Neonatal Lung Research Articles

Loss of Surfactant Protein A Alters Perinatal Lung Morphology and Susceptibility to Hyperoxia-Induced Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a condition of poor alveolar formation that causes chronic breathing impairment in infants born prematurely. Preterm lungs lack surfactant and are vulnerable to oxidative injuries driving the development of BPD. Our recent studies reported that surfactant protein A (SP-A) genetic variants influence susceptibility to neonatal lung disease. SP-A modulates activation of alveolar macrophages and parturition onset in late gestation. We asked whether a lack of SP-A alters alveolarization in a mouse model of hyperoxia-induced BPD. SP-A-deficient and control newborn mice were exposed to either clinically relevant 60% O2 hyperoxia or normoxia for 5–7 days. Alveolar formation was then assessed by mean linear intercept (MLI) and radial alveolar count (RAC) measurements in lung tissue sections. We report that the combination of SP-A deficiency and hyperoxia reduces alveolar growth compared to WT mice. The morphometric analysis of normoxic SP-A-deficient lungs showed lower RAC compared to controls, indicating reduced alveolar number. In the presence of hyperoxia, MLI was higher in SP-A-deficient lungs compared to controls. Differences were statistically significant for female pups. Spatial proteomic profiling of lung tissue sections showed that hyperoxia caused a 4-fold increase in the DNA damage marker γH2Ax in macrophages of SP-A-deficient lungs compared to normoxia. Our short report suggests an important role for SP-A in perinatal lung development and the protection of lung macrophages from oxidant injury. These studies warrant future investigation to discern the temporal interaction of SP-A, gender, oxidant injury, and lung macrophages in perinatal alveolar formation and development of BPD.

75 Lung ultrasound severity scores and its utility in predicting success of weaning off respiratory support in neonates born preterm

Abstract Background Preterm infants often require respiratory support in the newborn intensive care unit. Complete trial off around 30-34 weeks post-menstrual age (PMA) is by trial and error based on clinical and physiological variables. Lung ultrasound (LUS) is a reliable adjunct in the diagnosis and management of most neonatal lung conditions. However, its utility in accessing readiness for successful weaning off respiratory pressure support in preterm neonates has not been explored. Objectives To determine the utility of LUS severity score (LUS-sc) in predicting successful weaning off of respiratory pressure support after 32weeks CGA in neonates born ≤32 weeks gestational age (GA). Design/Methods Prospective cohort study involving preterm neonates born ≤32 weeks needing any respiratory pressure support modes, admitted to a single tertiary care center in Canada between Sept 2022-Sept 2023. Eligible neonates were assessed by LUS at two time points- LUS1 at 30-30 + 6 weeks for those born <30weeks GA and between 48-72hours of life for those born at 30-32 + 6 weeks GA; LUS2 within 12hours prior to trial off respiratory pressure support to room air or low flow after 32weeks PMA. LUS were scored for disease severity by two independent reviewers using the LUS-sc by Brat et al. Receiver operator characteristics (ROC) curves analyzed the reliability of LUS-sc to predict the successful cessation of respiratory pressure support to room air or low flow post LUS2. Results Of 50 preterm neonates included in the study, 32 (64%) were successfully weaned from pressure support after LUS2 at a mean (SD) GA of 33.03 (0.29). The mean (SD) GA at birth was 28.78 (0.46) in the successful group and 27.78 (0.62) in the unsuccessful group (p=0.197). The mean (SD) LUS-sc for LUS2 at which cessation of support was possible was significantly lower from those who failed [6.95(0.33) vs 8.69(0.55), p=0.006] (Table 1). The ROC curve (Figure 1) showed AUC of 0.717 (95%CI=0.56-0.86), for a cut-off of LUS-sc of 7.75, with sensitivity of 0.75 (95%CI=0.60-0.90) and specificity of 0.61 (95%CI=0.38-0.84). Independent of GA at birth and at respiratory pressure support trial off, LUS-sc ≤8 was associated with an increased odd of cessation of support by 9.0 (95%CI=1.9-42.6), p=0.005, and each additional week of GA at first trial off increased the odds of cessation by 2.2 (95%CI=1.1-4.4), p=0.031. Conclusion LUS is a reliable tool to assess readiness for successful non-invasive respiratory pressure support trial off. A LUS-sc ≤8 was associated with higher successful weaning off of non-invasive pressure support after 32weeks GA.

Betamethasone improved near-term neonatal lamb lung maturation in experimental maternal asthma.

Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant-producing cells and lower surfactant-protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term=150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45min before tissue collection. Lung function and structure were similar in control lambs (n=16, 11 ewes) and lambs from asthma ewes (n=14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n=12, 8 ewes) compared to those from controls (P=0.003) or asthma ewes (P=0.008). Lung expression of surfactant protein genes SFTPA (P=0.048) and SFTPB (P<0.001), but not SFTPC (P=0.177) or SFTPD (P=0.285), was higher in lambs from asthma+beta than those from asthma ewes. Female lambs had higher tidal volume (P=0.007), dynamic lung compliance (P<0.001), and SFTPA (P=0.037) and SFTPB gene expression (P=0.030) than males. These data suggest that betamethasone stimulates lung maturation and function of near-term neonates, even in the absence of impairment by maternal asthma.

Use of neonatal lung ultrasound in European neonatal units: a survey by the European Society of Paediatric Research

ObjectiveRegarding the use of lung ultrasound (LU) in neonatal intensive care units (NICUs) across Europe, to assess how widely it is used, for what indications and how its implementation might...

Bronchopulmonary Dysplasia in Children. An Up-to-Date View of Disease Outcomes

Introduction. Bronchopulmonary dysplasia (BPD) is a chronic neonatal lung disease, with oxygen dependence by 36 weeks post conceptual age (PCA). Over the past decade, the frequency of the disease has increased. More and more modern scientific data are published that BPD has an adverse effect not just the development of the lungs, but also on the cardiovascular system. There is a large amount of information in the literature about the outcomes of BPD, but there is not enough information about the consequences of cardiovascular disorders in children with a history of BPD. Lack of clear criteria to predict and prevent to demonstrate cardiovascular disorders, were the basis for a detailed study of the literature concerning this issue.Purpose of the study based on study of the results of studies by local and foreign authors, to analyze the nature of cardiovascular disorders in children with a history of BPD, and to determine directions for more detailed scientific and practical search for a solution to this problem.Materials and methods. Research articles were searched for keywords “bronchopulmonary dysplasia” and “сardiovascular disorders” in the PubMed, UpToDate, Google Scholar databases, eLibrary.ru. At least 80 publications have been extracted from search results for simplification. Analyses of the results of studies by local and foreign authors on outcomes, BPD, including cardiovascular disorders, was carried out.Results and discussion. At the moment, the outcomes of BPD are well understood, while few information on cardiovascular disorders and possible prognosis for children who have undergone BPD.Conclusion. Cardiovascular disorders in children with a history of BPD are a pressing problem in pediatric practice. The presented literature review summarizes the information accumulated over several years on the outcomes of cardiovascular changes and determines the direction for further study of the problem, involving pediatricians and doctors of other specialties in order to identify groups at increased risk for the development of these diseases in children.

Effect of different CPAP levels on ultrasound-assessed lung aeration and gas exchange in neonates

BackgroundRespiratory distress syndrome (RDS) and transient tachypnoea (TTN) are the two commonest neonatal respiratory disorders. The optimal continuous positive airway pressure (CPAP) to treat them is unknown. We aim to clarify the effect of different CPAP levels on lung aeration and gas exchange in patients with RDS and TTN.MethodsProspective, observational, pragmatic, physiological cohort study. CPAP was sequentially increased from 4 to 6 and 8 cmH2O and backwards, with interposed wash-out periods. Lung aeration was assessed with a validated neonatal lung ultrasound score. Gas exchange was non-invasively evaluated with transcutaneous monitoring. Ultrasound score and PtcO2/FiO2 ratio were the co-primary outcomes. PtcCO2 and other oxygenation metrics were the secondary outcomes.Results30 neonates with RDS and 30 with TTN were studied. Each CPAP increment significantly (overall always p < 0.001) improved both lung aeration and oxygenation, but the increase from 6 to 8 cmH2O achieved a small absolute benefit. In RDS patients, the absolute improvements were small and the diagnosis of TTN was significantly associated with greater improvement of lung aeration (β= -1.4 (95%CI: -2.4; -0.3), p = 0.01) and oxygenation (β = 39.6 (95%CI: 4.1; 75.1), p = 0.029). Aeration improved in 16 (53.3%) and 27 (90%) patients in the RDS and TTN groups, respectively (p = 0.034). Lung aeration showed significant hysteresis in TTN patients. Secondary outcomes gave similar results.ConclusionsIncreasing CPAP from 4 to 8 cmH2O improves ultrasound-assessed lung aeration and oxygenation in RDS and TTN. The absolute improvements are small when CPAP is beyond 6 cmH2O or for RDS patients.

The number of blood transfusions received and the incidence and severity of chronic lung disease among NICU patients born >31 weeks gestation.

We previously reported the possible pathogenic role, among infants born ≤29 weeks, of transfusions in bronchopulmonary dysplasia. The present study examined this association in infants born >31 weeks. Analysis of red blood cell (RBC) and platelet transfusions in five NICUs to infants born >31 weeks, and chronic neonatal lung disease (CNLD) at six-weeks of age. Seven-hundred-fifty-one infants born >31 weeks were still in the NICU when six-weeks of age. CNLD was identified in 397 (53%). RBC and platelet transfusions were independently associated with CNLD after controlling for potential confounders. For every transfusion, the adjusted odds of developing CNLD increased by a factor of1.64 (95% CI, 1.38-2.02; p < 0.001). Among NICU patients born >31 weeks, transfusions received by six weeks are associated with CNLD incidence and severity. Though we controlled for known confounding variables in our regression models, severity of illness is an important confounder that limits our conclusions.

Nintedanib preserves lung growth and prevents pulmonary hypertension in a hyperoxia-induced lung injury model.

Bronchopulmonary dysplasia (BPD), the chronic lung disease associated with prematurity, is characterized by poor alveolar and vascular growth, interstitial fibrosis, and pulmonary hypertension (PH). Although multifactorial in origin, the pathophysiology of BPD is partly attributed to hyperoxia-induced postnatal injury, resulting in lung fibrosis. Recent work has shown that anti-fibrotic agents, including Nintedanib (NTD), can preserve lung function in adults with idiopathic pulmonary fibrosis. However, NTD is a non-specific tyrosine kinase receptor inhibitor that can potentially have adverse effects on the developing lung, and whether NTD treatment can prevent or worsen risk for BPD and PH is unknown. We hypothesize that NTD treatment will preserve lung growth and function and prevent PH in an experimental model of hyperoxia-induced BPD in rats. Newborn rats were exposed to either hyperoxia (90%) or room air (RA) conditions and received daily treatment of NTD or saline (control) by intraperitoneal (IP) injections (1 mg/kg) for 14 days, beginning on postnatal day 1. At day 14, lung mechanics were measured prior to harvesting lung and cardiac tissue. Lung mechanics, including total respiratory resistance and compliance, were measured using a flexiVent system. Lung tissue was evaluated for radial alveolar counts (RAC), mean linear intercept (MLI), pulmonary vessel density (PVD), and pulmonary vessel wall thickness (PVWT). Right ventricular hypertrophy (RVH) was quantified with cardiac weights using Fulton's index (ratio of right ventricle to the left ventricle plus septum). When compared with RA controls, hyperoxia exposure reduced RAC by 64% (p < 0.01) and PVD by 65% (p < 0.01) and increased MLI by 108% (p < 0.01) and RVH by 118% (p < 0.01). Hyperoxia increased total respiratory resistance by 94% and reduced lung compliance by 75% (p < 0.01 for each). NTD administration restored RAC, MLI, RVH, PVWT and total respiratory resistance to control values and improved PVD and total lung compliance in the hyperoxia-exposed rats. NTD treatment of control animals did not have adverse effects on lung structure or function at 1 mg/kg. When administered at higher doses of 50 mg/kg, NTD significantly reduced alveolar growth in RA controls, suggesting dose-related effects on normal lung structure. We found that NTD treatment preserved lung alveolar and vascular growth, improved lung function, and reduced RVH in experimental BPD in infant rats without apparent adverse effects in control animals. We speculate that although potentially harmful at high doses, NTD may provide a novel therapeutic strategy for prevention of BPD and PH. Anti-fibrotic therapies may be a novel therapeutic strategy for the treatment or prevention of BPD. High-dose anti-fibrotics may have adverse effects on developing lungs, while low-dose anti-fibrotics may treat or prevent BPD. There is very little preclinical and clinical data on the use of anti-fibrotics in the developing lung. Dose timing and duration of anti-fibrotic therapies may be critical for the treatment of neonatal lung disease. Currently, strategies for the prevention and treatment of BPD are lacking, especially in the context of lung fibrosis, so this research has major clinical applicability.

6813 Des-Ciclesonide: A Novel Selective Glucocorticoid Receptor Modulator With Therapeutic Potential for Bronchopulmonary Dysplasia, a Chronic Lung Disease of Prematurity

Abstract Disclosure: N. El Khoury: None. J. Jaumotte: None. C. Min: None. C. Madigan: None. J. Wang: None. U. Chandran: None. V. Sampath: None. T.J. Cole: None. P. Monaghan-Nichols: None. R. Houtman: None. K.W. Nettles: None. D.B. DeFranco: None. Infants born before 30 weeks gestation are at risk of developing bronchopulmonary dysplasia (BPD), a prevalent chronic lung disease of prematurity. Glucocorticoids (GCs) such as dexamethasone (DEX) have been a mainstay of BPD prevention as they reduce lung inflammation and injury. However, their use is encumbered with several adverse effects including hyperglycemia, impaired somatic and brain growth and cerebral palsy. These major concerns have resulted in the AAP recommending caution in GC use in preterm infants.Ciclesonide (CIC), an inhaled GC prodrug approved for the treatment of asthma and allergic rhinitis in children, is converted to the potent glucocorticoid receptor (GR) agonist des-ciclesonide (DES) by enzymes enriched in the airways. We previously reported that s.c. delivery of CIC in neonatal rats activated GR transcriptional responses in lung but did not trigger the adverse effects on somatic growth, brain weight or cerebral white matter loss caused by DEX leading us to propose CIC as a potential new pharmacotherapy for BPD. To determine whether limited systemic metabolism of CIC in neonatal rats was solely responsible for its enhanced safety profile, we assessed various outcomes in neonatal rats followed s.c. delivery of its active metabolite DES. Consistent with previous studies, five daily s.c. injections of DEX led to a reduction in body and brain weight as well as reduced serum levels of insulin-like growth factor-1 and chronic hyperglycemia. Surprisingly, analogous s.c. injection of neonatal rats with DES, which has a higher binding affinity for GR than DEX, did not trigger any of these adverse effects. However, DES is as effective as DEX in reducing the expression of various proinflammatory cytokine mRNAs in neonatal rat lung induced by an 11-day systemic treatment with bleomycin. Bulk RNAseq analyses revealed transcriptional responses of neonatal lung and liver to DES, although less robust than that observed to DEX (i.e., 25% and 13% in lung and liver, respectively). Nonetheless, a NAPing assay for coregulator peptide binding showed increased binding of all the DES responsive peptide interactions relative to DEX and cortisol. All-atom molecular dynamics simulations revealed site-specific H-bonding changes within the GR ligand binding domain (LBD) caused by the bulky C16/C17substitution within DES, which was translated into broader changes in LBD structure, specifically revealed as differences in RMSF in helix 7/8 and the surfaces interacting with the NCOA2 peptide. Furthermore, network pathway analysis illustrated that DES mobility at helix 7/8 uniquely generated a meaningful allosteric signaling pathway between Q642 and NCOA2 peptide. In conclusion, the pharmacokinetic properties of the GR prodrug CIC coupled with the tissue-selective pharmacodynamic properties of its active metabolite DES make this FDA approved drug a potential new therapeutic agent for BPD. Presentation: 6/3/2024

Microbubble-laden aerosols improve post-nasal aerosol penetration efficiency in a preterm neonate model

Nebulized lung surfactant therapy has been a neonatology long-pursued goal. Nevertheless, many clinical trials have yet to show a clear clinical efficacy of nebulized surfactant, which, in part, is due to the technical challenges of delivering aerosols to the lungs of preterm neonates. The study aimed to test microbubbles for improving lung deposition in preterm neonates. An in vitro testing method was developed to replicate the clinical environment; it used a 3D-printed preterm neonate model, connected to a high-flow nasal cannula (HFNC) and a vibrating mesh nebulizer. The flow rate of the HFNC mirrored that used in the clinics (i.e., 4, 6, and 8 L/min). Followingly, the lung penetrations of aerosols with and without microbubbles were compared. The aerodynamic diameter of aerosols with microbubbles (MMAD=1.75 μm) was lower than that of the counterpart (MMAD=2.25 μm). Microbubble-laden aerosols had a significantly higher number of microbubbles that were below 1.0 μm. Microbubble-laden aerosols had dramatically higher lung penetration in the preterm model; lung penetration efficiencies were 30.0, 25.5, and 17.5 % at 4, 6, and 8 L/min, respectively, whereas the lung penetration efficiency for conventionally nebulized aerosols was below 1.25 % in the three flow rates.

Influence of Gut and Lung Microbiota and the Gut-Lung Axis on Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease, is a common respiratory disease in preterm infants. Preterm infants with BPD often exhibit changes in gut and lung microbiota. In recent years, with the development of high-throughput sequencing technology, more and more mechanisms of the gut-lung axis have been confirmed, helping to explore new directions for the treatment of BPD using microecological agents. This paper reviews the roles of gut microbiota, lung microbiota, and the gut-lung axis in the pathogenesis of BPD in preterm infants, providing new research avenues for the prevention and treatment of BPD.

Macrophage extracellular vesicle-packaged miR-23a-3p impairs maintenance and angiogenic capacity of human endothelial progenitor cells in neonatal hyperoxia-induced lung injury

BackgroundPremature 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.MethodsWe 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.ResultsInitial 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.ConclusionOur 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.

Stem cell-derived extracellular vesicles: a potential intervention for Bronchopulmonary Dysplasia.

Despite advances in neonatal care, the incidence of Bronchopulmonary Dysplasia (BPD) remains high among extreme preterm infants. The pathogenesis of BPD is multifactorial, with inflammation playing a central role. There is strong evidence that stem cell therapy reduces inflammatory changes and restores normal lung morphology in animal models of hyperoxia-induced lung injury. These therapeutic effects occur without significant engraftment of the stem cells in the host lung, suggesting more of a paracrine mechanism mediated by their secretome. In addition, there are multiple concerns with stem cell therapy which may be alleviated by administering only the effective vesicles instead of the cells themselves. Extracellular vesicles (EVs) are cell-derived components secreted by most eukaryotic cells. They can deliver their bioactive cargo (mRNAs, microRNAs, proteins, growth factors) to recipient cells, which makes them a potential therapeutic vehicle in many diseases, including BPD. The following review will highlight recent studies that investigate the effectiveness of EVs derived from stem cells in preventing or repairing injury in the preterm lung, and the potential mechanisms of action that have been proposed. Current limitations will also be discussed as well as suggestions for advancing the field and easing the transition towards clinical translation in evolving or established BPD. IMPACT: Extracellular vesicles (EVs) derived from stem cells are a potential intervention for neonatal lung diseases. Their use might alleviate the safety concerns associated with stem cell therapy. This review highlights recent studies that investigate the effectiveness of stem cell-derived EVs in preclinical models of bronchopulmonary dysplasia. It adds to the existing literature by elaborating on the challenges associated with EV research. It also provides suggestions to advance the field and ease the transition towards clinical applications. Optimizing EV research could ultimately improve the quality of life of extreme preterm infants born at vulnerable stages of lung development.

Bronchopulmonary Dysplasia with Pulmonary Hypertension Associates with Loss of Semaphorin Signaling and Functional Decrease in FOXF1 Expression.

Lung injury in preterm infants leads to structural and functional respiratory deficits, with a risk for bronchopulmonary dysplasia (BPD) that in its most severe form is accompanied by pulmonary hypertension (PH). To examine cellular and molecular dynamics driving evolving BPD in humans, we performed single-cell RNA sequencing of preterm infant lungs in early stages of BPD and BPD+PH compared to term infants. Analysis of the endothelium revealed a unique aberrant capillary cell-state primarily in BPD+PH marked by ANKRD1 expression. Predictive signaling analysis identified deficits in the semaphorin guidance-cue signaling pathway and decreased expression of pro-angiogenic transcription factor FOXF1 within the alveolar parenchyma in neonatal lung samples with BPD/BPD+PH. Loss of semaphorin signaling was replicated in a murine BPD model and in humans with alveolar capillary dysplasia (ACDMPV), suggesting a mechanistic link between the developmental programs underlying BPD and ACDMPV and a critical role for semaphorin signaling in normal lung development.

Recombinant fragment of human surfactant protein D to prevent neonatal chronic lung disease (RESPONSE): a protocol for a phase I safety trial in a tertiary neonatal unit

IntroductionChronic respiratory morbidity from bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth and has consequences for later respiratory, cardiovascular and neurodevelopmental outcomes. The early phases of respiratory...

The need for assisted ventilation corroborates the effectiveness of antenatal corticosteroid therapy in preventing premature lamb mortality

In premature births, deficiency and/or inactivation of surfactant and incomplete development of lung occur, leading to pulmonary complications and greater need for ventilatory interventions. Prenatal corticosteroid therapy is used to improve neonatal lung function and, thus, may reduce mortality and lower incidence and severity of lung injury. Therefore, this study aimed to assess the need for ventilatory support in preterm lambs subjected or not to prenatal betamethasone treatment, and to evaluate the effectiveness on neonatal survival. Lambing was induced and 13 premature lambs were assigned to Corticosteroid Group (n = 8; lambs from ewes subjected previously to 0.5 mg/kg betamethasone, IM, at 133 days of pregnancy) and Control Group (n = 5; non-treated lambs). Lambs were evaluated for vitality, neurologic reflexes, vital functions and birth weight. Three ventilatory modalities were preconized for critical lambs, according to specific criteria: mask oxygen therapy, self-inflating bag with tracheal tube and mechanical ventilation. Non-treated lambs had lower vitality score, muscle tonus and respiratory rate compared to Corticosteroid Group. Ventilatory support was needed for 3 Control lambs and only 1 Corticosteroid neonate. Corticosteroid lamb required significant less time-frame between birth and onset of ventilatory assistance and remained under ventilation for a shorter time. Percentage of ventilated non-treated lambs correlated negatively with birth weight, muscle tone, heart and respiratory rate. In conclusion, antenatal betamethasone treatment reduces the need for ventilatory assistance in premature lambs. Additionally, mortality is low when a protocol for inducing pulmonary maturity (maternal corticosteroid therapy) and/or ventilatory interventions are employed, ensuring the survival of premature lambs.

IL-33 released during challenge phase regulates allergic asthma in an age-dependent way.

Epithelial-derived cytokines, especially type 2 alarmins (TSLP, IL-25, and IL-33), have emerged as critical mediators of type 2 inflammation. IL-33 attracts more interest for its strong association with allergic asthma, especially in childhood asthma. However, the age-dependent role of IL-33 to the development of allergic asthma remains elusive. Here, using OVA-induced allergic asthma model in neonatal and adult mice, we report that IL-33 is the most important alarmin in neonatal lung both at steady state or inflammation. The deficiency of IL-33/ST2 abrogated the development of allergic asthma only in neonates, whereas in adults the effect was limited. Interestingly, the deficiency of IL-33/ST2 equally dampened the ILC2 responses in both neonatal and adult models. However, the effect of IL-33/ST2 deficiency on Th2 responses is age-dependent, which is only blocked in neonates. Furthermore, IL-33/ST2 signaling is dispensable for OVA sensitization. Following OVA challenge in adults, the deficiency of IL-33/ST2 results in compensational more TSLP, which in turn recruits and activates lung DCs and boosts Th2 responses. The enriched γδ T17 cells in IL-33/ST2 deficient neonatal lung suppress the expression of type 2 alarmins, CCL20 and GM-CSF via IL-17A, thus might confer the inhibition of allergic asthma. Finally, on the basis of IL-33 deficiency, the additive protective effects of TSLP blocking is much more pronounced than IL-25 blocking in adults. Our studies demonstrate that the role of IL-33 for ILC2 and Th2 responses varies among ages in OVA models and indicate that the factor of age should be considered for intervention of asthma.

Mitigating effects of selenium and zinc on oxidative stress and biochemical and histopathological changes in lung during prenatal and lactational exposure rats to barium chloride.

Selenium (Se) and zinc (Zn) are essential trace elements with antioxidant properties, and their supplementation has been shown to be protective against the toxicity of various environmental and dietary substances. The aim of this study was to investigate the potential protective effect of selenium and zinc as adjuvants against barium (Ba) toxicity in lactating rats and their offspring. The pregnant rats were divided into six groups: the first as control; group 2 received barium (67ppm) in the drinking water; group 3 had combined Ba + Se (0.5mg/kg) in the diet; group 4 received Zn (50mg/kg bw) by gavage together with Ba; groups 5 and 6, positive controls, were treated with selenium (0.5mg/kg) and zinc (50mg/kg bw), respectively. MDA, H2O2, AOPP, CAT, GPx, and SOD levels were measured and lung histopathology was performed. Our results showed that barium administration caused lung damage as evidenced by an increase in MDA, H2O2, and AOPP levels and a decrease in the activities of CAT, GPx, and SOD in mothers and their offspring. A decrease in lung GSH, NPSH, and MT levels was also observed. Supplementation of Ba-treated rats with Se and/or Zn significantly improved the pulmonary antioxidant status of mothers and their offspring. Histopathological examinations were also consistent with the results of biochemical parameters, suggesting the beneficial role of Se and Zn supplementation, as evidenced by less accumulation of collagen fibers as studied by hematoxylin and eosin (H&E) and Masson's trichrome staining. In conclusion, we demonstrate the adverse effects of maternal barium exposure during pregnancy and on neonatal lung health and the protective effects of selenium and zinc in preventing the adverse effects of barium exposure.

Hyperoxia exposure induces ferroptosis and apoptosis by downregulating PLAGL2 and repressing HIF-1α/VEGF signaling pathway in newborn alveolar typeII epithelial cell

ABSTRACT 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.

Role of sex as a biological variable in neonatal alveolar macrophages

The lung macrophages play a crucial role in health and disease. Sexual dimorphism significantly impacts the phenotype and function of tissue-resident macrophages. The primary mechanisms responsible for sexually dimorphic outcomes in bronchopulmonary dysplasia (BPD) remain unidentified. We tested the hypothesis that biological sex plays a crucial role in the transcriptional state of alveolar macrophages, using neonatal murine hyperoxia-induced lung injury as a relevant model for human BPD. The effects of neonatal hyperoxia exposure (95 % FiO2, PND1-5: saccular stage) on the lung myeloid cells acutely after injury and during normoxic recovery were measured. Alveolar macrophages (AM) from room air- and hyperoxia exposed from male and female neonatal murine lungs were subjected to bulk-RNA Sequencing. AMs are significantly depleted in the hyperoxia-exposed lung acutely after injury, with subsequent recovery in both sexes. The transcriptome of the alveolar macrophages is impacted by neonatal hyperoxia exposure and by sex as a biological variable. Pathways related to DNA damage and interferon-signaling were positively enriched in female AMs. Metabolic pathways related to glucose and carbohydrate metabolism were positively enriched in the male AMs, while oxidative phosphorylation was negatively enriched. These pathways were shared with monocytes and airway macrophages from intubated male and female human premature neonates.