treated RDS (0.37 [95% confidence interval: 0.23, 0.57]), severe IVH (0.21 [0.07, 0.63]), treated PDA (0.47 [0.29, 0.75]), and treated ROP (0.50 [0.25, 0.99]) compared with the no ACS group. The ACS ≥ 8 group also showed significantly reduced adjusted ORs for RDS (0.37 [0.20, 0.66]) and treated PDA (0.48 [0.25, 0.91]) compared with the no ACS group. However, the adjusted ORs for BPD significantly increased in both the ACS 1–7 (1.86 [1.06, 3.28]) and ACS ≥ 8 groups (2.94 [1.43, 6.05]) compared to the no ACS group. Conclusions: An ACS-to-delivery interval of 1–7 days achieved the lowest incidence of several complications in preterm neonates born at < 32 weeks of gestational age. Some of the favorable effects of ACS seem to continue even beyond ≥ 8 days from administration. In contrast, ACS might be associated with an increased incidence of BPD, which was most likely to be prominent in neonates delivered ≥ 8 days after receiving ACS. Based on these findings, the duration of the effect of ACS on neonatal complications should be studied further. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is the most common lung complication of prematurity. Despite extensive research, our understanding of its pathophysiology remains limited, as reflected by the stable prevalence of BPD. Prematurity is the primary risk factor for BPD, with oxidative stress (OS) and inflammation playing significant roles and being closely linked to premature birth. Understanding the interplay and temporal relationship between OS and inflammation is crucial for developing new treatments for BPD. Animal studies suggest that OS and inflammation can exacerbate each other. Clinical trials focusing solely on antioxidants or anti-inflammatory therapies have been unsuccessful. In contrast, vitamin A and caffeine, with antioxidant and anti-inflammatory properties, have shown some efficacy, reducing BPD by about 10%. However, more than one-third of very preterm infants still suffer from BPD. New therapeutic agents are needed. A novel tripeptide, N-acetyl-lysyltyrosylcysteine amide (KYC), is a reversible myeloperoxidase inhibitor and a systems pharmacology agent. It reduces BPD severity by inhibiting MPO, enhancing antioxidative proteins, and alleviating endoplasmic reticulum stress and cellular senescence in a hyperoxia rat model. KYC represents a promising new approach to BPD treatment. [ABSTRACT FROM AUTHOR]

Background: To evaluate the impact of implementation of 2019 European respiratory distress syndrome (RDS) guidelines on the incidence of bronchopulmonary dysplasia (BPD). Method: We retrospectively collected the clinical data of very preterm infants (VPIs) born before 32 gestational weeks from January 1st 2018 to December 31st 2021. VPIs were divided into group A and group B according to their birth date which was before or at/after January 1st 2020, when the 2019 European RDS guidelines were introduced. BPD is considered as primary outcome. We statistically analyzed all the data, and we compared the general characteristics, ventilation support, medication, nutrition and the outcomes between the two groups. Results: A total of 593 VPIs were enrolled, including 380 cases in group A and 213 cases in group B. There were no statistic differences regarding to gender ratio, gestational age, birth weight and delivery mode between the two groups. Compared with group A, group B showed higher rate of antenatal corticosteroid therapy (75.1% vs. 65.5%). The improvement of ventilation management in these latter patients included lower rate of invasive ventilation (40.4% vs. 50.0%), higher rate of volume guarantee (69.8% vs. 15.3%), higher positive end expiratory pressure (PEEP) [6 (5, 6) vs. 5 (5, 5) cmH2O] and higher rate of synchronized nasal intermittent positive pressure ventilation (sNIPPV) (36.2% vs. 5.6%). Compared with group A, group B received higher initial dose of pulmonary surfactant [200 (160, 200) vs. 170 (130, 200) mg/Kg], shorter antibiotic exposure time [13 (7, 23) vs. 17 (9, 33) days], more breast milk (86.4% vs. 70.3%) and earlier medication for hemodynamically significant patent ductus arteriosus (hsPDA) treatment [3 (3, 4) vs. 8 (4, 11) days] (p < 0.05). As the primary outcome, the incidence of BPD was significantly decreased (16.9% vs. 24.2%) (p < 0.05), along with lower extrauterine growth retardation (EUGR) rate (39.0% vs. 59.7%), while there were no statistic differences regarding to other secondary outcomes, including mortality, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of preterm (ROP) and necrotizing enterocolitis (NEC). However, in the subgroups of infants less than 28 gestational weeks or infants less than 1,000 g, the incidence of BPD was not significantly decreased (p > 0.05). Conclusions: After implementation of 2019 European RDS guidelines, the overall incidence of BPD was significantly decreased in VPIs. Continuous quality improvement is still needed in order to decrease the incidence of BPD in smaller infants who are less than 28 gestational weeks or less than 1,000 g. [ABSTRACT FROM AUTHOR]

Objective This study aimed to describe target oxygen saturation (SpO 2) ranges used for premature infants in United States' neonatal intensive care units (NICUs) and to describe if these target SpO 2 ranges have changed in recent years. Study Design A 29-question survey focused on target SpO 2 practices and policies was distributed via the NICU medical directors listservs for the American Academy of Pediatrics Section of Neonatal-Perinatal Medicine and Pediatrix Medical Group between August and October of 2021. Results were collected via Research Electronic Data Capture (REDCap). Results We received responses representing 170 unique, levels 2, 3, and 4 NICUs from 36 states. Most NICUs (130, 78%) have recently changed their SpO 2 targets in response to target SpO 2 clinical trials. Over time, the most commonly reported target SpO 2 range has shifted from 88–92% to 90–95. Of NICUs that changed limits, the most common lower SpO 2 limits increased from 88 to 90% and the upper SpO 2 limits changed from 92 to 95%. The interquartile range for lower SpO 2 limit shifted from 85–88% to 88–90% and the IQR for upper SpO 2 limit decreased from 92–95 to 94–95%. Most NICUs had designated conditions that would allow for deviations from standard target SpO 2 ranges. These most commonly include pulmonary hypertension (152, 95%), severe bronchopulmonary dysplasia (81, 51%), and retinopathy of prematurity (51, 32%). Conclusion Oxygen saturation limits have changed over time with an overall increase in targeted SpO 2. However, there remains considerable interunit variation in SpO 2 policies. There is a need to achieve consensus to optimize clinical outcomes. Key Points What are the SpO 2 ranges in United States' NICUs? There is a shift in SpO 2 ranges for preterm infants in NICUs across United States. Variability still persists in SpO 2 ranges for preterm infants in United States' NICUs. [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]

Rationale: The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of extreme prematurity. BPD results in impaired lung alveolar and vascular development and long-term respiratory morbidity, for which only supportive therapies exist. Umbilical cord–derived mesenchymal stromal cells (UC-MSCs) improve lung structure and function in experimental BPD. Results of clinical trials with MSCs for many disorders do not yet match the promising preclinical studies. A lack of specific criteria to define functionally distinct MSCs persists. Objectives: To determine and correlate single-cell UC-MSC transcriptomic profiles with therapeutic potential. Methods: UC-MSCs from five term donors and human neonatal dermal fibroblasts (HNDFs; control cells of mesenchymal origin) transcriptomes were investigated using single-cell RNA sequencing (scRNA-seq) analysis. The lung-protective effect of UC-MSCs with a distinct transcriptome and control HNDFs was tested in vivo in hyperoxia-induced neonatal lung injury in rats. Measurements and Main Results: UC-MSCs showed limited transcriptomic heterogeneity but were different from HNDFs. Gene Ontology enrichment analysis revealed distinct (progenitor-like and fibroblast-like) UC-MSC subpopulations. Only treatment with progenitor-like UC-MSCs improved lung function and structure and attenuated pulmonary hypertension in hyperoxia-exposed rat pups. Moreover, scRNA-seq identified major histocompatibility complex class I as a molecular marker of nontherapeutic cells and associated with decreased lung retention. Conclusions: UC-MSCs with a progenitor-like transcriptome, but not with a fibroblast-like transcriptome, provide lung protection in experimental BPD. High expression of major histocompatibility complex class I is associated with reduced therapeutic benefit. scRNA-seq may be useful to identify subsets of MSCs with superior repair capacity for clinical application. [ABSTRACT FROM AUTHOR]

Prematurity is associated with lower exercise capacity, which relies on the integrity of the cardiovascular, pulmonary, and skeletal muscle systems. Our animal model mimicking prematurity-associated conditions showed altered muscle composition and atrophy in adulthood. This study aimed to compare muscle composition and strength in adults born preterm versus full-term controls. This observational cohort study recruited 55 adults born preterm, ≤ 29 weeks’ of gestation and 53 full-term controls who underwent musculoskeletal ultrasound imaging to assess morphology of the rectus femoris at rest and during a maximal voluntary contraction. Maximal voluntary contraction of the hands and legs were measured by manual dynamometry. In adults born preterm, there was lower muscle strength (handgrip: − 4.8 kg, 95% CI − 9.1, − 0.6; knee extensor: − 44.6 N/m, 95% CI − 63.4, − 25.8) and smaller muscle area (− 130 mm2, 95% CI − 207, − 53), which was more pronounced with a history of bronchopulmonary dysplasia. Muscle stiffness was increased in the preterm versus term group (0.4 m/s, 95% CI 0.04, 0.7). Prematurity is associated with alterations in skeletal muscle composition, area, and function in adulthood. These findings highlight the necessity to implement preventive and/or curative approaches to improve muscle development and function following preterm birth to enhance overall health in this population. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) ranks among preterm infants’ most common and severe respiratory diseases. Lung ultrasound scores (LUS) play a vital role in predicting early BPD and guiding treatment and intervention strategies for affected patients. Performed a meta-analysis to assess the diagnostic LUS for newborns with BPD. Online electronic databases such as MEDLINE, CINAHL, the Cochrane Library, and Web of Science were used to retrieve relevant research until May 2023. A total of 117 literatures were collected, and ten eligible articles were selected for meta-analysis. Meta-analysis was performed on 10 studies (1274 neonates). LUS at 7 days after birth (7 days of life, DOL 7) showed good diagnostic accuracy for any type of BPD, moderate and severe BPD. DOL 7 was more accurate in predicting all types of BPD (AUC = 0.87, sensitivity = 0.75, specificity = 0.83) than moderate and severe BPD (AUC = 0.80, sensitivity = 0.69, specificity = 0.79). There was no statistical significance between DOL 7 and DOL 14 in their accuracy for predicting all types of BPD (difference in AUC = 0.04, p= 0.068). There was no notable distinction between DOL 7 and DOL 14 in their accuracy for predicting moderate and severe BPD (difference in AUC =-0.04, p= 0.104). The diagnostic efficacy of LUS on DOL 7 in predicting the occurrence of all types of BDP and moderate-severe BPD is determined. This will facilitate rapid and accurate detection and timely treatment, thereby reducing the risk of neonatal mortality and sequelae. [ABSTRACT FROM AUTHOR]

Background: Premature infants requiring mechanical ventilation and supplemental oxygen for respiratory support are at increased risk for bronchopulmonary dysplasia (BPD), wherein inflammation have been proposed as a driver of hyperoxia-induced injuries, including persistent loss of endothelial progenitor cells (EPCs), impaired vascularization and eventual alveolar simplification in BPD lungs. However, the underlying mechanisms linking these phenomena remain poorly defined. Methods: We used clodronate liposomes to deplete macrophages in a mouse model of neonatal hyperoxia-induced lung injury to evaluate if EPC loss in BPD lungs could be an effect of macrophage infiltration. We further generated in vitro culture systems initiated with cord blood (CB)-derived CD34+ EPCs and neonatal macrophages either polarized from CB-derived monocytes or isolated from tracheal aspirates of human preterm infants requiring mechanical ventilation and oxygen supplementation, to identify EV-transmitted molecular mechanism that is critical for inhibitory actions of hyperoxic macrophages on EPCs. Results: Initial experiments using mouse model identified the crucial role of macrophage infiltration in eliciting significant reduction of c-Kit+ EPCs in BPD lungs. Further examination of this concept in human system, we found that hyperoxia-exposed neonatal macrophages hamper human CD34+ EPC maintenance and impair endothelial function in the differentiated progeny via the EV transmission of miR-23a-3p. Notably, treatment with antagomiR-23a-3p to silence miR-23a-3p in vivo enhances c-Kit+ EPC maintenance, and increases capillary density, and consequently mitigates simplified alveolarization in BPD lungs. Conclusion: Our findings highlight the importance of pulmonary intercellular communication in the pathophysiology of BPD, by identifying a linkage through vesicle transfer of miR-23a-3p from hyperoxic macrophages to EPCs, and thus demonstrating potential for novel therapeutic target in BPD. [ABSTRACT FROM AUTHOR]

Background: Chronic lung disease of prematurity, called bronchopulmonary dysplasia (BPD), lacks effective therapies, stressing the need for preclinical testing systems that reflect human pathology for identifying causal pathways and testing novel compounds. Alveolar organoids derived from human pluripotent stem cells (hPSC) are promising test platforms for studying distal airway diseases like BPD, but current protocols do not accurately replicate the distal niche environment of the native lung. Herein, we investigated the contributions of cellular constituents of the alveolus and fetal respiratory movements on hPSC-derived alveolar organoid formation. Methods: Human PSCs were differentiated in 2D culture into lung progenitor cells (LPC) which were then further differentiated into alveolar organoids before and after removal of co-developing mesodermal cells. LPCs were also differentiated in Transwell® co-cultures with and without human fetal lung fibroblast. Forming organoids were subjected to phasic mechanical strain using a Flexcell® system. Differentiation within organoids and Transwell® cultures was assessed by flow cytometry, immunofluorescence, and qPCR for lung epithelial and alveolar markers of differentiation including GATA binding protein 6 (GATA 6), E-cadherin (CDH1), NK2 Homeobox 1 (NKX2-1), HT2-280, surfactant proteins B (SFTPB) and C (SFTPC). Results: We observed that co-developing mesenchymal progenitors promote alveolar epithelial type 2 cell (AEC2) differentiation within hPSC-derived lung organoids. This mesenchymal effect on AEC2 differentiation was corroborated by co-culturing hPSC-NKX2-1+ lung progenitors with human embryonic lung fibroblasts. The stimulatory effect did not require direct contact between fibroblasts and NKX2-1+ lung progenitors. Additionally, we demonstrate that episodic mechanical deformation of hPSC-derived lung organoids, mimicking in situ fetal respiratory movements, increased AEC2 differentiation without affecting proximal epithelial differentiation. Conclusion: Our data suggest that biophysical and mesenchymal components promote AEC2 differentiation within hPSC-derived distal organoids in vitro. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in infants and the most frequent adverse outcome of premature birth, despite major efforts to minimize injury. It is thought to result from aberrant repair response triggered by either prenatal or recurrent postnatal injury to the lungs during development. Intrauterine inflammation is an important risk factor for prenatal lung injury, which is also increasingly linked to BPD. However, the specific mechanisms remain unclear. This review summarizes clinical and animal research linking intrauterine inflammation to BPD. We assess how intrauterine inflammation affects lung alveolarization and vascular development. In addition, we discuss prenatal therapeutic strategies targeting intrauterine inflammation to prevent or treat BPD. [ABSTRACT FROM AUTHOR]

Introduction: This retrospective observational study was designed to examine early vs. late steroid use and if there was an impact on the incidence of bronchopulmonary dysplasia (BPD) and growth in our NICU. Methods: Between July 2019 and August 2021, 175 infants <30 weeks gestational age and/or 1500 grams at birth were enrolled in our retrospective observational study. Infants were classified into three cohorts based on initial steroid exposure and timing: no exposure, ≤21 days of life (DOL), and >21 DOL. We classified BPD using support-based criteria at 36 weeks and evaluated differences between the steroid groups using a chi-square test. Results: There were no statistical differences observed in infants who began steroids before or after DOL 21 concerning BPD or support required at discharge. ΔZ-scores from birth to DOL 42 demonstrated similar growth velocity between all cohorts (P=0.199). Conclusions: No significant difference was found in BPD outcomes when comparing early (≤21) vs. late postnatal steroid initiation (>21 days). Growth velocities were not adversely impacted by steroid exposure. [ABSTRACT FROM AUTHOR]

Background: Bronchopulmonary dysplasia (BPD) is the most common long-term complication of extreme preterm birth. It is associated with lifelong multisystemic consequences. Advances in neonatal care have not reduced the incidence of BPD and no new breakthrough therapy has been successfully translated into the clinic in recent decades. Summary: Current evidence demonstrates benefit of new modalities of first-line noninvasive positive pressure ventilation, selected strategies of postnatal corticosteroid administration, alternative surfactant delivery methods, and caffeine. Promising emerging therapies that are being translated from bench to bedside include mesenchymal stromal cells (MSCs), insulin-like growth factor 1/binding protein-3 (IGF-1/IGFBP-3), and interleukin 1 receptor (IL-1R) antagonist (anakinra). Strong preclinical data support efficacy of MSCs in attenuating neonatal lung injury. Early-phase clinical trials have already demonstrated safety and feasibility in preterm infants. Phase II studies that aimed at demonstrating efficacy are currently underway. Both IGF-1/IGFBP-3 and IL-1R antagonist present with biological plausibility and animal data of efficacy. Phase I/II clinical trials are currently recruiting patients. Key Messages: Early noninvasive respiratory support, late systemic dexamethasone, less invasive surfactant administration, and caffeine are proven strategies in reducing the risk of BPD. Potentially disruptive therapies – MSCs, IGF-1/IGFBP-3, and anakinra – are being advanced to clinical trials and their efficacy in remains to be demonstrated. Continued research efforts are needed in the growing population of extremely preterm infants at risk of developing BPD. [ABSTRACT FROM AUTHOR]

Background:Ureaplasma species are considered commensals of the adult urogenital tract. Yet, in pregnancy, Ureaplasma parvum and Ureaplasma urealyticum have been associated with chorioamnionitis and preterm birth. In preterm infants, Ureaplasma respiratory tract colonization has been correlated with the development of bronchopulmonary dysplasia and has been implicated in the pathogenesis of other complications of prematurity. Controversies on the impact of Ureaplasma exposure on neonatal morbidity, however, remain, and recommendations for screening practices and therapeutic management in preterm infants are missing. Summary: In this review, we outline clinical and experimental evidence of Ureaplasma-driven fetal and neonatal morbidity, critically examining inconsistencies across some of the existing studies. We explore underlying mechanisms of Ureaplasma-associated neonatal morbidity and discuss gaps in the current understanding including the interplay between Ureaplasma and the maternal urogenital tract and the preterm airway microbiome. Ultimately, we highlight the importance of adequate diagnostics and review the potential efficacy of anti-infective therapies. Key Messages: There is strong evidence that perinatal Ureaplasma exposure is causally related to the development of bronchopulmonary dysplasia, and there are conclusive data of the role of Ureaplasma in the pathogenesis of neonatal central nervous system infection. Observational and experimental findings indicate immunomodulatory capacities that might promote an increased risk of secondary infections. The burden of Ureaplasma exposure is inversely related to gestational age – leaving the tiniest babies at highest risk. A better knowledge of contributing pathogen and host factors and modulating conditions remains paramount to define screening and treatment recommendations allowing early intervention in preterm infants at risk. [ABSTRACT FROM AUTHOR]

Background: Despite the increasing use of non-invasive support modalities, many preterm infants still need invasive mechanical ventilation. Mechanical ventilation can lead to so-called ventilator-induced lung injury, which is considered an important risk factor in the development of bronchopulmonary dysplasia. Understanding the concepts of lung protective ventilation strategies is imperative to reduce the risk of BPD. Summary: Overdistension, atelectasis, and oxygen toxicity are the most important risk factors for VILI. A lung protective ventilation strategy should therefore optimize lung volume (resolve atelectasis), limit tidal volumes, and reduce oxygen exposure. Executing such a lung protective ventilation strategy requires basic knowledge on neonatal lung physiology. Studies have shown that volume-targeted ventilation (VTV) stabilizes tidal volume delivery, reduces VILI, and reduces BPD in preterm infants with respiratory distress syndrome. High-frequency ventilation (HFV) also reduces BPD although the effect is modest and inconsistent. It is unclear if these benefits also apply to infants with more heterogeneous lung disease. Key Messages: Understanding basic physiology and the concept of ventilator-induced lung injury is essential in neonatal mechanical ventilation. Current evidence suggests that the principles of lung protective ventilation are best captured by VTV and HFV. [ABSTRACT FROM AUTHOR]

Background: The rates of major neonatal morbidities, such as bronchopulmonary dysplasia, necrotizing enterocolitis, preterm white matter disease, and retinopathy of prematurity, remain high among surviving preterm infants. Exposure to inflammatory stimuli and the subsequent host innate immune response contribute to the risk of developing these complications of prematurity. Notably, the burden of inflammation and associated neonatal morbidity is inversely related to gestational age – leaving primarily but not exclusively the tiniest babies at highest risk. Summary: Avoidance, prevention, and treatment of inflammation to reduce this burden remain a major goal for neonatologists worldwide. In this review, we discuss the link between the host response to inflammatory stimuli and the disease state. We argue that inflammatory exposures play a key role in the pathobiology of preterm birth and that preterm neonates hereafter are highly susceptible to immune stimulation not only from their surrounding environment but also from therapeutic interventions employed in clinical care. Using bronchopulmonary dysplasia as an example, we report clinical studies demonstrating the potential utility of targeting inflammation to prevent this neonatal morbidity. On the contrary, we highlight limitations in our current understanding of how inflammation contributes to disease prevention and treatment. Key Message: To be successful in preventing and treating inflammation-driven morbidity in neonatal intensive care, it may be necessary to better identify at-risk patients and pair therapeutic interventions to key pathways and mediators of inflammation-associated neonatal morbidity identified in pre-clinical and translational studies. [ABSTRACT FROM AUTHOR]

The 18-kDa isoform of basic fibroblast growth factor (bFGF/FGF2) lacks a conventional signal peptide sequence and is exported by a novel membrane-associated transport pathway. Extracellular vesicles (EVs) are increasingly recognized as mediators of intercellular communication in the lung, and our prior work demonstrates that EVs carry cargo that contributes to hyperoxic lung injury and are biomarkers for bronchopulmonary dysplasia. We used primary human bronchial epithelial (HBE), pulmonary artery endothelial (HPAE), and fibroblast (HNF) cells to determine whether FGF2 was secreted in EVs. EVs were isolated by ultracentrifugation from HBE, HPAE, and HNF exposed to either normoxia or hyperoxia, followed by nanoparticle tracking analysis and electron microscopy. Hyperoxia exposure increased the total EV number. All three cell types released FGF2-18kDa both directly into the extracellular environment (secretome), as well as in EVs. HBE released more FGF2-18kDa in EVs during hyperoxia, and these were internalized and localized to both nuclei and cytoplasm of recipient cells. By co-immunoprecipitation, we identified potential binding partners of FGF2-18kDa in the nuclei, including histone 1.2 (H1.2) binding protein, that may mediate downstream effects that do not involve FGF2 binding to cell surface receptors. FGF2-18kDa interaction with H1.2 binding protein may indicate a mechanism by which FGF2 secreted in EVs modulates cellular processes. FGF2 was also found to increase angiogenesis by Matrigel assay. Further studies are necessary to determine the biological relevance of FGF2 in EVs as modulators of lung injury and disease. NEW & NOTEWORTHY: We found that multiple lung cell types release basic fibroblast growth factor (FGF2)-18kDa both directly into the extracellular environment (secretome), as well as in extracellular vesicles (EVs). Bronchial epithelial cells released more FGF2-18kDa in EVs during hyperoxia, which could be internalized rapidly by recipient cells. We also identified potential binding partners of FGF2-18kDa in nuclei that may mediate downstream effects that do not involve FGF2 binding to cell surface receptors. We also confirmed a potential angiogenic role for FGF2-18kDa. [ABSTRACT FROM AUTHOR]

Objective: Bronchopulmonary dysplasia (BPD) is among the most common complications of prematurity and is associated with high morbidity and mortality rates. Acute kidney injury (AKI) is also commonly observed in premature infants and significantly increases morbidity and mortality. Studies have shown that systemic changes in AKI may also trigger lung damage. Methods: This study aimed to determine the effects of AKI on the development of BPD in preterm infants with a postconceptional age of ≤32 weeks and/or birth weight of ≤1500 grams. The relationship between demographic features and accompanying perinatal and postnatal morbidities among the patients was investigated. Results: The incidence of BPD in infants with AKI was 52.6% (10 of 19 infants) and 38.3% (61 of 140 infants) in infants without AKI. In infants who developed BPD, the rate of AKI did not vary notably between babies born at ≤28 weeks and those born at >28 weeks [n=9, 17.3% (9 of 52 infants) and n= 1, 5.3%, (1 of 19 infants) respectively] of gestation (p>0.05). Conclusions: AKI was associated with a greater need for resuscitation at birth, a greater need for invasive mechanical ventilation, fewer ventilator-free days, and a higher incidence of sepsis, patent ductus arteriosus, and necrotizing enterocolitis in premature infants. It was also more frequently associated with fluid-electrolyte imbalance, blood pressure, and hemodynamic disorders in the first postnatal week. The rate of BPD development was higher in infants with AKI, but this disparity was not statistically notable (p>0.05). [ABSTRACT FROM AUTHOR]

Background: Concerns are prevalent about preterm infant long‐term growth regarding plotting low on growth charts at discharge, stunting, underweight, high body fat and subsequent cardiometabolic morbidities. Objectives: To examine (a) longitudinal growth patterns of extremely and very preterm infants to 3 years corrected age (CA) (outcome), categorised by their birthweight for gestational age: small, appropriate and large for gestational age (SGA, AGA and LGA, respectively) (exposure); and (b) the ability of growth faltering (<−2 z‐scores) to predict suboptimal cognitive scores at 3 years CA. Methods: Post‐discharge head, length, weight and weight‐4‐length growth patterns of the PreM Growth cohort study infants born <30 weeks and < 1500 g, who had dietitian and multi‐disciplinary support before and after discharge, were plotted against the World Health Organization growth standard. Infants with brain injuries, necrotising enterocolitis and bronchopulmonary dysplasia were excluded. Results: Of the included 405 infants, the proportions of infants with anthropometric measures > − 2 z‐scores improved with age. The highest proportions <−2 z‐scores for length (24.2%) and weight (24.0%) were at 36 gestational weeks. The proportion with small heads was low by 0 months CA (1.8%). By 3 years CA, only a few children plotted lower than −2 z‐scores for length, weight‐4‐length and weight (<6%). After zero months CA, high weight‐4‐length and body mass index > + 2 z‐scores were rare (2.1% at 3 years CA). Those born SGA had higher proportions with shorter heights (16.7% vs. 5.2%) and lower weights (27.8% vs. 3.5%) at 3 years CA compared to those born AGA. The ability of growth faltering to predict cognitive scores was limited (AUROC 0.42, 95% CI 0.39, 0.45 to 0.52, 95% CI 0.41, 0.63). Conclusions: Although children born <30 weeks gestation without major neonatal morbidities plot low on growth charts at 36 weeks CA most catch up to growth chart curves by 3 years CA. [ABSTRACT FROM AUTHOR]

In 2016, the Spanish Research Group on Bronchopulmonary Dysplasia (BPD) (GEIDIS) established a national registry with participation of 66 hospitals to collect information on clinical characteristics and long-term outcomes of BPD infants into adulthood. The aim of this observational study is to examine forced spirometry data in early childhood and to assess their correlation with the respiratory support required at 36 weeks postmenstrual age (PMA). The study analyzed data from preterm infants with BPD born between January 2016 and December 2017 who underwent forced spirometry at 5–7 years of age. Statistical analyses were conducted to investigate the relationships between spirometry results, perinatal factors, and the required respiratory support at 36 weeks PMA. The study involved 143 patients with a median gestational age (GA) of 27.3 weeks (range 25.7–28.7) and a median weight of 880 g (range 740–1135). Abnormal spirometry results were observed in 39.2% (56) of the patients. Among patients diagnosed with BPD type 3, those requiring over 30% oxygen at 36 weeks PMA exhibited an increased risk of abnormal spirometry results (OR 4.48; 95% CI 1.11–18.13) compared to those requiring positive pressure with less than 30% oxygen. In addition, this subgroup had a higher risk of developing a restrictive-mixed pattern compared to those with BPD type 1 (OR 10.65; 95% CI 2.06–54.98) and BPD type 2 (OR 6.76; 95% CI 1.09–42.06). No significant differences were found in the incidence of an obstructive pattern between BPD types. Conclusion: The requirement of more than 30% oxygen at 36 weeks PMA serves as a risk indicator for pulmonary function impairment in school-aged children with BPD. These findings suggest persistent airway and parenchymal injury in this specific patient population, and highlight the importance of careful monitoring to evaluate their long-term effects on lung function. What is Known: • Premature patients with bronchopulmonary dysplasia (BPD) may present abnormalities in pulmonary function tests during school age. However, the predictive accuracy of consensus BPD severity classification remains uncertain. What is New: • The requirement of more than 30% oxygen at 36 weeks postmenstrual age (PMA) indicates a potential risk of pulmonary function impairment in school-aged children with BPD. Additionally, a significant correlation has been observed between a restrictive-mixed pattern with exposure to mechanical ventilation and the development of severe forms of BPD. [ABSTRACT FROM AUTHOR]

Introduction: Treatment of oligohydramnios in the mid‐trimester is challenging, because of the high incidence of adverse perinatal outcomes mainly due to bronchopulmonary dysplasia. Antenatal amnioinfusion has been proposed as a possible treatment for oligohydramnios with intact amnions, but there are few relevant studies. This study aimed to evaluate the effectiveness of transabdominal amnioinfusion in the management of oligohydramnios without fetal lethal malformations in the second and early third trimesters. Material and Methods: It is a historical cohort study. A total of 79 patients diagnosed with oligohydramnios at 18–32 weeks gestation were enrolled. In the amnioinfusion group (n = 39), patients received transabdominal amnioinfusion with the assistance of real‐time ultrasound guidance. In the expectant group (n = 41), patients were treated with 3000 mL of intravenous isotonic fluids daily. The perioperative complications and perinatal outcomes were analyzed. Results: Compared with the expectant group, the delivery latency was significantly prolonged, and the rate of cesarean delivery was significantly reduced in the amnioinfusion group (p < 0.05). Although the rate of intrauterine fetal death was significantly reduced, the incidence of spontaneous miscarriage, premature rupture of membranes (PROMs), and threatened preterm labor were significantly higher in the amnioinfusion group than in the expectant group (p < 0.05). There was no significant difference in terms of perinatal mortality (28.9% vs. 41.4%, p > 0.05). Multivariate logistic regression revealed that amnioinfusion (odds ratio [OR] 0.162, 95% confidence interval [CI] 0.04–0.61, p = 0.008) and gestational age at diagnosis (OR 0.185, 95% CI 0.04–0.73, p = 0.016) were independently associated with neonatal adverse outcomes. Further subgrouping showed that amnioinfusion significantly reduced the frequency of bronchopulmonary hypoplasia for patients ≤26 weeks (26.7% vs. 75.0%, p = 0.021). The rates of other neonatal complications were similar in both groups. Conclusions: Amnioinfusion has no significant effect on improving the perinatal mortality of oligohydramnios in the second and early third trimesters. It may lead to a relatively high rate of PROM and spontaneous abortion. However, amnioinfusion may significantly improve the latency period, the rate of cesarean delivery, and neonatal outcomes of oligohydramnios, especially for women ≤26 weeks with high risk of neonatal bronchopulmonary hypoplasia. [ABSTRACT FROM AUTHOR]

Purpose: Bronchopulmonary dysplasia (BPD) is a respiratory morbidity related to prematurity. Early prediction of BPD allows the selection of patients who would benefit from new therapies. Lung ultrasound (LUS) is a non-invasive diagnostic tool that has proven to be reliable for many neonatal diseases recently. The study aimed to detect the role of LUS in predicting BPD at days 7 and 14 of life in preterm babies. Methods: This was a prospective cohort study that included 95 preterm babies ≤ 34 weeks. Lung ultrasounds were performed on days 7 and 14 of life. Results: The mean gestational age of the studied neonates was 30.25 ± 2.21 weeks. The mean birth weight was 1347.66 ± 432.14 gm. Patients who developed BPD had statistically significantly higher LUS scores on both days 7 and 14 of life. At first examination, a LUS score > 8 showed a sensitivity of 83.33% and a specificity of 60.87%, whereas at follow-up, a LUS score > 8 showed a sensitivity of 76.39% and a specificity of 82.61%. The multivariate logistic regression analysis shows that the most important factors associated with BPD were gestational age ≤ 30 weeks, LUS score at first examination > 8, platelets ≤ 245 × 109/L, segment neutrophils ≤ 42%, and CRP > 5 mg/l. Conclusions: The LUS score predicts BPD at 7 and 14 days of life. LUS scores increased with increasing BPD severity. LUS score > 8 was an independent factor in the prediction of BPD. [ABSTRACT FROM AUTHOR]

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Bronchopulmonary dysplasia (BPD), caused by hyperoxia exposure, is the most common complication affecting preterm infants. The C-X-C motif chemokine ligand 17 (CXCL17) belongs to the chemokine family that plays important roles in various processes, but the function in BPD is unknown. Elevated serum CXCL17 levels were observed in human premature infants with hyperoxia-induced lung injury, suggesting that CXCL17 might be involved in BPD. To further validate our speculation, studies were conducted in a hyperoxia-induced lung injury mouse model and primary murine alveolar epithelial cells Type II (T2AEC) cells exposed to hyperoxia. RT-qPCR and western blot were used to validate CXCL17 expression in newborn mice. Hyperoxia exposure-induced lung injury was determined by assessing the lung wet-weight/dry-weight ratio and histological changes. Oxidative stress and inflammatory factors were examined by ELISA assay and RT-qPCR. Reactive oxygen species (ROS) level was evaluated by DHE staining. Apoptosis was assessed by TUNEL staining and western blot. The results showed that hyperoxia exposure increased CXCL17 levels in newborn mice pups. Hyperoxia exposure increased lung wet-weight/dry-weight ratio, increased alveolar diameter and enlarged alveoli, and reduced surfactant protein C expression. However, recombinant CXCL17 (rCXCL17) treatment alleviated hyperoxia-induced lung injury. rCXCL17 treatment inhibited hyperoxia-induced inflammation, oxidative stress, and apoptosis in neonatal mice. These results were further verified in T2AEC cells. Additionally, rCXCL17 treatment activated the AKT pathway, which is a protective pathway in BPD. Collectively, rCXCL17 alleviates hyperoxia-induced lung injury in neonatal mice by activating the AKT pathway, indicating that CXCL17 may be a promising target for BPD therapy. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids (PUFAs), especially arachidonic acid (ARA) and docosahexaenoic acid (DHA), are extremely important fatty acids for brain development in the fetus and early childhood. Premature infants face challenges obtaining these two fatty acids from their mothers. It has been reported that supplementation with triacylglycerols (TAGs) with an ARA:DHA (w/w) ratio of 2:1 may be optimal for preterm infants, as presented in commercial formulas such as Formulaid™. This study explored methods to produce TAGs with a 2:1 ratio (ARA:DHA), particularly at the more bioavailable sn-2 position of the glycerol backbone. Blending and enzymatic acidolysis of microalgae oil (rich in DHA) and ARA-rich oil yielded products with the desired ARA:DHA ratio, enhancing sn-2 composition compared to Formulaid™ (1.6 for blending and 2.3 for acidolysis versus 0.9 in Formulaid™). Optimal acidolysis conditions were 45 °C, a 1:3 substrate molar ratio, 10% Candida antarctica lipase, and 4 h. The process was reproducible, and scalable, and the lipase could be reused. In vitro digestion showed that 75.5% of the final product mixture was bio-accessible, comprising 19.1% monoacylglycerols, ~50% free fatty acids, 14.6% TAGs, and 10.1% diacylglycerols, indicating better bio-accessibility than precursor oils. [ABSTRACT FROM AUTHOR]

Background: The existing literature lacks conclusive evidence regarding the relationship between bronchopulmonary dysplasia (BPD) and cerebral palsy (CP). This large epidemiological study aimed to explore the co-occurrence of BPD and CP among children. Methods: This retrospective cohort analysis utilized the National Inpatient Sample (NIS) dataset from 2016 to 2019, investigating pediatric patients with BPD and CP diagnoses. Descriptive and inferential statistics, including univariate and multivariate regression analyses, were conducted to explore the association between BPD and CP. Results: Overall, 3,951,039 patients were analyzed. Among them, 28,880 patients had CP (n = 796 with BPD and n = 28,084 without BPD). The rates of intraventricular hemorrhage grade 3 and 4, central nervous system anomalies, chromosomal disorders, retinopathy of prematurity (≥grade 3), periventricular leukomalacia, prematurity, and low birth weight were significantly higher in the CP-with-BPD arm contrasted to the CP-without-BPD arm. Univariate regression demonstrated a significant BPD–CP association (odds ratio [OR] = 7.78, 95% confidence interval [CI]: 7.24–8.37, p < 0.0001). Multivariate analysis, adjusting for various confounders, reinforced this association (OR = 5.70, 95% CI: 5.17–6.28, p < 0.0001). We observed a significant association between increasing prematurity in neonates with BPD and an elevated risk of CP. Conclusions: This nationwide study identified a strong correlation between the co-occurrence of BPD and CP, though it does not establish causality. Rigorous adjustments revealed that patients with BPD appear to have a six-fold increased likelihood of being diagnosed with CP later on, compared to those without BPD. While aligned with the existing literature, this study represents the largest sample size with recommendations for targeted preventive strategies to mitigate the burden of CP. [ABSTRACT FROM AUTHOR]

The gut microbiota undergoes substantial development from birth, and its development in the initial years of life has a potentially lifelong effect on the health of the individual. However, various factors can disrupt the development of the gut microbiota, leading to a condition known as dysbiosis, particularly in preterm infants. Current studies involving adults have suggested that the gut microbiota not only influences the gut but also has multidimensional effects on remote organs; these pathways are often referred to as the gut–organ axis. Imbalance of the gut microbiota may lead to the development of multiple diseases. Recent studies have revealed that gut dysbiosis in preterm infants may cause several acute morbidities—such as necrotizing enterocolitis, late‐onset sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity—and it may also influence long‐term outcomes including neurodevelopment and somatic growth. This review mainly presents the existing evidence regarding the relationships between the gut microbiota and these morbidities in preterm infants and explores the role of the gut–organ axis in these morbidities. This paper thus offers insights into the future perspectives on microbiota interventions for promoting the health of preterm infants. [ABSTRACT FROM AUTHOR]

Abstract Numerous studies have attempted to identify potential biomarkers for early detection of bronchopulmonary dysplasia (BPD) in preterm infants using metabolomics techniques. However, the presence of consistent evidence remains elusive. Our study aimed to conduct a systematic review and meta-analysis to identify differences in small-molecule metabolites between BPD and non-BPD preterm infants. Through meticulous screening of numerous samples, we identified promising candidates, providing valuable insights for future research. We searched PubMed, the Cochrane Library, Embase, Web of Science, China National Knowledge Internet, Wan-fang database, Chinese Science and Technique Journal Database and Chinese Biomedical Literature Database from inception until January 16, 2024. Studies were comprehensively reviewed against inclusion criteria. We included case-control studies and adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Study quality was assessed with the Newcastle-Ottawa scale. We compared the changes in metabolite levels between the BPD and non-BPD preterm infants. A meta-analysis was conducted on targeted metabolomics research data based on the strategy of standardized mean differences (MD) and 95% confidence intervals (CI).Fifteen studies (1357 participants) were included. These clinical-based metabolomics studies clarified 110 differential metabolites between BPD and non-BPD preterm infants. The meta-analysis revealed higher glutamate concentration in the BPD group compared to the non-BPD group (MD = 1, 95% CI 0.59 to 1.41, p

Abstract Background Cytokines and growth factors (GF) have been implicated in the development of retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD). We hypothesize that even small coordinated changes in inflammatory proteins or GFs may reveal changes in underlying regulating mechanisms that do not induce obvious changes in concentration of individual proteins. We therefore applied correlation network analysis of serum factors to determine early characteristics of these conditions. Methods Concentrations of 17 cytokines and five GFs were measured and analysed in blood samples from cord blood, on day one and during the following month in 72 extremely preterm infants. Spearman’s correlation networks distinguishing BPD and severe ROP patients from non-affected were created. Results Most cytokine concentrations correlated positively with each other and negatively with GFs. Very few individual cytokines differed between patients with and without ROP or BPD. However, networks of differently correlated serum factors were characteristic of the diseases and changed with time. In ROP networks, EPO, G-CSF and IL-8 (cord blood), BDNF and VEGF-A (first month) were prominent. In BPD networks, IL-1β, IGF-1 and IL-17 (day one) were noted. Conclusions Network analysis identifies protein signatures related to ROP or BPD in extremely preterm infants. The identified interactions between serum factors are not evident from the analysis of their individual levels, but may reveal underlying pathophysiological mechanisms in the development of these diseases.

Abstract Background Bronchopulmonary dysplasia (BPD) affects up to half of extremely preterm infants, and is associated with adverse long-term respiratory, neurodevelopmental, and educational sequelae and costly health service and family economic outcomes. The NICHD Neonatal Research Network Hydrocortisone for Bronchopulmonary Dysplasia (BPD) Trial evaluated the efficacy and safety of hydrocortisone treatment to prevent BPD in high-risk infants. The trial enrolled 800 very preterm infants with respiratory failure and followed the participants until 2 years corrected age to assess safety of the trial intervention. Longer-term impacts of hydrocortisone exposure and severity of BPD on functional outcomes of high-risk infants remain unknown. The HYdrocortisone for BPD Respiratory and Developmental (HYBRiD) Outcomes Study extends follow-up of all surviving children enrolled in the Hydrocortisone for BPD Trial until early school age. It aims to characterize the childhood functional motor, cognitive, academic, and pulmonary outcomes of this large, well-phenotyped trial cohort. Methods Parents of surviving trial participants complete telephone questionnaires when their children are 3 and 4 years corrected age. A single in-person study visit takes place at early school age (5 years, 0 months to 7 years, 11 months corrected age). Children undergo a multidimensional assessment of functional outcomes and parents complete a battery of questionnaires. In 5 of 19 participating centers, respiratory mechanics are evaluated with impulse oscillometry. Discussion The HYBRiD Outcomes Study will be the largest and most comprehensive evaluation to date of the functional early school age outcomes of children with a history of severe neonatal lung disease and of children exposed to HC during infancy. This will substantially improve understanding of the longer-term implications of severe neonatal lung disease; provide data to facilitate the development of future randomized intervention trials in this population; and inform public policy by enhancing knowledge about school age resource requirements in children with a history of prematurity and lung disease. Trial registration clinicaltrials.gov ID NCT01353313. Primary trial registration 5/11/11 modified to include followup through school age 12/13/17. This manuscript reflects version 3 of the trial manuscript, dated 10/12/2020.

Abstract Background and purposes Liver X receptors (LXRs) are specialized nuclear receptors essential for maintaining cholesterol homeostasis, modulating LXR activity could have therapeutic potential in lung diseases. Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by impaired alveolar development, in which apoptosis of alveolar epithelial cells is a key contributing factor. The current research focuses on exploring the potential mechanism by which the LXR pathway regulating alveolar epithelial type II cell apoptosis in response to hyperoxia exposure. Methods BPD infants and non-BPD preterm infants were enrolled to measure serum total cholesterol (TC) levels. To further investigate the role of cholesterol metabolism in BPD, a neonatal rat model of BPD was established, and in vitro studies were conducted using mouse lung epithelial cells (MLE12). These experiments aimed to explore the impact of hyperoxia on cholesterol metabolism and assess the effects of LXR agonist intervention. Results Elevated serum TC levels in BPD infants were observed, accompanied by lung cholesterol overload in BPD rats. Hyperoxia exposure also led to intracellular cholesterol accumulation in MLE12 cells, which may be attributed to the downregulated LXR signaling pathway. Activation of the LXR pathway prevented apoptosis and mitochondrial dysfunction in MLE12 cell. In BPD rats, intervention with the LXR agonist restored alveolar architecture and reduced alveolar epithelial type II cell apoptosis, which was associated with decreased oxidative stress and lung cholesterol accumulation. Conclusions Disrupted cholesterol metabolism and impaired homeostasis in premature infants may contribute to the development of BPD. Targeting LXR signaling may provide potential therapeutic targets in BPD. Clinical trial number Not applicable.

Abstract Bronchopulmonary dysplasia (BPD) is the predominant chronic lung disease in preterm infants, linked with various adverse long-term outcomes. Multiple prenatal and postnatal risk factors can impede lung development, leading to BPD. Current management of BPD relies heavily on pharmacotherapies and alterations in ventilatory strategies. However, these interventions only mitigate BPD symptoms without addressing underlying alveolar, vascular, structural, and functional deficiencies. Given the retarded lung development in infants with BPD and the limitations of existing modalities, new therapeutic approaches are imperative. The induced differentiation of stem/progenitor cells and the spatiotemporal expression patterns of growth factors associated with lung developmental processes are critical for lung development reactivation in BPD, which focuses on stimulating pulmonary vasculogenesis and alveolarization. This review summarizes the process of lung development and offers a comprehensive overview of advancements in therapies designed to reinitiate lung development in BPD. Furthermore, we assessed the potential of these therapies for maintaining lung homeostasis and effectively restoring pulmonary structure and function through stem/progenitor cells and growth factors, which have been widely researched.

Abstract Background To evaluate the impact of implementation of 2019 European respiratory distress syndrome (RDS) guidelines on the incidence of bronchopulmonary dysplasia (BPD). Method We retrospectively collected the clinical data of very preterm infants (VPIs) born before 32 gestational weeks from January 1st 2018 to December 31st 2021. VPIs were divided into group A and group B according to their birth date which was before or at/after January 1st 2020, when the 2019 European RDS guidelines were introduced. BPD is considered as primary outcome. We statistically analyzed all the data, and we compared the general characteristics, ventilation support, medication, nutrition and the outcomes between the two groups. Results A total of 593 VPIs were enrolled, including 380 cases in group A and 213 cases in group B. There were no statistic differences regarding to gender ratio, gestational age, birth weight and delivery mode between the two groups. Compared with group A, group B showed higher rate of antenatal corticosteroid therapy (75.1% vs. 65.5%). The improvement of ventilation management in these latter patients included lower rate of invasive ventilation (40.4% vs. 50.0%), higher rate of volume guarantee (69.8% vs. 15.3%), higher positive end expiratory pressure (PEEP) [6 (5, 6) vs. 5 (5, 5) cmH2O] and higher rate of synchronized nasal intermittent positive pressure ventilation (sNIPPV) (36.2% vs. 5.6%). Compared with group A, group B received higher initial dose of pulmonary surfactant [200 (160, 200) vs. 170 (130, 200) mg/Kg], shorter antibiotic exposure time [13 (7, 23) vs. 17 (9, 33) days], more breast milk (86.4% vs. 70.3%) and earlier medication for hemodynamically significant patent ductus arteriosus (hsPDA) treatment [3 (3, 4) vs. 8 (4, 11) days] (p 0.05). Conclusions After implementation of 2019 European RDS guidelines, the overall incidence of BPD was significantly decreased in VPIs. Continuous quality improvement is still needed in order to decrease the incidence of BPD in smaller infants who are less than 28 gestational weeks or less than 1,000 g.

Abstract Background Antenatal corticosteroids (ACS) are administered to prevent neonatal complications and death in women at risk of imminent preterm birth. Internationally, the optimal interval from ACS to delivery (ACS-to-delivery interval) is within seven days; however, evidence in Asian populations specifically is limited. This study aimed to investigate the association between ACS-to-delivery interval and the incidence of neonatal complications in Japan. Methods This retrospective observational study enrolled singleton neonates born preterm at

Abstract Background Metabolic acidosis occurs frequently during the first postnatal days in extremely preterm infants and is mainly attributed to renal immaturity. Recent studies suggested a link between metabolic acidosis and the development of BPD. The aim of this study was to systematically investigate the association between severe metabolic acidosis during the first two weeks of life and bronchopulmonary dysplasia (BPD) / mortality among preterm infants born before 28 weeks’ gestation. Methods Monocentric observational cohort study including 1748 blood gas samples of 138 extremely preterm infants born 2020–2022. Metabolic acidosis was defined as pH

Abstract Background Premature infants requiring mechanical ventilation and supplemental oxygen for respiratory support are at increased risk for bronchopulmonary dysplasia (BPD), wherein inflammation have been proposed as a driver of hyperoxia-induced injuries, including persistent loss of endothelial progenitor cells (EPCs), impaired vascularization and eventual alveolar simplification in BPD lungs. However, the underlying mechanisms linking these phenomena remain poorly defined. Methods We used clodronate liposomes to deplete macrophages in a mouse model of neonatal hyperoxia-induced lung injury to evaluate if EPC loss in BPD lungs could be an effect of macrophage infiltration. We further generated in vitro culture systems initiated with cord blood (CB)-derived CD34+ EPCs and neonatal macrophages either polarized from CB-derived monocytes or isolated from tracheal aspirates of human preterm infants requiring mechanical ventilation and oxygen supplementation, to identify EV-transmitted molecular mechanism that is critical for inhibitory actions of hyperoxic macrophages on EPCs. Results Initial experiments using mouse model identified the crucial role of macrophage infiltration in eliciting significant reduction of c-Kit+ EPCs in BPD lungs. Further examination of this concept in human system, we found that hyperoxia-exposed neonatal macrophages hamper human CD34+ EPC maintenance and impair endothelial function in the differentiated progeny via the EV transmission of miR-23a-3p. Notably, treatment with antagomiR-23a-3p to silence miR-23a-3p in vivo enhances c-Kit+ EPC maintenance, and increases capillary density, and consequently mitigates simplified alveolarization in BPD lungs. Conclusion Our findings highlight the importance of pulmonary intercellular communication in the pathophysiology of BPD, by identifying a linkage through vesicle transfer of miR-23a-3p from hyperoxic macrophages to EPCs, and thus demonstrating potential for novel therapeutic target in BPD.

Abstract Prematurity is associated with lower exercise capacity, which relies on the integrity of the cardiovascular, pulmonary, and skeletal muscle systems. Our animal model mimicking prematurity-associated conditions showed altered muscle composition and atrophy in adulthood. This study aimed to compare muscle composition and strength in adults born preterm versus full-term controls. This observational cohort study recruited 55 adults born preterm, ≤ 29 weeks’ of gestation and 53 full-term controls who underwent musculoskeletal ultrasound imaging to assess morphology of the rectus femoris at rest and during a maximal voluntary contraction. Maximal voluntary contraction of the hands and legs were measured by manual dynamometry. In adults born preterm, there was lower muscle strength (handgrip: − 4.8 kg, 95% CI − 9.1, − 0.6; knee extensor: − 44.6 N/m, 95% CI − 63.4, − 25.8) and smaller muscle area (− 130 mm2, 95% CI − 207, − 53), which was more pronounced with a history of bronchopulmonary dysplasia. Muscle stiffness was increased in the preterm versus term group (0.4 m/s, 95% CI 0.04, 0.7). Prematurity is associated with alterations in skeletal muscle composition, area, and function in adulthood. These findings highlight the necessity to implement preventive and/or curative approaches to improve muscle development and function following preterm birth to enhance overall health in this population.

Abstract Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in infants and the most frequent adverse outcome of premature birth, despite major efforts to minimize injury. It is thought to result from aberrant repair response triggered by either prenatal or recurrent postnatal injury to the lungs during development. Intrauterine inflammation is an important risk factor for prenatal lung injury, which is also increasingly linked to BPD. However, the specific mechanisms remain unclear. This review summarizes clinical and animal research linking intrauterine inflammation to BPD. We assess how intrauterine inflammation affects lung alveolarization and vascular development. In addition, we discuss prenatal therapeutic strategies targeting intrauterine inflammation to prevent or treat BPD.

Background: Perinatal inflammation increases the risk for bronchopulmonary dysplasia in preterm neonates, but the underlying pathophysiological mechanisms remain largely unknown. Given their anti-inflammatory and regenerative capacity, multipotent adult progenitor cells (MAPC) are a promising cell-based therapy to prevent and/or treat the negative pulmonary consequences of perinatal inflammation in the preterm neonate. Therefore, the pathophysiology underlying adverse preterm lung outcomes following perinatal inflammation and pulmonary benefits of MAPC treatment at the interface of prenatal inflammatory and postnatal ventilation exposures were elucidated. Methods: Instrumented ovine fetuses were exposed to intra-amniotic lipopolysaccharide (LPS 5 mg) at 125 days gestation to induce adverse systemic and peripheral organ outcomes. MAPC (10 × 106 cells) or saline were administered intravenously two days post LPS exposure. Fetuses were delivered preterm five days post MAPC treatment and either killed humanely immediately or mechanically ventilated for 72 h. Results: Antenatal LPS exposure resulted in inflammation and decreased alveolar maturation in the preterm lung. Additionally, LPS-exposed ventilated lambs showed continued pulmonary inflammation and cell junction loss accompanied by pulmonary edema, ultimately resulting in higher oxygen demand. MAPC therapy modulated lung inflammation, prevented loss of epithelial and endothelial barriers and improved lung maturation in utero. These MAPC-driven improvements remained evident postnatally, and prevented concomitant pulmonary edema and functional loss. Conclusion: In conclusion, prenatal inflammation sensitizes the underdeveloped preterm lung to subsequent postnatal inflammation, resulting in injury, disturbed development and functional impairment. MAPC therapy partially prevents these changes and is therefore a promising approach for preterm infants to prevent adverse pulmonary outcomes.