Mesenchymal stromal cell extracellular vesicles improve lung development in mechanically ventilated preterm lambs.

Novel therapies are needed for bronchopulmonary dysplasia (BPD) because no effective treatment exists. Mesenchymal stromal cell extracellular vesicles (MSC-sEVs) have therapeutic efficacy in a mouse pup neonatal hyperoxia BPD model. We tested the hypothesis that MSC-sEVs will improve lung functional and structural development in mechanically ventilated preterm lambs. Preterm lambs (∼129 days; equivalent to human lung development at ∼28 wk gestation) were exposed to antenatal steroids, surfactant, caffeine, and supported by mechanical ventilation for 6-7 days. Lambs were randomized to blinded treatment with either MSC-sEVs (human bone marrow MSC-derived; 2 × 1011 particles iv; n = 8; 4 F/4 M) or vehicle control (saline iv; 4 F/4 M) at 6 and 78 h post delivery. Physiological targets were pulse oximetry O2 saturation 90-94% ([Formula: see text] 60-90 mmHg), [Formula: see text] 45-60 mmHg (pH 7.25-7.35), and tidal volume 5-7 mL/kg. MSC-sEVs-treated preterm lambs tolerated enteral feedings compared with vehicle control preterm lambs. Differences in weight patterns were statistically significant. Respiratory severity score, oxygenation index, A-a gradient, distal airspace wall thickness, and smooth muscle thickness around terminal bronchioles and pulmonary arterioles were significantly lower for the MSC-sEVs group. S/F ratio, radial alveolar count, secondary septal volume density, alveolar capillary surface density, and protein abundance of VEGF-R2 were significantly higher for the MSC-sEVs group. MSC-sEVs improved respiratory system physiology and alveolar formation in mechanically ventilated preterm lambs. MSC-sEVs may be an effective and safe therapy for appropriate functional and structural development of the lung in preterm infants who require mechanical ventilation and are at risk of developing BPD.NEW & NOTEWORTHY This study focused on potential treatment of preterm infants at risk of developing bronchopulmonary dysplasia (BPD), for which no effective treatment exists. We tested treatment of mechanically ventilated preterm lambs with human mesenchymal stromal cell extracellular vesicles (MSC-sEVs). The results show improved respiratory gas exchange and parenchymal growth of capillaries and epithelium that are necessary for alveolar formation. Our study provides new mechanistic insight into potential efficacy of MSC-sEVs for preterm infants at risk of developing BPD.

Retrospective analysis of referrals for hypoxic challenge testing in children born preterm.

INTRODUCTION: Children with a history of bronchopulmonary dysplasia (BPD) may be at risk of hypoxaemia at altitude, such as during air travel. We have performed preflight hypoxic challenge testing (HCT) since 2006, incorporating British Thoracic Society (BTS) guidance since 2011, to determine which children may require oxygen during air travel. AIMS: We aimed to compare the outcome of HCTs in children with a history of BPD who met the 2011 BTS criteria and those who did not and, in addition to this, to interrogate the data for factors that may predict the outcome of HCT in this population. METHODS: We performed a retrospective analysis of data from HCTs of children with a history of BPD referred 2006-2020. Cases were excluded if the patient had a respiratory comorbidity, was still on oxygen therapy, if the test was a repeat or if the clinical record was incomplete. Descriptive and univariate analysis of the data was performed, and a binary logistic regression model was fitted. RESULTS: There were 79 HCTs, of which 24/79 (30%) did not meet BTS 2011 guidelines referral criteria. The analysis showed a greater proportion of desaturation in the group that did not meet criteria: 46% vs 27% (no statistical significance). Baseline oxygen saturations were higher in those who did not require oxygen during HCT and this variable was significant when adjusted for confounders. CONCLUSIONS: This study found that the current criteria for referral for preflight testing may incorrectly identify those most at risk and highlights the need for further investigation to ensure those most at risk are being assessed prior to air travel.

Repeated intravenous doses of human umbilical cord-derived mesenchymal stromal cells for bronchopulmonary dysplasia: results of a phase 1 clinical trial with 2-year follow-up.

BACKGROUND: Currently, there is a lack of effective treatments or preventive strategies for bronchopulmonary dysplasia (BPD). Pre-clinical studies with mesenchymal stromal cells (MSCs) have yielded encouraging results. The safety of administering repeated intravenous doses of umbilical cord tissue-derived mesenchymal stromal cells (UC-MSCs) has not yet been tested in extremely-low-gestational-age newborns (ELGANs). AIMS: to test the safety and feasibility of administering three sequential intravenous doses of UC-MSCs every 7 days to ELGANs at risk of developing BPD. METHODS: In this phase 1 clinical trial, we recruited ELGANs (birth weight ≤1250 g and ≤28 weeks in gestational age [GA]) who were on invasive mechanical ventilation (IMV) with FiO2 ≥ 0.3 at postnatal days 7-14. Three doses of 5 × 106/kg of UC-MSCs were intravenously administered at weekly intervals. Adverse effects and prematurity-related morbidities were recorded. RESULTS: From April 2019 to July 2020, 10 patients were recruited with a mean GA of 25.2 ± 0.8 weeks and a mean birth weight of 659.8 ± 153.8 g. All patients received three intravenous UC-MSC doses. The first dose was administered at a mean of 16.6 ± 2.9 postnatal days. All patients were diagnosed with BPD. All patients were discharged from the hospital. No deaths or any serious adverse events related to the infusion of UC-MSCs were observed during administration, hospital stays or at 2-year follow-up. CONCLUSIONS: The administration of repeated intravenous infusion of UC-MSCs in ELGANs at a high risk of developing BPD was feasible and safe in the short- and mid-term follow-up.

Quality improvement in the golden hour for premature infants: a scoping review.

BACKGROUND AND OBJECTIVE: Evidence-based research has shown that golden hour quality improvement (QI) measures can improve the quality of care and reduce serious complications of premature infants. Herein, we sought to review golden hour QI studies to evaluate the impact on the outcome of preterm infants. METHODS: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and SinoMed databases from inception to April 03, 2023. Only studies describing QI interventions in the golden hour of preterm infants were included. Outcomes were summarized and qualitative synthesis was performed. RESULTS: Ten studies were eligible for inclusion. All studies were from single centers, of which nine were conducted in the USA and one in Israel. Seven were pre-post comparative studies and three were observational studies. Most included studies were of medium quality (80%). The most common primary outcome was admission temperatures and glucose. Five studies (n = 2308) reported improvements in the admission temperature and three studies (n = 2052) reported improvements in hypoglycemia after QI. Four studies (n = 907) showed that the incidence of bronchopulmonary dysplasia (BPD) was lower in preterm infants after QI: 106/408 (26.0%) vs. 122/424(29.5%) [OR = 0.68, 95% CI 0.48-0.97, p = 0.04]. CONCLUSIONS: Our study showed that the golden hour QI bundle can improve the short-term and long-term outcomes for extremely preterm infants. There was considerable heterogeneity and deficiencies in the included studies, and the variation in impact on outcomes suggests the need to use standardized and validated measures. Future studies are needed to develop locally appropriate, high-quality, and replicable QI projects.

Nutritional support during the first week for infants with bronchopulmonary dysplasia and respiratory distress: a multicenter cohort study in China.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major complication affecting the survival rate and long-term outcomes of preterm infants. A large, prospective, multicenter cohort study was conducted to evaluate early nutritional support during the first week of life for preterm infants with a gestational age < 32 weeks and to verify nutritional risk factors related to BPD development. METHODS: A prospective multicenter cohort study of very preterm infants was conducted in 40 tertiary neonatal intensive care units across mainland China between January 1, 2020, and December 31, 2021. Preterm infants who were born at a gestational age < 32 weeks, < 72 h after birth and had a respiratory score > 4 were enrolled. Antenatal and postnatal information focusing on nutritional parameters was collected through medical systems. Statistical analyses were also performed to identify BPD risk factors. RESULTS: The primary outcomes were BPD and severity at 36 weeks postmenstrual age. A total of 1410 preterm infants were enrolled in this study. After applying the exclusion criteria, the remaining 1286 infants were included in this analysis; 614 (47.7%) infants were in the BPD group, and 672 (52.3%) were in the non-BPD group. In multivariate logistic regression model, the following six factors were identified of BPD: birth weight (OR 0.99, 95% CI 0.99-0.99; p = 0.039), day of full enteral nutrition (OR 1.03, 95% CI 1.02-1.04; p < 0.001), parenteral protein > 3.5 g/kg/d during the first week (OR 1.65, 95% CI 1.25-2.17; p < 0.001), feeding type (formula: OR 3.48, 95% CI 2.21-5.49; p < 0.001, mixed feed: OR 1.92, 95% CI 1.36-2.70; p < 0.001; breast milk as reference), hsPDA (OR 1.98, 95% CI 1.44-2.73; p < 0.001), and EUGR ats 36 weeks (OR 1.40, 95% CI 1.02-1.91; p = 0.035). CONCLUSIONS: A longer duration to achieve full enteral nutrition in very preterm infants was associated with increased BPD development. Breastfeeding was demonstrated to have a protective effect against BPD. Early and rapidly progressive enteral nutrition and breastfeeding should be promoted in very preterm infants. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR2000030125 on 24/02/2020) and in www.ncrcch.org (No. ISRCTN84167642 on 25/02/2020).

Family Integrated Care Shortens the Duration of Home Oxygen Therapy in Infants With Bronchopulmonary Dysplasia.

BACKGROUND: There have been few reports on whether family integrated care (FIC) can help premature infants with moderate to severe bronchopulmonary dysplasia (BPD) to shorten the duration of home oxygen therapy (HOT). PURPOSE: To investigate the effect of FIC on the duration of HOT in premature infants with moderate to severe BPD. METHODS: The subjects were retrospectively selected from premature infants with moderate to severe BPD in our center between June 2019 and December 2021. Patients were divided into the FIC group (n = 47) and the non-FIC group (n = 34). For univariate analysis, t test, Mann-Whitney U test, Pearson χ 2 test, or Fisher exact test was performed to explore the differences between the 2 groups. For multivariate analysis, simple and multiple linear regression was conducted to explore the effect of FIC on the duration of HOT. RESULTS: (1) The duration of HOT and length of stay after grouping were significantly shorter in the FIC group than in the non-FIC group ( P < .05). (2) The results of linear regression further revealed that FIC could significantly shorten the duration of HOT (simple linear regression, FIC [A] B : -12.709, 95% confidence interval (CI): -21.665 to -3.753; multiple linear regression, FIC [B] B : -11.419, 95% CI: -18.055 to -4.783). IMPLICATIONS FOR PRACTICE AND RESEARCH: FIC improved the optimal target oxygen saturation ratio before discharge and shortened the duration of HOT in premature infants with moderate and severe BPD. FIC should be promoted in China's neonatal intensive care units, though it puts forward new requirements for nursing education and training.

A Review of the Use of Extracellular Vesicles in the Treatment of Neonatal Diseases: Current State and Problems with Translation to the Clinic.

Neonatal disorders, particularly those resulting from prematurity, pose a major challenge in health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects of EVs and mechanistic insights into EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic-ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes evidence for the therapeutic potential of EVs, analyzes evidence of their mechanisms of action and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.

Five-year follow-up of phase II trial of stromal cells for bronchopulmonary dysplasia.

BACKGROUND: We previously performed a phase II randomised double-blind clinical trial of mesenchymal stromal cell (MSCs) transplantation to prevent bronchopulmonary dysplasia in extremely premature infants. Subsequently, we followed the infants enrolled in this clinical trial to determine the safety and effectiveness of MSCs against bronchopulmonary dysplasia at 5-year follow-up. METHODS: We evaluated infants at 5 years of age receiving placebo or MSCs in a prospective follow-up study. RESULTS: In terms of the primary end point of composite respiratory morbidities, including respiratory problem-related readmission, emergency department visits or oxygen therapy, the MSC group had a rate of 60.7% for composite morbidities, while the control group showed a tendency of higher rate of 83.9% for the same outcomes without statistical significance. In terms of the secondary outcomes, the MSC group infants showed a tendency of being less likely to visit emergency department (control 67.7% vs MSC 35.7%) and to receive oxygen therapy (control 29.0% vs MSC 3.6%). No difference was observed in the incidence of respiratory problem-related hospital readmission or wheezing episodes between the groups. CONCLUSION: Intratracheally instilled MSCs showed the possibility of potential to decrease respiratory symptom-related emergency department visits and oxygen therapy episodes in infants born extremely preterm during the 5 years after a phase II randomised controlled, double-blind trial of MSCs transplantation for bronchopulmonary dysplasia. This small size study suggests preliminary insights that can be further tested using larger sample sizes. TRIAL REGISTRATION NUMBER: NCT01897987.

Discharge Practices for Infants with Bronchopulmonary Dysplasia: A Survey of National Experts.

OBJECTIVE: To establish consensus practices among a panel of national experts for the discharge of premature infants with bronchopulmonary dysplasia (BPD) from the hospital to home. STUDY DESIGN: We conducted a Delphi study that included US neonatologists and pediatric pulmonologists from the Bronchopulmonary Dysplasia Collaborative to establish consensus practices-defined as recommendations with at least 80% agreement-for infants with BPD being discharged from the hospital. Specifically, we evaluated recommendations for diagnostic tests to be completed around discharge, follow-up respiratory care, and family education. RESULTS: Thirty-one expert participants completed 3 rounds of surveys, with a 99% response rate (92 of 93). Consensus was established that infants with moderate-severe BPD (ie, those who remain on respiratory support at 36 weeks) and those discharged on oxygen should be targeted for in-person pulmonary follow-up within 1 month of hospital discharge. Specialized neonatal follow-up is an alternative for infants with mild BPD. Infants with moderate or severe BPD should have an echocardiogram performed after 36 weeks to screen for pulmonary hypertension. Infants with BPD warrant additional evaluations if they have growth restriction or poor growth, pulmonary hypertension, or tachypnea and if they are discharged to home on oxygen, diuretics, or nonoral feeds. CONCLUSIONS: This Delphi survey establishes expert consensus around best practices for follow-up respiratory management and routine evaluation for infants with BPD surrounding neonatal discharge. Areas of disagreement for which consensus was not established are discussed.

Age at First Extubation Attempt and Death or Respiratory Morbidities in Extremely Preterm Infants.

OBJECTIVE: To describe the timing of first extubation in extremely preterm infants and explore the relationship between age at first extubation, extubation outcome, and death or respiratory morbidities. STUDY DESIGN: In this subanalysis of a multicenter observational study, infants with birth weights of 1250 g or less and intubated within 24 hours of birth were included. After describing the timing of first extubation, age at extubation was divided into early (within 7 days from birth) vs late (days of life 8-35), and extubation outcome was divided into success vs failure (reintubation within 7 days after extubation), to create 4 extubation groups: early success, early failure, late success, and late failure. Logistic regression analyses were performed to evaluate associations between the 4 groups and death or bronchopulmonary dysplasia, bronchopulmonary dysplasia among survivors, and durations of respiratory support and oxygen therapy. RESULTS: Of the 250 infants included, 129 (52%) were extubated within 7 days, 93 (37%) between 8 and 35 days, and 28 (11%) beyond 35 days of life. There were 93, 36, 59, and 34 infants with early success, early failure, late success, and late failure, respectively. Although early success was associated with the lowest rates of respiratory morbidities, early failure was not associated with significantly different respiratory outcomes compared with late success or late failure in unadjusted and adjusted analyses. CONCLUSIONS: In a contemporary cohort of extremely preterm infants, early extubation occurred in 52% of infants, and only early and successful extubation was associated with decreased respiratory morbidities. Predictors capable of promptly identifying infants with a high likelihood of early extubation success or failure are needed.

Ranking Future Outcomes Most Important to Parents of Children with Bronchopulmonary Dysplasia.

OBJECTIVE: To assess which potential future outcomes are most important to parents of children with bronchopulmonary dysplasia, a disease that affects future respiratory, medical, and developmental outcomes for children born preterm. STUDY DESIGN: We recruited parents from 2 children's hospitals' neonatal follow-up clinics and elicited their importance rating for 20 different potential future outcomes associated with bronchopulmonary dysplasia. These outcomes were identified and selected through a literature review and discussions with panels of parents and clinician stakeholders, via a discrete choice experiment. RESULTS: One hundred and 5 parents participated. Overall, parents ranked "Will my child be more vulnerable to other problems because of having lung disease?" as the most important outcome, with other respiratory health related outcomes also highly ranked. Outcomes related to child development and effects on the family were among the lowest ranked. Individually, parents rated outcomes differently, resulting in a broad distribution of importance scores for many of the outcomes. CONCLUSIONS: The overall rankings suggest that parents prioritize future outcomes related to physical health and safety. Notably, for guiding research, some top-rated outcomes are not traditionally measured in outcome studies. For guiding individual counseling, the broad distribution of importance scores for many outcomes highlights the extent to which parents differ in their prioritization of outcomes.

Practices and Outcomes from a Prospective, Multicenter Registry for Preterm Newborns with Pulmonary Hypertension.

OBJECTIVE: To describe current treatment practices of preterm infants with early hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) and their association with patient outcomes. STUDY DESIGN: We developed a prospective, observational, multicenter clinical registry of preterm newborns <34 weeks' gestation with HRF and PH, based on either clinical or echocardiographic evidence during the first 72 hours of life, from 28 neonatal intensive care units in the US from 2017 through 2022. The primary end point was mortality among those who did or did not receive PH-targeted treatment, and the secondary end points included comparisons of major morbidities. Variables were compared using t tests, Wilcoxon rank-sum tests, Fisher exact tests, and χ² tests. RESULTS: We analyzed the results of 224 preterm infants enrolled in the registry. Of which, 84% (188/224) received PH-targeted treatment, most commonly inhaled nitric oxide (iNO). Early mortality in this cohort was high, as 33% (71/224) of this sample died in the first month of life, and 77% of survivors (105/137) developed bronchopulmonary dysplasia. Infants who received PH-targeted treatment had higher oxygenation indices at the time of enrollment (28.16 [IQR: 13.94, 42.5] vs 15.46 [IQR: 11.94, 26.15]; P = .0064). Patient outcomes did not differ between those who did or did not receive PH-targeted therapy. CONCLUSIONS: Early-onset HRF with PH in preterm infants is associated with a high early mortality and a high risk of developing bronchopulmonary dysplasia. iNO is commonly used to treat early-onset PH in preterm infants with HRF. In comparison with untreated infants with lower oxygenation indices, iNO treatment in severe PH may prevent poorer outcomes.

Nesfatin-1 alleviates hyperoxia-induced lung injury in newborn mice by inhibiting oxidative stress through regulating SIRT1/PGC-1α pathway.

Bronchopulmonary dysplasia (BPD) is a pulmonary disease commonly observed in premature infants and it is reported that oxidative stress is a critical induction factor in BPD and is considered as a promising target for treating BPD. Nesfatin-1 is a brain-gut peptide with inhibitory effects on food intake, which is recently evidenced to show suppressive effect on oxidative stress. The present study aims to explore the therapeutic effect and mechanism of Nesfatin-1 in BPD mice. AECIIs were extracted from newborn rats and exposed to hyperoxia for 24 h, followed by treatment with 5 and 10 nM Nesfatin-1. Declined cell viability, increased apoptotic rate, upregulated Bax, downregulated Bcl-2, increased release of ROS and MDA, and suppressed SOD activity were observed in hyperoxia-treated AECIIs, which were extremely reversed by Nesfatin-1. Newborn rats were exposed to hyperoxia, followed by treated with 10 µg/kg Nesfatin-1 and 20 µg/kg Nesfatin-1. Severe pathological changes, elevated MDA level, and declined SOD activity were observed in lung tissues of BPD mice, which were rescued by Nesfatin-1. Furthermore, the protective effect of Nesfatin-1 on hyperoxia-challenged AECIIs was abolished by silencing SIRT1. Collectively, Nesfatin-1 alleviated hyperoxia-induced lung injury in newborn mice by inhibiting oxidative stress through regulating SIRT1/PGC-1α pathway.

Mesenchymal Stromal/Stem Cell Extracellular Vesicles and Perinatal Injury: One Formula for Many Diseases.

Over the past decades, substantial advances in neonatal medical care have increased the survival of extremely premature infants. However, there continues to be significant morbidity associated with preterm birth with common complications including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neuronal injury such as intraventricular hemorrhage (IVH) or hypoxic ischemic encephalopathy (HIE), as well as retinopathy of prematurity (ROP). Common developmental immune and inflammatory pathways underlie the pathophysiology of such complications providing the opportunity for multisystem therapeutic approaches. To date, no single therapy has proven to be effective enough to prevent or treat the sequelae of prematurity. In the past decade mesenchymal stem/stromal cell (MSC)-based therapeutic approaches have shown promising results in numerous experimental models of neonatal diseases. It is now accepted that the therapeutic potential of MSCs is comprised of their secretome, and several studies have recognized the small extracellular vesicles (sEVs) as the paracrine vector. Herein, we review the current literature on the MSC-EVs as potential therapeutic agents in neonatal diseases and comment on the progress and challenges of their translation to the clinical setting.

Single-Cell RNA Sequencing-Based Characterization of Resident Lung Mesenchymal Stromal Cells in Bronchopulmonary Dysplasia.

Late lung development is a period of alveolar and microvascular formation, which is pivotal in ensuring sufficient and effective gas exchange. Defects in late lung development manifest in premature infants as a chronic lung disease named bronchopulmonary dysplasia (BPD). Numerous studies demonstrated the therapeutic properties of exogenous bone marrow and umbilical cord-derived mesenchymal stromal cells (MSCs) in experimental BPD. However, very little is known regarding the regenerative capacity of resident lung MSCs (L-MSCs) during normal development and in BPD. In this study we aimed to characterize the L-MSC population in homeostasis and upon injury. We used single-cell RNA sequencing (scRNA-seq) to profile in situ Ly6a+ L-MSCs in the lungs of normal and O2-exposed neonatal mice (a well-established model to mimic BPD) at 3 developmental timepoints (postnatal days 3, 7, and 14). Hyperoxia exposure increased the number and altered the expression profile of L-MSCs, particularly by increasing the expression of multiple pro-inflammatory, pro-fibrotic, and anti-angiogenic genes. In order to identify potential changes induced in the L-MSCs transcriptome by storage and culture, we profiled 15 000 Ly6a+ L-MSCs after in vitro culture. We observed great differences in expression profiles of in situ and cultured L-MSCs, particularly those derived from healthy lungs. Additionally, we have identified the location of Ly6a+/Col14a1+ L-MSCs in the developing lung and propose Serpinf1 as a novel, culture-stable marker of L-MSCs. Finally, cell communication analysis suggests inflammatory signals from immune and endothelial cells as main drivers of hyperoxia-induced changes in L-MSCs transcriptome.

Bone Marrow Stromal Cell-Secreted Extracellular Vesicles Containing miR-34c-5p Alleviate Lung Injury and Inflammation in Bronchopulmonary Dysplasia Through Promotion of PTEN Degradation by Targeting OTUD3.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the predominant chronic disorder in preterm neonates. This study explored impacts of miR-34c-5p carried by bone marrow stromal cells-secreted extracellular vesicles (BMSC-EVs) on BPD progression. METHODS: A BPD mouse model was established, followed by measurement of miR-34c-5p, OTUD3, and PTEN expression. EVs were isolated from BMSCs transfected with miR-34c-5p mimic or mimic NC and intratracheally injected into mice. CD31 and Ki67 expression was detected and the pathological changes of lung tissues and lung function indexes were observed for mice. A neonatal human pulmonary microvascular endothelial cell (HPMEC) model was developed with hyperoxia, followed by co-culture with extracted EVs and ectopic experiments for measurement of cell viability, migration, and angiogenesis. IL-4, IL-13, IL-1ß, and IL-6 levels were measured in cell supernatants and lung tissues. Dual-luciferase reporter, ubiquitination, Co-IP, and RIP assays were adopted to determine the relationship among miR-34c-5p, OTUD3, and PTEN. RESULTS: Lung tissues of BPD mice had downregulated miR-34c-5p expression and upregulated OTUD3 and PTEN expression. BMSC-EVs and BMSC-EVs-miR-34c-5p treatment improved lung injury and alveolar structure, decreased lung resistance and IL-4, IL-13, IL-1ß, and IL-6 levels, and elevated dynamic lung compliance in BPD mice, as well as enhanced proliferation, angiogenesis, and migration and restrained inflammation in HPMECs. Mechanistically, miR-34c-5p negatively targeted OTUD3 which restrained ubiquitination to promote PTEN protein stabilization. Upregulation of OTUD3 or PTEN negated the changes in the proliferation, angiogenesis, migration, and inflammation of hyperoxia-treated HPMECs induced by BMSC-EVs-miR-34c-5p. CONCLUSION: BMSC-EVs-miR-34c-5p alleviated lung injury and inflammation in hyperoxia-induced BPD by blocking the OTUD3/PTEN axis.

The infant with bronchopulmonary dysplasia on home oxygen: The oxygen weaning conundrum in the absence of good evidence.

Bronchopulmonary dysplasia [BPD] is the most common complication of extremely preterm delivery and its optimal management remains challenging because of a lack of evidence to guide management. There has been improvement in the management of evolving BPD in the neonatal intensive care unit (NICU). The threshold for provision of home oxygen therapy, often occurring because of a preference for earlier discharge from the NICU, creates tensions for clincians and families. Once discharged in supplemental oxygen, the approaches for the weaning of this therapy vary considerably across the world. Regardless of guidelines and multidisciplinary team support, up to a third of families of an infant with BPD elect to withdraw home oxygen therapy independently of medical advice. There is a pressing need to derive evidence to better inform practice, generate international consensus and undertake large, appropriately funded, longitudinal studies of BPD with clinically meaningful outcomes (respiratory, cardiovascular and neurodevelopmental) from infancy to adulthood.

Insulin-like growth factor-1 replacement therapy after extremely premature birth: An opportunity to optimize lifelong lung health by preserving the natural sequence of lung development.

The past decades have seen markedly improved survival of increasingly immature preterm infants, yet major health complications persist. This is particularly true for bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, which has become the most common sequelae of prematurity and a significant predictor of respiratory morbidity throughout childhood as well as adult life, neurodevelopmental disability, cardiovascular disease, and even death. The need for novel approaches to reduce BPD and related complications of prematurity has never been more critical. Thus, despite major advances in the use of antenatal steroids, surfactant therapy, and improvements in respiratory support, there is a persistent need for developing therapeutic strategies that more specifically reflect our growing understanding of BPD in the post-surfactant age, or the "new BPD." In contrast with the severe lung injury leading to marked fibroproliferative disease from the past, the "new BPD" is primarily characterized by an arrest of lung development as related to more extreme prematurity. This distinction and the continued high incidence of BPD and related sequelae suggest the need to identify therapies that target critical mechanisms that support lung growth and maturation in conjunction with treatments to improve respiratory outcomes across the lifespan. As the prevention of BPD and its severity remains a primary goal, we highlight the concept from preclinical and early clinical observations that insulin-like growth factor 1 (IGF-1) can potentially support the natural sequence of lung growth as a replacement therapy after preterm birth. Data supporting this hypothesis are robust and include observations that low IGF-1 levels persist after extremely preterm birth in human infants and strong preclinical data from experimental models of BPD highlight the therapeutic benefit of IGF-1 in reducing disease. Importantly, phase 2a clinical data in extremely premature infants where replacement of IGF-1 with a human recombinant human IGF-1 complexed with its main IGF-1 binding protein 3, significantly reduced the most severe form of BPD, which is strongly associated with multiple morbidities that have lifelong consequences. As physiologic replacement therapy of surfactant heralded the success of reducing acute respiratory distress syndrome in preterm infants, the paradigm has the potential to become the platform for discovering the next generation of therapies like IGF-1, which becomes deficient after extremely premature birth where endogenous production by the infant is not sufficient to maintain the physiologic levels adequate to support normal organ development and maturation.

Prematurity and BPD: what general pediatricians should know.

More and more very low birth weight (VLBW) infants around the world survive nowadays, with consequently larger numbers of children developing prematurity-related morbidities, especially bronchopulmonary dysplasia (BPD). BPD is a multifactorial disease and its rising incidence in recent years means that general pediatricians are much more likely to encounter a child born extremely preterm, possibly with BPD, in their clinical practice. Short- and long-term sequelae in VLBW patients may affect not only pulmonary function (principally characterized by an obstructive pattern), but also other aspect including the neurological (neurodevelopmental and neuropsychiatric disorders), the sensorial (earing and visual impairment), the cardiological (systemic and pulmonary hypertension, reduced exercise tolerance and ischemic heart disease in adult age), nutritional (feeding difficulties and nutritional deficits), and auxological (extrauterine growth restriction). For the most premature infants at least, a multidisciplinary follow-up is warranted after discharge from the neonatal intensive care unit in order to optimize their respiratory and neurocognitive potential, and prevent respiratory infections, nutritional deficiencies or cardiovascular impairments.  Conclusion: The aim of this review is to summarize the main characteristics of preterm and BPD infants, providing the general pediatrician with practical information regarding these patients' multidisciplinary complex follow-up. We explore the current evidence on respiratory outcomes and their management that actually does not have a definitive available option. We also discuss the available investigations, treatments, and strategies for prevention and prophylaxis to improve the non-respiratory outcomes and the quality of life for these children and their families, a critical aspect not always considered. This comprehensive approach, added to the increased needs of a VLBW subjects, is obviously related to very high health-related costs that should be beared in mind. What is Known: • Every day, a general pediatrician is more likely to encounter a former very low birth weight infant. • Very low birth weight and prematurity are frequently related not only with worse respiratory outcomes, but also with neurological, sensorial, cardiovascular, renal, and nutritional issues. What is New: • This review provides to the general pediatrician a comprehensive approach for the follow-up of former premature very low birth weight children, with information to improve the quality of life of this special population.

Pulmonary and Neurologic Effects of Mesenchymal Stromal Cell Extracellular Vesicles in a Multifactorial Lung Injury Model.

Rationale: Bronchopulmonary dysplasia, a chronic respiratory condition originating from preterm birth, is associated with abnormal neurodevelopment. Currently, there is an absence of effective therapies for bronchopulmonary dysplasia and its associated brain injury. In preclinical trials, mesenchymal stromal cell therapies demonstrate promise as a therapeutic alternative for bronchopulmonary dysplasia. Objectives: To investigate whether a multifactorial neonatal mouse model of lung injury perturbs neural progenitor cell function and to assess the ability of human umbilical cord-derived mesenchymal stromal cell extracellular vesicles to mitigate pulmonary and neurologic injury. Methods: Mice at Postnatal Day 7 or 8 were injected intraperitoneally with LPS and ventilated with 40% oxygen at Postnatal Day 9 or 10 for 8 hours. Treated animals received umbilical cord-mesenchymal stromal cell-derived extracellular vesicles intratracheally preceding ventilation. Lung morphology, vascularity, and inflammation were quantified. Neural progenitor cells were isolated from the subventricular zone and hippocampus and assessed for self-renewal, in vitro differentiation ability, and transcriptional profiles. Measurements and Main Results: The multifactorial lung injury model produced alveolar and vascular rarefaction mimicking bronchopulmonary dysplasia. Neural progenitor cells from lung injury mice showed reduced neurosphere and oligodendrocyte formation, as well as inflammatory transcriptional signatures. Mice treated with mesenchymal stromal cell extracellular vesicles showed significant improvement in lung architecture, vessel formation, and inflammatory modulation. In addition, we observed significantly increased in vitro neurosphere formation and altered neural progenitor cell transcriptional signatures. Conclusions: Our multifactorial lung injury model impairs neural progenitor cell function. Observed pulmonary and neurologic alterations are mitigated by intratracheal treatment with mesenchymal stromal cell-derived extracellular vesicles.