RARE DISEASE
Bronchopulmonary dysplasia
Bronchopulmonary dysplasia
Bronchopulmonary dysplasia
Synonyms: BPD
Synonyms: BPD
Synonyms: BPD
Drug discovery
34
drugs
With orphan designations
Overview
Bronchopulmonary dysplasia (BPD) is a chronic lung disease primarily affecting preterm infants, characterized by prolonged oxygen dependency and ventilatory support due to disrupted alveolar and vascular development. Diagnosed when supplemental oxygen is required beyond 28 days or at 36 weeks postmenstrual age, it often results from interventions like mechanical ventilation in immature lungs [1][6][11]. Management focuses on minimizing lung injury, optimizing nutrition, and stepwise weaning from respiratory support [1][3][8].
Burden
Healthcare costs: Up to $799,499 per infant during initial hospitalization, with 58% requiring ≥2 readmissions in the first year [4][14]
Morbidity: 33-75% develop pulmonary hypertension; 46% experience recurrent respiratory symptoms post-discharge [9][16]
Long-term impacts: 2-4× higher risk of neurodevelopmental delays and asthma-like symptoms through childhood [5][12][16]
BPD remains a critical driver of neonatal healthcare utilization, with gestational age at birth being the strongest predictor of outcomes [4][12][14].
Therapies
Supportive care: Oxygen titration, fluid restriction, caffeine for apnea prevention, and nutritional optimization [3][8][13]
Pharmacologic: Late systemic dexamethasone (after 7 days), diuretics, and inhaled bronchodilators/corticosteroids [3][8][18]
Preventive: Antenatal corticosteroids, surfactant therapy, non-invasive ventilation, and vitamin A supplementation [1][13]
Emerging therapies under investigation: Mesenchymal stromal cells, IGF-1/IGFBP-3, and interleukin-1 receptor antagonists [3][13]
Categories: rare developmental anomalies during embryogenesis, rare respiratory diseases, rare surgical thoracic diseases
Research Papers
4,247 drug discovery papers about Bronchopulmonary dysplasia, with 5 first-in-class and 39 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
4,247 drug discovery papers about Bronchopulmonary dysplasia, with 5 first-in-class and 39 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Sildenafil in bronchopulmonary dysplasia-associated pulmonary hypertension: developmental and translational insights.
Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) is increasingly viewed as a developmental pulmonary vascular disorder rather than a purely reactive vasoconstrictive complication of chronic lung disease. It involves impaired angiogenesis, reduced pulmonary vascular surface area, alveolar simplification, and progressive right ventricle-pulmonary artery uncoupling. Sildenafil, a phosphodiesterase type 5 inhibitor, is widely used because it enhances nitric oxide-cyclic guanosine monophosphate signaling and may reduce pulmonary vascular tone. However, neonatal-specific evidence remains limited, dosing approaches are heterogeneous, and its long-term effects on vascular remodeling and clinical outcomes are uncertain. This narrative review integrates developmental biology, translational evidence, clinical studies, pharmacokinetics, and safety considerations to critically evaluate sildenafil in BPD-PH. Current data support short-term improvements in echocardiographic hemodynamics and oxygenation in selected infants, but do not demonstrate durable remodeling reversal or improved survival. Experimental studies suggest effects on endothelial survival, smooth muscle proliferation, angiogenic signaling, and oxidative stress, although relevance to human preterm infants remains incompletely validated. Developmental pharmacokinetics, including CYP3A maturation, weight, postnatal age, route, and drug interactions, contribute to variable exposure. Sildenafil use should therefore be individualized, phenotype-guided, and evaluated in future trials with pharmacokinetic-guided dosing and longitudinal outcomes. IMPACT: Reframes bronchopulmonary dysplasia-associated pulmonary hypertension as a disorder of impaired pulmonary vascular development rather than a purely reactive vasoconstrictive process. Integrates developmental biology, translational evidence, and neonatal pharmacokinetics to critically evaluate sildenafil beyond its traditional vasodilatory role. Highlights the need for precision pharmacology approaches and pharmacokinetic-guided dosing to optimize therapeutic strategies in preterm infants.
2026-09-30 | The immune system in postnatal lung development.
The human lungs begin their development early in gestation. Both in utero and postnatally, the lungs undergo intricate morphological changes, the complex regulation of which has been extensively studied for decades. Even before the first breath, immune cells migrate into the lungs in a specific temporal, wave-like manner. Recent evidence suggests that both innate and adaptive immune cells actively participate in alveolarization. In this article, we provide an overview of how the immune system interfaces with the developing lungs. By examining the pathways utilized by the immune system in this context, we can enhance our understanding of their roles in specific developmental processes. Further, we review the effects of dysregulated lung immunity on lung development and the role of immunity in bronchopulmonary dysplasia.
2026-09-29 | Intratracheal budesonide combined with surfactant for respiratory distress syndrome in preterm infants: A randomized clinical trial.
BackgroundBronchopulmonary dysplasia (BPD) remains a major cause of morbidity among preterm infants with respiratory distress syndrome (RDS). Intratracheal budesonide combined with surfactant may reduce pulmonary inflammation and improve neonatal outcomes.MethodsIn this randomized clinical trial, 160 preterm infants (gestational age 26-32 weeks; birth weight <1500 g) requiring surfactant therapy for RDS were assigned to receive either surfactant alone (n = 80) or surfactant plus budesonide (0.25 mg/kg; n = 80). Primary outcomes were oxygen dependency or respiratory support beyond 21 days of life (the prespecified study respiratory outcome) and in-hospital mortality. Secondary outcomes included sepsis, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, respiratory support duration, and repeat surfactant administration.ResultsBaseline characteristics were comparable between groups. The primary respiratory outcome occurred in 16/80 infants (20.0%) in the budesonide-surfactant group and 26/80 infants (32.5%) in the surfactant-alone group (absolute risk difference -12.5 percentage points; P = 0.105). Mortality was significantly lower in the combination group (1.2% vs 11.2%, P = 0.018), as was culture-proven sepsis (5.0% vs 21.2%, P = 0.004). Infants receiving budesonide required fewer repeat surfactant doses (38.8% vs 61.3%, P = 0.016) and had a shorter duration of nasal continuous positive airway pressure support (10.1 ± 6.0 vs 17.9 ± 11.3 days, P = 0.001). The composite outcome of death or oxygen dependency/respiratory support beyond 21 days of life occurred in 35 infants (43.8%) in the control group and 17 infants (21.3%) in the combination group (P = 0.003).ConclusionsIn preterm infants with RDS, budesonide-surfactant therapy was associated with reduced mortality, sepsis, respiratory support duration, and repeat surfactant use. Although fewer infants in the intervention group met the prespecified respiratory outcome, the difference was not statistically significant. Larger multicenter trials using contemporary BPD definitions and incorporating long-term neurodevelopmental follow-up are needed before efficacy and safety can be established.
2026-09-26 | HSP90 Inhibitor, AT13387 Mitigates Chronic Lung Injury in Pre-Pubertal Mice: A Therapeutic Axis in Bronchopulmonary Dysplasia.
Exposure to hydrochloric acid (HCl) can provoke severe chronic pulmonary injury. Children are particularly vulnerable due to their smaller airways, higher respiratory rate, and stronger inflammatory response; yet no countermeasures exist for HCl-induced chronic lung injury in the pediatric population. We have previously demonstrated the involvement of HSP90 during HCl-induced lung injury in pre-pubertal (p24) mice, who develop stronger persistent inflammation with higher NLRP3 inflammasome activation, but less pulmonary fibrosis compared to adults. Here, we tested the hypothesis that post-treatment with the second-generation HSP90 inhibitor AT13387 (Onalespib), administered subcutaneously beginning 24 h after HCl instillation, would prevent HCl-induced chronic lung injury and pulmonary fibrosis in young (p24) C57BL/6J mice. Pre-pubertal (p24) C57BL/6J mice received a single intratracheal instillation of 0.1 N HCl and were treated with AT13387 (10 mg/kg, s.c., 3×/week for 30 days) beginning 24 h post-exposure. Bronchoalveolar lavage fluid (BALF) analysis, lung function measurements, histological assessment (Ashcroft fibrosis score), and Western blot analysis of key signaling mediators were performed. Additionally, publicly available single-nucleus RNA sequencing (snRNA-Seq) data from a cohort of 13 infants with bronchopulmonary dysplasia (BPD) and 11 age-matched controls were analyzed to evaluate HSP90 isoform expression in human pediatric lung disease. AT13387 significantly reduced BALF white blood cell concentration without affecting total BALF protein levels. Importantly, AT13387 did not impair normal weight gain or development over the 30-day observation period. AT13387 abrogated HCl-induced expression of TGF-β1, phosphorylation of HSP90, ERK1/2, SMAD2, IκBα, and upregulation of the inflammasome NLRP3. Additionally, AT13387 prevented changes in lung function dynamics and reduced the Ashcroft fibrosis score. Analysis of the human snRNA-Seq BPD dataset revealed a widespread pan-overexpression of all three HSP90 isoforms, i.e., HSP90AA1, HSP90AB1, and HSP90B1. These findings suggest that the HSP90 inhibitor AT13387 exhibits strong antidotal properties against HCl-induced chronic lung injury and pulmonary fibrosis in a pre-clinical pediatric model and identify HSP90 as a conserved therapeutic target in pediatric chronic lung disease.
2026-09-23 | The gut-lung axis in early life: microbiome-associated mechanisms and clinical relevance.
The early-life microbiome is increasingly recognised as a contributor to immune maturation and respiratory health. Early-life microbial colonisation is highly dynamic and shaped by multiple factors. Recently, the gut-lung axis has emerged as a framework describing bidirectional communication between the intestinal microbiota and the respiratory system via microbial metabolites, immune mediators and neuroimmune pathways. Although current evidence is largely derived from studies of bacterial communities, emerging data suggest that other microbial components, including fungi and viruses, may also contribute to gut-lung interactions. This review synthesises current mechanistic and clinical evidence on the gut-lung axis with a specific focus on neonatology. We discuss how early microbiome composition may influence immune regulation, lung development and inflammatory response. Associations between intestinal microbiota alterations and major neonatal morbidities, including bronchopulmonary dysplasia, are discussed, as well as emerging evidence linking early-life microbial imbalance to long-term respiratory outcomes such as recurrent infections and asthma. We further examine emerging translational opportunities, including microbiome- and metabolome-based biomarkers for early risk stratification, and microbiota-targeted interventions. Attention is given to the strengths and limitations of the current evidence base, including the predominance of observational human studies and preclinical animal models. Overall, available evidence suggests that the developing microbiome represents a potentially important mediator of gut-lung communication in early life. However, substantial gaps remain regarding causality, underlying mechanisms and clinical applicability. Further longitudinal and interventional studies are needed to define the role of microbiome-targeted strategies in improving neonatal and long-term respiratory outcomes.
antibodies
2026-09-13 | Survival without major morbidity in very preterm infants (<32 weeks' gestation): prevalence, temporal trends, and associated factors in a single-center retrospective cohort.
To determine the proportion of very preterm infants (VPIs) surviving without major morbidity (SWMM), assess temporal trends from 2021 to 2025, and identify associated factors. This single-center retrospective cohort study included all inborn VPIs admitted to the neonatal intensive care unit (NICU) of Guangdong Women and Children Hospital between January 2021 and October 2025. Primary analyses were performed among infants receiving complete care, whereas infants discharged against medical advice (DAMA) were analyzed separately. SWMM was defined as survival without bronchopulmonary dysplasia (BPD), severe brain injury, necrotizing enterocolitis (NEC) stage II or higher, late-onset sepsis (LOS), or severe retinopathy of prematurity (ROP). Temporal trends were evaluated using logistic regression with gestational age (GA)-adjusted annual rates estimated by marginal standardization. Factors associated with SWMM were assessed using multivariable logistic regression. A total of 1,172 VPIs were included, with a median GA of 30.0 weeks (IQR, 28.6-31.1) and a median birth weight of 1,270 g (IQR, 1,050-1,500). In the complete-care cohort (n = 1,094), survival was 95.5% (1,045/1,094) and SWMM was 59.9% (655/1,094). From 2021 to 2025, survival remained high and stable. After GA adjustment, BPD, severe ROP, and LOS increased over time, whereas SWMM declined. Multivariable analysis showed that higher GA (per week: OR 2.62, 95% CI 2.30-3.01) and greater birth weight z score (per SD: OR 2.13, 95% CI 1.76-2.59) were associated with higher odds of SWMM, whereas male sex (OR 0.66, 95% CI 0.48-0.91), additional surfactant doses (per dose: OR 0.47, 95% CI 0.37-0.59), and a 5-minute Apgar score ≤7 (OR 0.27, 95% CI 0.10-0.69) were associated with lower odds. DAMA occurred in 6.7% of VPIs (78/1,172) and decreased with increasing GA, from 30.0% at ≤25 weeks to 1.9% at 31 weeks. The estimated post-DAMA survival rate was 24.4% (19/78). Survival among VPIs remained high and stable, whereas SWMM remained suboptimal and declined over time. The increasing burden of BPD and severe ROP underscores the importance of improving the quality of survival. Strategies including GA-stratified care, optimized perinatal stabilization, early respiratory management, and reduced DAMA may improve outcomes in this high-risk population.
2026-09-10 | Temporal regulation of wnt signaling in alveolar development and regeneration: mechanistic insights and therapeutic advances in chronic lung diseases.
Wnt signaling coordinates lung specification, alveolar maturation, adult epithelial maintenance, and injury repair, but its biological output varies with developmental or disease stage, anatomical compartment, responding cell type, receptor context, and signal duration. This review organizes current evidence using a temporal-spatial framework that links Wnt ligands and receptors to source and responding cells, downstream canonical or noncanonical pathways, interacting signaling networks, and cellular outcomes. During development, mesenchymal Wnt2/2 b-β-catenin signaling specifies pulmonary endoderm, whereas canonical and noncanonical Wnt programs subsequently regulate distal progenitor expansion, branching geometry, epithelial differentiation, secondary septation, pulmonary microvascular maturation, and postnatal lung growth; maintenance of an AXIN2 + alveolar type 2 (AT2) progenitor niche becomes a distinct function in the adult lung. After adult alveolar injury, Wnt activity is dynamically remodeled as AT2 cells proliferate and traverse damage-associated transient progenitor and keratin 8-positive (KRT8+) transitional states before restoring the alveolar type 1 cell layer. This framework helps reconcile apparently discordant observations in chronic lung diseases. Bronchopulmonary dysplasia disrupts Wnt timing during alveologenesis; chronic obstructive pulmonary disease can combine deficient canonical Wnt responsiveness in the alveolar compartment with Wnt5a-associated inhibition of repair and distinct airway Wnt activation; and idiopathic pulmonary fibrosis features persistent Wnt-transforming growth factor-β signaling in abnormal epithelial and fibroblast niches. Therapeutic translation should therefore avoid indiscriminate pathway activation or inhibition and instead pursue reversible, local, biomarker-guided modulation matched to disease stage, cellular compartment, receptor profile, dose, and duration.
2026-07-30 | The IL-33-ILC2 axis: a key regulator of type 2 immunity in respiratory disease.
Respiratory diseases represent a major global public health burden, and type 2 immunity plays a key role in their pathogenesis. The interleukin-33 (IL-33)-group 2 innate lymphoid cell (ILC2) axis regulates airway type 2 immune responses, thereby triggering, amplifying, and maintaining pathological inflammation. This review addresses the characteristics of IL-33 and pulmonary ILC2s, including the alarmin function and tissue-specific expression of IL-33, and the origin, localization, functional heterogeneity, and microenvironment-driven plasticity of ILC2s. In particular, we discuss how disease-specific microenvironments shape divergent ILC2 states, including classical type 2 cytokine-producing ILC2s, tissue-repairing AREG-producing ILC2s, ILC1-like cells, and IL-17-producing ILC2-like states. We further review the regulatory mechanisms of the IL-33-ILC2 axis in bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and viral respiratory infections are also discussed, highlighting the remarkable functional plasticity of ILC2s. Targeting the IL-33-ILC2 axis and modulating ILC2 function represent therapeutic strategies for various type 2-mediated airway diseases.
2026-07-16 | Systems-level insights into bronchopulmonary dysplasia from meta-analysis of genome-scale studies.
Despite marked improvements in survival following preterm birth, the incidence of bronchopulmonary dysplasia (BPD) remains the most prevalent complication of prematurity and carries the risk of long-term morbidity. Characterising the cellular and molecular mechanisms driving disease progression is critical for informing clinical management and improving outcomes. To this end, we conducted a meta-analysis of genome-scale studies to identify molecular pathways implicated in BPD progression in both human cohorts and animal models. Gene lists associated with BPD in humans, and in rodent models, were extracted from systematically identified genome-scale studies. These gene lists were subsequently analysed using the meta-analysis by information content (MAIC) algorithm, which integrates multiple datasets to generate a single aggregated, ranked gene list based on the cumulative strength of evidence for each gene. Comparative analyses were then performed between the human and rodent BPD datasets, as well as between the human BPD dataset and our previously generated Acute Respiratory Distress Syndrome MAIC dataset. Across all analyses, a consistent enrichment of genes involved in leukocyte-mediated antigen presentation and lymphocyte development and activation was observed, suggesting a shift from acute innate immune injury toward a more sustained lymphoid-driven inflammatory process during BPD progression. Comparative analyses revealed limited overlap between BPD and ARDS gene sets, suggesting divergent disease mechanisms, while still highlighting shared immune activation pathways. Human-rodent comparisons showed divergence in tissue remodelling signatures, likely reflecting differences in sample sources, yet converged on key conserved signals such as CD3E and IL1R2, implicating common inflammatory regulatory mechanisms. MAIC effectively identifies conserved molecular signatures in BPD highlighting lymphoid lineage signatures that are not readily apparent in the primary data. These signatures offer insights relevant to immune-modulatory therapeutic strategies, highlighting key processes involved in antigen presentation and modulation of T-cell activation and development during the progression of Bronchopulmonary Dysplasia.
2026-05-06 | Hyperoxia promotes bronchopulmonary dysplasia via Noggin-mediated BMP4 antagonism and cellular senescence.
Bronchopulmonary dysplasia (BPD) represents the most prevalent chronic pulmonary complication in preterm infants, with incompletely understood pathophysiological mechanisms. Hyperoxia exposure constitutes a major risk factor for BPD development, inducing cellular senescence that impairs alveolar maturation. While senescence is predominantly mediated by the p53/p21 signaling pathway, upstream regulatory mechanisms remain inadequately defined. This study aimed to identify critical genes through bioinformatics and elucidate the molecular mechanisms by which the Noggin-BMP4 signaling axis mediates cellular senescence in BPD pathogenesis. Integrating BPD transcriptomic datasets with aging-related databases via WGCNA, Noggin was identified as a hub gene linking BPD and cellular senescence (AUC = 0.80). In HPMECs exposed to 85% hyperoxia, Noggin expression increased approximately 2.5-fold (mRNA) and 2.0-fold (protein), while BMP4 decreased to 50% of controls, accompanied by elevated p53 and p21 expression and positive SA-β-gal staining. Noggin silencing restored BMP4 expression and significantly attenuated hyperoxia-induced p53/p21 upregulation, suggesting that Noggin promotes senescence by suppressing BMP4. In a neonatal rat hyperoxia-induced BPD model, alveolar simplification was observed alongside a threefold increase in Noggin mRNA, a reduction of BMP4 to 30% of controls, and elevated p53/p21 at day 14, corroborating the in vitro findings. These findings suggest that hyperoxia upregulates Noggin to antagonize BMP4 signaling, thereby activating p53/p21-mediated senescence and contributing to alveolar developmental arrest. The Noggin-BMP4 axis may represent a potential therapeutic target for BPD.
proteins
2026-09-06 | Bronchopulmonary dysplasia and prematurity-associated lung disease: emerging therapies to improve lifelong respiratory outcomes.
Survival of extremely preterm infants has improved owing to advances in perinatal and neonatal care. However, bronchopulmonary dysplasia (BPD) has remained unabated, and research into preventive measures for the broader spectrum of prematurity-associated lung disease (PLD) has met with limited success. We summarize emerging therapeutic strategies with the potential to favorably influence the lifelong trajectory of lung health of preterm infants, especially the most immature. This narrative review examines recent preclinical and clinical studies on therapies for BPD prevention, focusing on mechanism-based interventions, biologic strategies, and innovative translational tools. Preclinical evidence converges on actionable targets in alveolarization, inflammatory pathways, redox and mitochondrial homeostasis, vascular and matrix remodeling. Novel molecules and drug-repurposing strategies are being tested in animal models, while patient-derived platforms may enable personalized therapeutic approaches. Mechanism-based approaches are progressing through Phase 1-2 clinical trials; pending efficacy analyses, insulin-like growth factor-1 replacement may become the first pharmacological therapy specifically approved to reduce or attenuate BPD. In parallel, cell-based therapies and extracellular vesicle strategies offer a complementary paradigm, acting through pleiotropic biological reprogramming of the injured lung. Ethical-regulatory complexity and the challenges of standardizing and scaling cell-based and cell-free therapies may limit clinical translation. A growing repertoire of therapies for BPD holds promise for modifying early respiratory illness and the long-term burden of PLD. Realizing this potential will benefit from both mechanism-informed combinatorial approaches and pleiotropic strategies, supported by patient-derived translational tools and adequately powered efficacy evaluations. Equally essential are tailored neonatal-first regulatory pathways linking the continuum of BPD to the later respiratory morbidity of PLD, a life-course condition with significant public health relevance beyond the neonatal period. • Bronchopulmonary dysplasia (BPD) is the current clinical and regulatory endpoint for neonatal pulmonary therapies. • BPD definitions capture the most severe manifestations of prematurity-associated lung disease (PLD), a broader continuum of respiratory morbidity reaching into adulthood; attenuating BPD may improve the whole spectrum of PLD. • Therapies targeting alveolar, inflammatory, oxidative, vascular, and remodeling pathways are in clinical development; pending late-stage trials, IGF-1 replacement may become the first disease-modifying therapy to reduce BPD. • Novel targets, experimental platforms, and repurposed drugs hold promise for precision therapies in preterm infants.
2026-08-30 | A recombinant fragment of human surfactant protein D reduces lung inflammation in preterm lambs.
Bronchopulmonary dysplasia (BPD), the major chronic respiratory morbidity in extremely preterm infants, is largely driven by inflammation. Preterm lungs are deficient of surfactant protein D (SP-D), an immunomodulatory protein absent in current commercial surfactant preparations. We hypothesised that using a recombinant fragment of human SP-D (rfhSP-D) as an adjuvant to exogenous surfactant therapy would reduce ventilator-induced inflammation. We utilised a preterm lamb model of ventilator-associated lung injury. Mechanically ventilated preterm lambs were randomised into control and two treated groups, receiving endotracheal surfactant at 15 min post-delivery. Physiological parameters were measured throughout the experiment. Lung tissue was analysed for changes in alveolar architecture and expression levels of pro-inflammatory cytokines. Bronchioalveolar lavage (BAL) was analysed for SP-D concentration, and inflammatory cells. Intratracheal administration of rfhSP-D improved respiratory outcomes, significantly increased airspace and lung compliance in treated groups. Treated lambs also showed a reduction in lung tissue gene expression of inflammatory cytokines and inflammatory cell counts. Intratracheal administration of rfhSP-D did not negatively impact standard surfactant therapy and appeared to complement it. The administration of rfhSP-D as an adjuvant to standard surfactant therapy effectively reduced lung inflammation supporting the potential therapeutic use of rfhSP-D for preterm infants at risk of developing BPD. We have successfully developed and tested a novel recombinant fragment of human surfactant protein D (rfhSP-D) capable of reducing ventilator-associated lung inflammation in a pre-term lamb model. These results suggest rfhSP-D may be a novel potentially useful therapy for Bronchopulmonary dysplasia (BPD) in combination with currently available surfactant replacement therapies and serves as justification for a first in human clinical trial in mechanically ventilated infants. If successful, rfhSP-D could become a therapeutic candidate to mitigate pulmonary inflammation and improve lung outcomes, potentially offering a novel therapeutic avenue in the prevention or management of BPD.
2026-08-27 | A Premature Rabbit Kitten Model for Evaluation of Bronchopulmonary Dysplasia Therapies Reproduces Myeloperoxidase-Associated Pathology and Therapeutic Responses.
Myeloperoxidase (MPO) plays a significant role in the development and progression of bronchopulmonary dysplasia (BPD). The neonatal rat model has shown that the tripeptide N-acetyl-lysyltyrosylcysteine amide (KYC) attenuates hyperoxia-induced BPD-like injury, in part by reducing MPO-mediated toxic oxidants and additional cytoprotective mechanisms. However, the rat model does not fully replicate the key characteristics of surfactant deficiency and immature antioxidant capacity in premature human neonates. In contrast, premature rabbit kittens share key features with those of premature human neonates. For this study, premature rabbit kittens delivered at 29 days of gestation (term is 31 days) were exposed to 95% oxygen for 7 days. Hyperoxia caused a BPD-like phenotype characterized by increased MPO-positive inflammatory cell infiltration, elevated MPO expression, alveolar simplification, septal wall thickening, and pulmonary arterial medial wall thickening. Daily intraperitoneal KYC administration attenuated lung inflammatory cell infiltration, reduced MPO expression, improved alveolar morphometric indices, and mitigated pulmonary arterial medial wall thickening compared with phosphate-buffered saline treatment. There were no significant differences in weight changes or survival between the groups. These findings demonstrate that premature rabbit kittens provide a useful developmental model for the evaluation of candidate BPD therapies and reproduce MPO-associated pathological and therapeutic responses previously observed in neonatal rat studies.
2026-08-08 | Brain-derived neurotrophic factor (BDNF) in neonatal blood: associations with respiratory disease in extremely preterm infants.
Neurotrophins, including brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), have been associated with the development of bronchopulmonary dysplasia (BPD) in preterm infants. To evaluate relationships between early postnatal BDNF and NT-4 levels and adverse pulmonary outcomes among preterm infants. We analyzed data from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Serum BDNF and NT-4 were measured at birth and postnatal days 7, 14, 21, and 28. Pulmonary outcomes included BPD and early respiratory patterns predictive of BPD, specifically, pulmonary deterioration (PD) and early and persistent pulmonary dysfunction (EPPD). Associations were evaluated using regression models adjusted for perinatal confounders. NT-4 levels were not associated with BPD risk. Persistently high BDNF trajectories were associated with reduced risk, while persistently low BDNF was associated with increased risk of BPD, PD, and EPPD (BPD: OR 2.75; 95% CI 1.83-4.15; PD: OR 3.13; 95% CI 1.60-6.14; and EPPD: OR 7.94; 95% CI 3.70-17.04). Infants with persistently low and intermediate BDNF trajectories had higher risk of adverse pulmonary outcomes compared with those with persistently high BDNF levels. Longitudinal BDNF trajectories identify subgroups of preterm infants at differential risk for adverse respiratory outcomes. Persistently high BDNF during the first month of life may be protective and a potential target for preventive strategies. Persistently low brain-derived neurotrophic factor (BDNF) levels during the first postnatal month are associated with increased risk and severity of bronchopulmonary dysplasia (BPD) and early adverse respiratory phenotypes in extremely preterm infants. Longitudinal BDNF trajectories provide greater discrimination of respiratory risk than single time-point measurements. Infants with persistently high BDNF have the lowest risk of pulmonary deterioration, early persistent pulmonary dysfunction, and severe BPD. These findings support BDNF as a potential early biomarker of lung disease progression in preterm infants.
2026-07-03 | Inhibition of thrombospondin-1 signaling prevents experimental bronchopulmonary dysplasia.
Bronchopulmonary dysplasia (BPD) is a neonatal lung injury characterized by inflammation, and alveolar and vascular hypoplasia that currently lacks effective treatment. Thrombospondin (TSP)-1 is an angiostatic and pro-inflammatory protein, recently implicated in BPD pathogenesis, that both activates transforming growth factor (TGF)-β1 and suppresses nitric oxide (NO) signaling. In order to gain further insight into the relative importance of downstream effects of TSP-1, our objective in a neonatal rat model of hyperoxia-intermittent hypoxia (H-IH)-induced lung injury was to compare effects of inhibiting: 1) TSP-1-mediated TGF-β1 activation alone (LSKL) or 2) global TSP-1 signaling (soluble CD47 receptor ligand trap; sCD47r). From postnatal days (PND) 1-21, rat pups were exposed to air or to H-IH (PND 1-7 85% O2, PND 7-14 60% O2 and PND 14-21 air with intermittent exposure to 10% O2 for 10 min every 4 hours) while either receiving daily s.c. LSKL (20 mg/kg) or third daily sCD47r (3 mg/kg). Controls were treated with vehicle or were continuously exposed to normoxia. Exposure to H-IH increased lung contents of TSP-1 and active TGF-β1, and caused macrophage influx, alveolar and pulmonary vascular hypoplasia, and pulmonary hypertension (PH). Both strategies prevented H-IH-mediated effects on active TGF-β1 content, macrophage influx, abnormal lung morphology and PH, while only sCD47r increased lung NO content and signaling. These observations in a clinically-relevant model indicate that multiple strategies aimed at suppressing TSP-1 signaling are effective in preventing lung injury and that targeting TSP-1-mediated activation of TGF-β1 is sufficient to achieve these effects.
cell therapies
2026-08-07 | Human Umbilical Cord Mesenchymal Stem Cell-Derived Microvesicles Alleviate Bronchopulmonary Dysplasia in Preterm Rats by Inhibiting Neutrophil Extracellular Trap Formation.
Among preterm infants, bronchopulmonary dysplasia (BPD) is the most prevalent chronic pulmonary disorder. Its pathogenesis involves a complex interplay between prenatal inflammatory exposure and abnormal immune activation. Neutrophil extracellular traps (NETs) are mediators of tissue damage, but whether they bridge intrauterine inflammation and the subsequent development of BPD is not yet clear. We used a prenatal lipopolysaccharide (LPS)-exposed rat model to ask two questions: first, whether excessive NETs drive BPD pathogenesis, and second, whether human umbilical cord mesenchymal stem cell-derived microvesicles (hUCMSC-MVs) can alleviate lung injury by inhibiting this process. We established a BPD model in preterm rats via prenatal LPS exposure and assessed lung morphometry, neutrophil infiltration, and NETs markers. We then compared the therapeutic effects of hUCMSC-MVs with NET extrusion (NETosis) inhibitors in vivo and also examined direct neutrophil effects in vitro. Prenatal LPS exposure led to significantly elevated NET markers in both lung tissue and circulation, which correlated with severe alveolar simplification. Neutrophils in this model exhibited a "primed" phenotype with enhanced potential for NETs release. In vivo, hUCMSC-MVs suppressed NET formation, attenuated neutrophilic inflammation, and restored alveolar structure, matching the efficacy of conventional NETosis inhibitors. In vitro, they were internalized by neutrophils and abrogated LPS-induced NETosis. These findings point to excessive NETosis as a key mechanistic link between prenatal inflammation and postnatal lung impairment. hUCMSC-MVs directly inhibit this pathological process and alleviate BPD-like lung injury. This work advances the mechanistic understanding of BPD and supports hUCMSC-MVs as a promising cell-free therapeutic candidate.
2026-07-30 | Mitochondrial programmed cell death in bronchopulmonary dysplasia: mechanisms and therapeutic targets.
Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in preterm infants, primarily characterized by arrested alveolarization and dysregulated pulmonary microvascular development. Mitochondria are crucial for normal lung development, supporting cellular energy and homeostasis. In BPD, mitochondrial homeostasis is severely disrupted, characterized by excessive fission, suppressed fusion, deficient biogenesis, imbalanced mitophagy, a collapsed antioxidant system, and a consequent energy crisis. Following mitochondrial damage, a spectrum of mitochondria-associated programmed cell death pathways is activated in pulmonary cells, including mitophagy-dependent death, apoptosis, necroptosis, pyroptosis, and ferroptosis. Within alveolar epithelial cells, vascular endothelial cells, and other pulmonary cells, these death pathways operate both independently and through extensive crosstalk, forming a complex regulatory network. This network synergistically disrupts pulmonary cell survival, proliferation, and differentiation, ultimately arresting lung development. Therapeutic strategies aim to restore mitochondrial homeostasis, inhibit specific death pathways, and utilize regenerative approaches like exosome-based delivery. This review examines the role of mitochondrial dysfunction and interconnected cell death pathways in BPD pathogenesis and discusses emerging treatments.
2026-07-29 | Five-year follow-up of phase II trial of autologous cord blood mononuclear cells for bronchopulmonary dysplasia prevention in very preterm infants.
We previously performed a phase II clinical trial involving the intravenous infusion of autologous cord blood mononuclear cells (ACBMNCs) to prevent bronchopulmonary dysplasia in premature infants. We reported the outcomes before discharge and at 2-year follow-up of the enrolled infants. We have reported the developmental outcomes at the 5-year follow-up visit. We evaluated the 5-year long-term outcomes of ACBMNCs infusion, including growth, respiratory, and neurodevelopmental outcomes, by interviewing the parents. Children's development was assessed using scores on the Chinese version of the Ages & Stages Questionnaires (ASQ), third edition (ASQ-3), completed by the parents or guardians. The primary outcome was the neurodevelopmental outcome. The secondary outcomes were growth and respiratory outcomes. In terms of the primary endpoint, intravenously infused ACBMNCs significantly improved the scores of the fine motor and personal-social domains in the ASQ (P = .044 and P = .048, respectively). This study also showed high consistency between the motor index in the Bayley score at a 2-year follow-up with both gross and fine motor domain scores, as well as the language index with communication, problem-solving, and personal-social domain scores. Although pneumonia-related hospitalizations were similar between the two groups, the intervention group showed a lower possibility of nocturnal cough. Infants who received intravenous ACBMNC infusion had better fine motor and personal-social abilities at 5 years than those in the control group. In addition to providing reassuring safety data, the study suggested longer-term neurodevelopmental benefits of ACBMNC intervention early in the NICU course. Further randomized placebo-controlled trials are essential to confirm these findings. The trial was prospectively registered at ClinicalTrials.gov (NCT02999373), registered on December 21, 2016.
2026-07-24 | Regenerative strategies for surfactant deficiency in neonatal and pediatric lung disease: the role of mesenchymal stem cells and their extracellular vesicles.
Surfactant deficiency underlies several neonatal and pediatric lung diseases, including respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and genetic surfactant disorders. Although advances in neonatal care and surfactant replacement therapy have improved survival in preterm infants, current treatments mainly provide supportive management and do not fully address mechanisms of lung injury and impaired lung development. Regenerative approaches based on mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) have emerged as potential strategies to promote lung repair and restore alveolar homeostasis. This narrative review summarizes experimental and clinical evidence on MSC- and EV-based regenerative strategies for surfactant-related lung diseases. Relevant studies investigating MSCs or MSC-derived EVs in neonatal and pediatric lung injury were identified through searches in PubMed, Scopus and Web of Science and were qualitatively analyzed. Preclinical studies show that MSCs reduce inflammation, protect type II alveolar epithelial cells and promote alveolar development in models of immature lung injury. These effects are largely mediated by paracrine mechanisms, including the release of MSC-derived EVs, which transfer bioactive molecules to target cells and regulate inflammatory and regenerative pathways. Accordingly, EV-based therapies, as a cell-free derivative of MSCs, reproduce several beneficial effects of MSC transplantation in animal models. Early clinical studies in preterm infants at risk of BPD show encouraging safety profiles, although evidence of long-term efficacy remains limited. MSC- and EV-based regenerative approaches represent promising strategies for surfactant-related lung diseases. Further studies are needed to clarify mechanisms of action and evaluate their efficacy in well-designed clinical trials involving neonatal and pediatric populations.
2026-07-07 | Helping Underdeveloped Lungs with Cells (HULC-2): mesenchymal stromal cells in extreme preterm infants at risk of developing bronchopulmonary dysplasia - a study protocol of a phase 2 multicentre double blind randomised controlled trial in Canada.
Bronchopulmonary dysplasia (BPD) remains a major complication among extremely low gestational age (ELGA) infants, with long-term respiratory and neurodevelopmental consequences. Despite advances in neonatal care, effective therapies to prevent BPD are lacking. Mesenchymal stromal cells (MSCs), particularly those derived from umbilical cord (UC-MSC), offer promise due to their pleiotropic effects. Preclinical and early-phase clinical studies have demonstrated safety and potential efficacy of MSC in neonatal lung injury. The Helping Underdeveloped Lungs with Cells (HULC)-2 trial aims to evaluate whether multiple intravenous doses of human allogenic UC-MSC can reduce mechanical ventilation duration and improve the respiratory outcome in ELGA infants at high risk of developing BPD. HULC-2 is a multicentre, double-blind, randomised controlled Phase II trial conducted in Canadian Neonatal Intensive Care Units. ELGA infants (gestational age <28 weeks) who remain ventilator-dependent between 4 and 14 days of life will be randomised to receive either 3 weekly intravenous doses of UC-MSC (10×106 cells/kg/dose) or a sham procedure. The primary outcome is ventilation-free days (VFDs) at 120 days postrandomisation, accounting for mortality. Secondary outcomes include cell administration safety, respiratory and neurodevelopmental outcomes and complications of prematurity. A total of 168 participants will be enrolled to detect a clinically meaningful difference in VFDs. The study was approved through Clinical Trials Ontario by the Ottawa Health Science Network Research Ethics Board. Results will be disseminated via peer-reviewed publications, conferences and public engagement platforms. Parent partners are actively involved in study design and dissemination to ensure relevance and transparency. NCT07058025.
other
2026-08-31 | Downregulation of UNC5B-AS1 in Preterm Infants with Bronchopulmonary Dysplasia and Its Protective Mechanism via the miR-134-5p/IGF1 Axis.
Bronchopulmonary dysplasia (BPD) is a major chronic lung disease in preterm infants. This study was designed to elucidate the functional significance and molecular mechanism of the long non-coding RNA UNC5B-AS1 in BPD pathogenesis. This study included 50 preterm infants with BPD and 42 healthy newborns. The levels of UNC5B-AS1, miR-134-5p, IGF1, Bax, and Bcl-2 were detected by RT-qPCR. In in vitro experiments, A549 and MLE-12 cells were used to establish a hyperoxia-induced BPD model. A series of assays was performed to evaluate the cellular phenotypes, including CCK-8 for viability, flow cytometry for apoptosis, ELISA for inflammatory factors (TNF-α, IL-1β, IL-6), and SOD activity, and DCFH-DA probing for ROS levels. IGF1 protein expression was examined by Western blot. Dual-luciferase reporter assay and RIP experiments were performed to validate the targeting relationships between UNC5B-AS1 and miR-134-5p, and between miR-134-5p and IGF1. Serum levels of UNC5B-AS1 were significantly downregulated, while miR-134-5p expression was significantly upregulated in BPD infants, both showing good diagnostic value. UNC5B-AS1 directly binds to miR-134-5p. In the cellular model, the protective effect of UNC5B-AS1 overexpression against hyperoxia-induced injury was reversed by miR-134-5p overexpression. Furthermore, IGF1 was confirmed as a direct target of miR‑134‑5p, and knockdown of IGF1 abolished the protective effects achieved by miR‑134‑5p inhibition. Serum UNC5B‑AS1 is downregulated and miR‑134‑5p is upregulated in preterm BPD infants. Mechanistically, UNC5B‑AS1 may sponges miR‑134‑5p to upregulate IGF1, protecting against hyperoxia‑induced alveolar injury.
2026-07-19 | SRPRA affects hyperoxia-induced bronchopulmonary dysplasia by modulating endoplasmic reticulum stress through the CHOP pathway.
Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease among preterm infants, largely attributed to hyperoxia-induced injury to alveolar epithelial cells. Excessive endoplasmic reticulum (ER) stress plays a vital role in BPD progression. SRPRA, a subunit of the ER-localized SRP receptor, is upregulated in BPD, while its function and link with ER stress remain largely unclear. This study aimed to explore the role of SRPRA in hyperoxia-induced BPD and its underlying mechanism. A hyperoxia-exposed alveolar type II epithelial cell (AECII) model was established to mimic BPD in vitro. Cell viability, cell proliferation and apoptosis were detected by CCK-8, EdU assay and flow cytometry, respectively. The secretion of inflammatory factors was evaluated via ELISA assay. ROS levels were detected by DCFH-DA fluorescence staining. Commercial kits were used to detect MDA and SOD levels. The SRPRA mRNA level and protein expression was measured using qRT-PCR and Western blot. Expression levels of apoptosis-related proteins (Bax, Bcl2), inflammation-related proteins (iNOS, Cox2) and CHOP pathway-related proteins were assessed by western blotting. SRPRA was markedly upregulated in hyperoxia-induced alveolar epithelial cells. Hyperoxia stimulation decreased viability and proliferation, and enhanced apoptosis in AECIIs, accompanied by elevated inflammatory responses and oxidative stress. SRPRA knockdown alleviated hyperoxia-induced cell damage, inflammation and oxidative stress, and downregulated the expression of CHOP (a key mediator of ER stress). The protective effects mediated by SRPRA silencing were largely reversed by thapsigargin. SRPRA knockdown alleviates hyperoxia-induced AECII injury by attenuating CHOP-mediated ER stress. Our findings reveal the pathogenic role of SRPRA in BPD, and suggest SRPRA as a potential therapeutic target for this disease.
2025-11-09 | IRF4 exacerbates pulmonary inflammation in bronchopulmonary dysplasia mice model by regulating macrophage polarization and phagocytosis.
This study investigates the critical function of interferon regulatory factor 4 (IRF4) during bronchopulmonary dysplasia (BPD) progression by regulating alveolar macrophages (AMs) polarization and phagocytic function. We developed IRF4 knockout mice using CRISPR/Cas9 technology and established an animal model for neonatal bronchopulmonary dysplasia (BPD) by hyperoxia exposure. Lung tissue pathology was analyzed by Hematoxylin and eosin staining (HE). The concentrations of TNF-α, IL-1β, IL-10, and TGF-β were ascertained by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to investigate M1/M2 macrophage polarization in bronchoalveolar lavage fluid (BALF) and lung tissue, while Western blotting and quantitative real-time PCR (qRT-PCR) were employed to detect IRF4, iNOS, and Arg-1 protein and mRNA expression. At cellular level, we silenced IRF4 in murine alveolar macrophage cell lines using IRF4 siRNA to investigate its effect on inflammatory cytokine secretion, polarization, and phagocytic function. To assess the effect of IRF4 on alveolar macrophage phagocytosis after hyperoxia, we utilized flow cytometry to ascertain the mean fluorescence intensity of engulfed fluorescent microspheres and fluorescence microscopy to quantify phagocytic cells. Hyperoxia-exposed mice showed markedly upregulated IRF4 expression, increased M1 macrophage and iNOS levels, and decreased M2 macrophages and Arg-1 expression. This cytokine shift was characterized by a marked upregulation of inflammatory factors such as TNF-α and IL-1β, accompanied by a notable decline in anti-inflammatory factors encompassing IL-10 and TGF-β, indicating an imbalance towards a pro-inflammatory state. IRF4 knockout or siRNA-mediated silencing attenuated the inflammatory response, promoting M2 macrophage differentiation while suppressing M1 differentiation. Phagocytic assays showed that hyperoxia impaired the phagocytic activity of AMs, while transfection of IRF4 siRNA restored the phagocytic activity of macrophage. IRF4 functions as a crucial regulator in the progression of hyperoxia-induced bronchopulmonary dysplasia, exerting its effects by influencing the polarization state and phagocytic function of alveolar macrophages. Deletion of IRF4 promotes an M2-dominant anti-inflammatory response, attenuates hyperoxia-induced inflammation, and increases the phagocytosis capacity of macrophages.
2025-10-09 | TXNIP mediates ferroptosis in a bronchopulmonary dysplasia mouse model by regulating the SLC7A11/GPX4 pathway.
Bronchopulmonary dysplasia (BPD) is one of the most common respiratory diseases in preterm infants. Studies have shown that ferroptosis is involved in the pathogenesis of BPD, and thioredoxin-interacting protein (TXNIP)-mediated oxidative stress also plays a role in its development. The solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway is one of the key pathways regulating ferroptosis. This study aimed to investigate the mechanism by which TXNIP regulates SLC7A11/GPX4 pathway-mediated ferroptosis in BPD. Mice were randomly divided into ten treatment groups: Air, Hyperoxia, Hyperoxia + RSL3, Hyperoxia + Ferrostatin-1, Hyperoxia + Ad-shNC, Hyperoxia + Ad-shTXNIP, Hyperoxia + Ad-vector, Hyperoxia + Ad-TXNIP, Hyperoxia + Ad-shSLC7A11, and Hyperoxia + Ad-shTXNIP + Ad-shSLC7A11. Lung tissues were collected for hematoxylin and eosin (H&E) staining to observe pathological changes, and transmission electron microscopy (TEM) was used to examine mitochondrial morphology. Real-time quantitative polymerase chain reaction (qPCR) was performed to measure the mRNA expression of TXNIP, SLC7A11, and GPX4. Western blotting was used to analyze the protein levels of TXNIP, SLC7A11, and GPX4. GPX4 activity was determined using an enzyme-linked immunosorbent assay (ELISA). Additionally, glutathione (GSH), malondialdehyde (MDA), and ferrous iron (Fe2+) levels in lung tissues were measured using corresponding detection kits. H&E staining and TEM confirmed successful modeling of lung injury after hyperoxia. MDA and Fe2+ increased, GSH decreased, and GPX4 activity declined after hyperoxia. TXNIP mRNA and protein were upregulated by hyperoxia, while SLC7A11 and GPX4 were downregulated. Ferroptosis activation exacerbated lung injury, whereas inhibition alleviated it. TXNIP overexpression using adenovirus serotype 5 (Ad5) aggravated ferroptosis in BPD, and this was ameliorated by TXNIP knockdown. Knockdown of the upstream signal SLC7A11 increased ferroptosis in BPD, and simultaneous knockdown of TXNIP and SLC7A11 reversed the ferroptosis reduction. In conclusion, in the BPD model, TXNIP expression was increased, and TXNIP promoted ferroptosis by downregulating the SLC7A11/GPX4 pathway. These findings suggest that gene therapy targeting TXNIP knockdown using adenovirus as a vector may serve as a therapeutic strategy for BPD.
2025-09-15 | Pulmonary Hypertension Outcomes After Closure of Atrial Septal Defect in Infants With Developmental Lung Disease.
Pulmonary hypertension (PHTN) in infants with developmental lung disease, such as bronchopulmonary dysplasia (BPD), chronic lung disease of infancy (CLD), or congenital diaphragmatic hernia (CDH), can be exacerbated by atrial septal shunts secondary to atrial septal defects (ASD). While transcatheter ASD closure may reduce pulmonary overcirculation, data on post-closure hemodynamic and pharmacologic outcomes remain limited. This single-center retrospective study aimed to characterize changes in PHTN severity, respiratory support, and medication use 1 year after early transcatheter ASD closure (defined as closure at ≤ 1 year of age). Eligible patients were infants with BPD, CLD, or CDH who underwent early transcatheter ASD closure between 2021 and 2024 and had preprocedural PHTN medication use and respiratory support. Sixteen infants met the inclusion criteria. At 1 year, excluding the 3 who died, 10 of 13 infants (76.9%) showed improved PHTN severity, including 6 (60%) with complete resolution. Of the 13 infants, 6 (46.2%) weaned off all respiratory support. Average diuretic dosage (mg/kg/day) decreased by 92.9%, and vasodilator dosage declined by 47.0%. Infants with ASDs ≥ 5 mm and gestational age (GA) < 32 weeks required significantly longer diuretic therapy than those with smaller ASDs (< 5 mm) and GA ≥ 32 weeks. No similar associations were found with vasodilator weaning. These findings suggest early transcatheter ASD closure may offer therapeutic benefit in select high-risk infants, resulting in improved hemodynamics and reduced medication dependence. Although limited by small sample size and retrospective design, this study supports the potential for individualized weaning strategies and the need for prospective multicenter investigations.
small molecules
2026-09-30 | Sildenafil in bronchopulmonary dysplasia-associated pulmonary hypertension: developmental and translational insights.
Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) is increasingly viewed as a developmental pulmonary vascular disorder rather than a purely reactive vasoconstrictive complication of chronic lung disease. It involves impaired angiogenesis, reduced pulmonary vascular surface area, alveolar simplification, and progressive right ventricle-pulmonary artery uncoupling. Sildenafil, a phosphodiesterase type 5 inhibitor, is widely used because it enhances nitric oxide-cyclic guanosine monophosphate signaling and may reduce pulmonary vascular tone. However, neonatal-specific evidence remains limited, dosing approaches are heterogeneous, and its long-term effects on vascular remodeling and clinical outcomes are uncertain. This narrative review integrates developmental biology, translational evidence, clinical studies, pharmacokinetics, and safety considerations to critically evaluate sildenafil in BPD-PH. Current data support short-term improvements in echocardiographic hemodynamics and oxygenation in selected infants, but do not demonstrate durable remodeling reversal or improved survival. Experimental studies suggest effects on endothelial survival, smooth muscle proliferation, angiogenic signaling, and oxidative stress, although relevance to human preterm infants remains incompletely validated. Developmental pharmacokinetics, including CYP3A maturation, weight, postnatal age, route, and drug interactions, contribute to variable exposure. Sildenafil use should therefore be individualized, phenotype-guided, and evaluated in future trials with pharmacokinetic-guided dosing and longitudinal outcomes. IMPACT: Reframes bronchopulmonary dysplasia-associated pulmonary hypertension as a disorder of impaired pulmonary vascular development rather than a purely reactive vasoconstrictive process. Integrates developmental biology, translational evidence, and neonatal pharmacokinetics to critically evaluate sildenafil beyond its traditional vasodilatory role. Highlights the need for precision pharmacology approaches and pharmacokinetic-guided dosing to optimize therapeutic strategies in preterm infants.
2026-09-30 | The immune system in postnatal lung development.
The human lungs begin their development early in gestation. Both in utero and postnatally, the lungs undergo intricate morphological changes, the complex regulation of which has been extensively studied for decades. Even before the first breath, immune cells migrate into the lungs in a specific temporal, wave-like manner. Recent evidence suggests that both innate and adaptive immune cells actively participate in alveolarization. In this article, we provide an overview of how the immune system interfaces with the developing lungs. By examining the pathways utilized by the immune system in this context, we can enhance our understanding of their roles in specific developmental processes. Further, we review the effects of dysregulated lung immunity on lung development and the role of immunity in bronchopulmonary dysplasia.
2026-09-29 | Intratracheal budesonide combined with surfactant for respiratory distress syndrome in preterm infants: A randomized clinical trial.
BackgroundBronchopulmonary dysplasia (BPD) remains a major cause of morbidity among preterm infants with respiratory distress syndrome (RDS). Intratracheal budesonide combined with surfactant may reduce pulmonary inflammation and improve neonatal outcomes.MethodsIn this randomized clinical trial, 160 preterm infants (gestational age 26-32 weeks; birth weight <1500 g) requiring surfactant therapy for RDS were assigned to receive either surfactant alone (n = 80) or surfactant plus budesonide (0.25 mg/kg; n = 80). Primary outcomes were oxygen dependency or respiratory support beyond 21 days of life (the prespecified study respiratory outcome) and in-hospital mortality. Secondary outcomes included sepsis, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, respiratory support duration, and repeat surfactant administration.ResultsBaseline characteristics were comparable between groups. The primary respiratory outcome occurred in 16/80 infants (20.0%) in the budesonide-surfactant group and 26/80 infants (32.5%) in the surfactant-alone group (absolute risk difference -12.5 percentage points; P = 0.105). Mortality was significantly lower in the combination group (1.2% vs 11.2%, P = 0.018), as was culture-proven sepsis (5.0% vs 21.2%, P = 0.004). Infants receiving budesonide required fewer repeat surfactant doses (38.8% vs 61.3%, P = 0.016) and had a shorter duration of nasal continuous positive airway pressure support (10.1 ± 6.0 vs 17.9 ± 11.3 days, P = 0.001). The composite outcome of death or oxygen dependency/respiratory support beyond 21 days of life occurred in 35 infants (43.8%) in the control group and 17 infants (21.3%) in the combination group (P = 0.003).ConclusionsIn preterm infants with RDS, budesonide-surfactant therapy was associated with reduced mortality, sepsis, respiratory support duration, and repeat surfactant use. Although fewer infants in the intervention group met the prespecified respiratory outcome, the difference was not statistically significant. Larger multicenter trials using contemporary BPD definitions and incorporating long-term neurodevelopmental follow-up are needed before efficacy and safety can be established.
2026-09-26 | HSP90 Inhibitor, AT13387 Mitigates Chronic Lung Injury in Pre-Pubertal Mice: A Therapeutic Axis in Bronchopulmonary Dysplasia.
Exposure to hydrochloric acid (HCl) can provoke severe chronic pulmonary injury. Children are particularly vulnerable due to their smaller airways, higher respiratory rate, and stronger inflammatory response; yet no countermeasures exist for HCl-induced chronic lung injury in the pediatric population. We have previously demonstrated the involvement of HSP90 during HCl-induced lung injury in pre-pubertal (p24) mice, who develop stronger persistent inflammation with higher NLRP3 inflammasome activation, but less pulmonary fibrosis compared to adults. Here, we tested the hypothesis that post-treatment with the second-generation HSP90 inhibitor AT13387 (Onalespib), administered subcutaneously beginning 24 h after HCl instillation, would prevent HCl-induced chronic lung injury and pulmonary fibrosis in young (p24) C57BL/6J mice. Pre-pubertal (p24) C57BL/6J mice received a single intratracheal instillation of 0.1 N HCl and were treated with AT13387 (10 mg/kg, s.c., 3×/week for 30 days) beginning 24 h post-exposure. Bronchoalveolar lavage fluid (BALF) analysis, lung function measurements, histological assessment (Ashcroft fibrosis score), and Western blot analysis of key signaling mediators were performed. Additionally, publicly available single-nucleus RNA sequencing (snRNA-Seq) data from a cohort of 13 infants with bronchopulmonary dysplasia (BPD) and 11 age-matched controls were analyzed to evaluate HSP90 isoform expression in human pediatric lung disease. AT13387 significantly reduced BALF white blood cell concentration without affecting total BALF protein levels. Importantly, AT13387 did not impair normal weight gain or development over the 30-day observation period. AT13387 abrogated HCl-induced expression of TGF-β1, phosphorylation of HSP90, ERK1/2, SMAD2, IκBα, and upregulation of the inflammasome NLRP3. Additionally, AT13387 prevented changes in lung function dynamics and reduced the Ashcroft fibrosis score. Analysis of the human snRNA-Seq BPD dataset revealed a widespread pan-overexpression of all three HSP90 isoforms, i.e., HSP90AA1, HSP90AB1, and HSP90B1. These findings suggest that the HSP90 inhibitor AT13387 exhibits strong antidotal properties against HCl-induced chronic lung injury and pulmonary fibrosis in a pre-clinical pediatric model and identify HSP90 as a conserved therapeutic target in pediatric chronic lung disease.
2026-09-23 | The gut-lung axis in early life: microbiome-associated mechanisms and clinical relevance.
The early-life microbiome is increasingly recognised as a contributor to immune maturation and respiratory health. Early-life microbial colonisation is highly dynamic and shaped by multiple factors. Recently, the gut-lung axis has emerged as a framework describing bidirectional communication between the intestinal microbiota and the respiratory system via microbial metabolites, immune mediators and neuroimmune pathways. Although current evidence is largely derived from studies of bacterial communities, emerging data suggest that other microbial components, including fungi and viruses, may also contribute to gut-lung interactions. This review synthesises current mechanistic and clinical evidence on the gut-lung axis with a specific focus on neonatology. We discuss how early microbiome composition may influence immune regulation, lung development and inflammatory response. Associations between intestinal microbiota alterations and major neonatal morbidities, including bronchopulmonary dysplasia, are discussed, as well as emerging evidence linking early-life microbial imbalance to long-term respiratory outcomes such as recurrent infections and asthma. We further examine emerging translational opportunities, including microbiome- and metabolome-based biomarkers for early risk stratification, and microbiota-targeted interventions. Attention is given to the strengths and limitations of the current evidence base, including the predominance of observational human studies and preclinical animal models. Overall, available evidence suggests that the developing microbiome represents a potentially important mediator of gut-lung communication in early life. However, substantial gaps remain regarding causality, underlying mechanisms and clinical applicability. Further longitudinal and interventional studies are needed to define the role of microbiome-targeted strategies in improving neonatal and long-term respiratory outcomes.
antibodies
2026-09-13 | Survival without major morbidity in very preterm infants (<32 weeks' gestation): prevalence, temporal trends, and associated factors in a single-center retrospective cohort.
To determine the proportion of very preterm infants (VPIs) surviving without major morbidity (SWMM), assess temporal trends from 2021 to 2025, and identify associated factors. This single-center retrospective cohort study included all inborn VPIs admitted to the neonatal intensive care unit (NICU) of Guangdong Women and Children Hospital between January 2021 and October 2025. Primary analyses were performed among infants receiving complete care, whereas infants discharged against medical advice (DAMA) were analyzed separately. SWMM was defined as survival without bronchopulmonary dysplasia (BPD), severe brain injury, necrotizing enterocolitis (NEC) stage II or higher, late-onset sepsis (LOS), or severe retinopathy of prematurity (ROP). Temporal trends were evaluated using logistic regression with gestational age (GA)-adjusted annual rates estimated by marginal standardization. Factors associated with SWMM were assessed using multivariable logistic regression. A total of 1,172 VPIs were included, with a median GA of 30.0 weeks (IQR, 28.6-31.1) and a median birth weight of 1,270 g (IQR, 1,050-1,500). In the complete-care cohort (n = 1,094), survival was 95.5% (1,045/1,094) and SWMM was 59.9% (655/1,094). From 2021 to 2025, survival remained high and stable. After GA adjustment, BPD, severe ROP, and LOS increased over time, whereas SWMM declined. Multivariable analysis showed that higher GA (per week: OR 2.62, 95% CI 2.30-3.01) and greater birth weight z score (per SD: OR 2.13, 95% CI 1.76-2.59) were associated with higher odds of SWMM, whereas male sex (OR 0.66, 95% CI 0.48-0.91), additional surfactant doses (per dose: OR 0.47, 95% CI 0.37-0.59), and a 5-minute Apgar score ≤7 (OR 0.27, 95% CI 0.10-0.69) were associated with lower odds. DAMA occurred in 6.7% of VPIs (78/1,172) and decreased with increasing GA, from 30.0% at ≤25 weeks to 1.9% at 31 weeks. The estimated post-DAMA survival rate was 24.4% (19/78). Survival among VPIs remained high and stable, whereas SWMM remained suboptimal and declined over time. The increasing burden of BPD and severe ROP underscores the importance of improving the quality of survival. Strategies including GA-stratified care, optimized perinatal stabilization, early respiratory management, and reduced DAMA may improve outcomes in this high-risk population.
2026-09-10 | Temporal regulation of wnt signaling in alveolar development and regeneration: mechanistic insights and therapeutic advances in chronic lung diseases.
Wnt signaling coordinates lung specification, alveolar maturation, adult epithelial maintenance, and injury repair, but its biological output varies with developmental or disease stage, anatomical compartment, responding cell type, receptor context, and signal duration. This review organizes current evidence using a temporal-spatial framework that links Wnt ligands and receptors to source and responding cells, downstream canonical or noncanonical pathways, interacting signaling networks, and cellular outcomes. During development, mesenchymal Wnt2/2 b-β-catenin signaling specifies pulmonary endoderm, whereas canonical and noncanonical Wnt programs subsequently regulate distal progenitor expansion, branching geometry, epithelial differentiation, secondary septation, pulmonary microvascular maturation, and postnatal lung growth; maintenance of an AXIN2 + alveolar type 2 (AT2) progenitor niche becomes a distinct function in the adult lung. After adult alveolar injury, Wnt activity is dynamically remodeled as AT2 cells proliferate and traverse damage-associated transient progenitor and keratin 8-positive (KRT8+) transitional states before restoring the alveolar type 1 cell layer. This framework helps reconcile apparently discordant observations in chronic lung diseases. Bronchopulmonary dysplasia disrupts Wnt timing during alveologenesis; chronic obstructive pulmonary disease can combine deficient canonical Wnt responsiveness in the alveolar compartment with Wnt5a-associated inhibition of repair and distinct airway Wnt activation; and idiopathic pulmonary fibrosis features persistent Wnt-transforming growth factor-β signaling in abnormal epithelial and fibroblast niches. Therapeutic translation should therefore avoid indiscriminate pathway activation or inhibition and instead pursue reversible, local, biomarker-guided modulation matched to disease stage, cellular compartment, receptor profile, dose, and duration.
2026-07-30 | The IL-33-ILC2 axis: a key regulator of type 2 immunity in respiratory disease.
Respiratory diseases represent a major global public health burden, and type 2 immunity plays a key role in their pathogenesis. The interleukin-33 (IL-33)-group 2 innate lymphoid cell (ILC2) axis regulates airway type 2 immune responses, thereby triggering, amplifying, and maintaining pathological inflammation. This review addresses the characteristics of IL-33 and pulmonary ILC2s, including the alarmin function and tissue-specific expression of IL-33, and the origin, localization, functional heterogeneity, and microenvironment-driven plasticity of ILC2s. In particular, we discuss how disease-specific microenvironments shape divergent ILC2 states, including classical type 2 cytokine-producing ILC2s, tissue-repairing AREG-producing ILC2s, ILC1-like cells, and IL-17-producing ILC2-like states. We further review the regulatory mechanisms of the IL-33-ILC2 axis in bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and viral respiratory infections are also discussed, highlighting the remarkable functional plasticity of ILC2s. Targeting the IL-33-ILC2 axis and modulating ILC2 function represent therapeutic strategies for various type 2-mediated airway diseases.
2026-07-16 | Systems-level insights into bronchopulmonary dysplasia from meta-analysis of genome-scale studies.
Despite marked improvements in survival following preterm birth, the incidence of bronchopulmonary dysplasia (BPD) remains the most prevalent complication of prematurity and carries the risk of long-term morbidity. Characterising the cellular and molecular mechanisms driving disease progression is critical for informing clinical management and improving outcomes. To this end, we conducted a meta-analysis of genome-scale studies to identify molecular pathways implicated in BPD progression in both human cohorts and animal models. Gene lists associated with BPD in humans, and in rodent models, were extracted from systematically identified genome-scale studies. These gene lists were subsequently analysed using the meta-analysis by information content (MAIC) algorithm, which integrates multiple datasets to generate a single aggregated, ranked gene list based on the cumulative strength of evidence for each gene. Comparative analyses were then performed between the human and rodent BPD datasets, as well as between the human BPD dataset and our previously generated Acute Respiratory Distress Syndrome MAIC dataset. Across all analyses, a consistent enrichment of genes involved in leukocyte-mediated antigen presentation and lymphocyte development and activation was observed, suggesting a shift from acute innate immune injury toward a more sustained lymphoid-driven inflammatory process during BPD progression. Comparative analyses revealed limited overlap between BPD and ARDS gene sets, suggesting divergent disease mechanisms, while still highlighting shared immune activation pathways. Human-rodent comparisons showed divergence in tissue remodelling signatures, likely reflecting differences in sample sources, yet converged on key conserved signals such as CD3E and IL1R2, implicating common inflammatory regulatory mechanisms. MAIC effectively identifies conserved molecular signatures in BPD highlighting lymphoid lineage signatures that are not readily apparent in the primary data. These signatures offer insights relevant to immune-modulatory therapeutic strategies, highlighting key processes involved in antigen presentation and modulation of T-cell activation and development during the progression of Bronchopulmonary Dysplasia.
2026-05-06 | Hyperoxia promotes bronchopulmonary dysplasia via Noggin-mediated BMP4 antagonism and cellular senescence.
Bronchopulmonary dysplasia (BPD) represents the most prevalent chronic pulmonary complication in preterm infants, with incompletely understood pathophysiological mechanisms. Hyperoxia exposure constitutes a major risk factor for BPD development, inducing cellular senescence that impairs alveolar maturation. While senescence is predominantly mediated by the p53/p21 signaling pathway, upstream regulatory mechanisms remain inadequately defined. This study aimed to identify critical genes through bioinformatics and elucidate the molecular mechanisms by which the Noggin-BMP4 signaling axis mediates cellular senescence in BPD pathogenesis. Integrating BPD transcriptomic datasets with aging-related databases via WGCNA, Noggin was identified as a hub gene linking BPD and cellular senescence (AUC = 0.80). In HPMECs exposed to 85% hyperoxia, Noggin expression increased approximately 2.5-fold (mRNA) and 2.0-fold (protein), while BMP4 decreased to 50% of controls, accompanied by elevated p53 and p21 expression and positive SA-β-gal staining. Noggin silencing restored BMP4 expression and significantly attenuated hyperoxia-induced p53/p21 upregulation, suggesting that Noggin promotes senescence by suppressing BMP4. In a neonatal rat hyperoxia-induced BPD model, alveolar simplification was observed alongside a threefold increase in Noggin mRNA, a reduction of BMP4 to 30% of controls, and elevated p53/p21 at day 14, corroborating the in vitro findings. These findings suggest that hyperoxia upregulates Noggin to antagonize BMP4 signaling, thereby activating p53/p21-mediated senescence and contributing to alveolar developmental arrest. The Noggin-BMP4 axis may represent a potential therapeutic target for BPD.
proteins
2026-09-06 | Bronchopulmonary dysplasia and prematurity-associated lung disease: emerging therapies to improve lifelong respiratory outcomes.
Survival of extremely preterm infants has improved owing to advances in perinatal and neonatal care. However, bronchopulmonary dysplasia (BPD) has remained unabated, and research into preventive measures for the broader spectrum of prematurity-associated lung disease (PLD) has met with limited success. We summarize emerging therapeutic strategies with the potential to favorably influence the lifelong trajectory of lung health of preterm infants, especially the most immature. This narrative review examines recent preclinical and clinical studies on therapies for BPD prevention, focusing on mechanism-based interventions, biologic strategies, and innovative translational tools. Preclinical evidence converges on actionable targets in alveolarization, inflammatory pathways, redox and mitochondrial homeostasis, vascular and matrix remodeling. Novel molecules and drug-repurposing strategies are being tested in animal models, while patient-derived platforms may enable personalized therapeutic approaches. Mechanism-based approaches are progressing through Phase 1-2 clinical trials; pending efficacy analyses, insulin-like growth factor-1 replacement may become the first pharmacological therapy specifically approved to reduce or attenuate BPD. In parallel, cell-based therapies and extracellular vesicle strategies offer a complementary paradigm, acting through pleiotropic biological reprogramming of the injured lung. Ethical-regulatory complexity and the challenges of standardizing and scaling cell-based and cell-free therapies may limit clinical translation. A growing repertoire of therapies for BPD holds promise for modifying early respiratory illness and the long-term burden of PLD. Realizing this potential will benefit from both mechanism-informed combinatorial approaches and pleiotropic strategies, supported by patient-derived translational tools and adequately powered efficacy evaluations. Equally essential are tailored neonatal-first regulatory pathways linking the continuum of BPD to the later respiratory morbidity of PLD, a life-course condition with significant public health relevance beyond the neonatal period. • Bronchopulmonary dysplasia (BPD) is the current clinical and regulatory endpoint for neonatal pulmonary therapies. • BPD definitions capture the most severe manifestations of prematurity-associated lung disease (PLD), a broader continuum of respiratory morbidity reaching into adulthood; attenuating BPD may improve the whole spectrum of PLD. • Therapies targeting alveolar, inflammatory, oxidative, vascular, and remodeling pathways are in clinical development; pending late-stage trials, IGF-1 replacement may become the first disease-modifying therapy to reduce BPD. • Novel targets, experimental platforms, and repurposed drugs hold promise for precision therapies in preterm infants.
2026-08-30 | A recombinant fragment of human surfactant protein D reduces lung inflammation in preterm lambs.
Bronchopulmonary dysplasia (BPD), the major chronic respiratory morbidity in extremely preterm infants, is largely driven by inflammation. Preterm lungs are deficient of surfactant protein D (SP-D), an immunomodulatory protein absent in current commercial surfactant preparations. We hypothesised that using a recombinant fragment of human SP-D (rfhSP-D) as an adjuvant to exogenous surfactant therapy would reduce ventilator-induced inflammation. We utilised a preterm lamb model of ventilator-associated lung injury. Mechanically ventilated preterm lambs were randomised into control and two treated groups, receiving endotracheal surfactant at 15 min post-delivery. Physiological parameters were measured throughout the experiment. Lung tissue was analysed for changes in alveolar architecture and expression levels of pro-inflammatory cytokines. Bronchioalveolar lavage (BAL) was analysed for SP-D concentration, and inflammatory cells. Intratracheal administration of rfhSP-D improved respiratory outcomes, significantly increased airspace and lung compliance in treated groups. Treated lambs also showed a reduction in lung tissue gene expression of inflammatory cytokines and inflammatory cell counts. Intratracheal administration of rfhSP-D did not negatively impact standard surfactant therapy and appeared to complement it. The administration of rfhSP-D as an adjuvant to standard surfactant therapy effectively reduced lung inflammation supporting the potential therapeutic use of rfhSP-D for preterm infants at risk of developing BPD. We have successfully developed and tested a novel recombinant fragment of human surfactant protein D (rfhSP-D) capable of reducing ventilator-associated lung inflammation in a pre-term lamb model. These results suggest rfhSP-D may be a novel potentially useful therapy for Bronchopulmonary dysplasia (BPD) in combination with currently available surfactant replacement therapies and serves as justification for a first in human clinical trial in mechanically ventilated infants. If successful, rfhSP-D could become a therapeutic candidate to mitigate pulmonary inflammation and improve lung outcomes, potentially offering a novel therapeutic avenue in the prevention or management of BPD.
2026-08-27 | A Premature Rabbit Kitten Model for Evaluation of Bronchopulmonary Dysplasia Therapies Reproduces Myeloperoxidase-Associated Pathology and Therapeutic Responses.
Myeloperoxidase (MPO) plays a significant role in the development and progression of bronchopulmonary dysplasia (BPD). The neonatal rat model has shown that the tripeptide N-acetyl-lysyltyrosylcysteine amide (KYC) attenuates hyperoxia-induced BPD-like injury, in part by reducing MPO-mediated toxic oxidants and additional cytoprotective mechanisms. However, the rat model does not fully replicate the key characteristics of surfactant deficiency and immature antioxidant capacity in premature human neonates. In contrast, premature rabbit kittens share key features with those of premature human neonates. For this study, premature rabbit kittens delivered at 29 days of gestation (term is 31 days) were exposed to 95% oxygen for 7 days. Hyperoxia caused a BPD-like phenotype characterized by increased MPO-positive inflammatory cell infiltration, elevated MPO expression, alveolar simplification, septal wall thickening, and pulmonary arterial medial wall thickening. Daily intraperitoneal KYC administration attenuated lung inflammatory cell infiltration, reduced MPO expression, improved alveolar morphometric indices, and mitigated pulmonary arterial medial wall thickening compared with phosphate-buffered saline treatment. There were no significant differences in weight changes or survival between the groups. These findings demonstrate that premature rabbit kittens provide a useful developmental model for the evaluation of candidate BPD therapies and reproduce MPO-associated pathological and therapeutic responses previously observed in neonatal rat studies.
2026-08-08 | Brain-derived neurotrophic factor (BDNF) in neonatal blood: associations with respiratory disease in extremely preterm infants.
Neurotrophins, including brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), have been associated with the development of bronchopulmonary dysplasia (BPD) in preterm infants. To evaluate relationships between early postnatal BDNF and NT-4 levels and adverse pulmonary outcomes among preterm infants. We analyzed data from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Serum BDNF and NT-4 were measured at birth and postnatal days 7, 14, 21, and 28. Pulmonary outcomes included BPD and early respiratory patterns predictive of BPD, specifically, pulmonary deterioration (PD) and early and persistent pulmonary dysfunction (EPPD). Associations were evaluated using regression models adjusted for perinatal confounders. NT-4 levels were not associated with BPD risk. Persistently high BDNF trajectories were associated with reduced risk, while persistently low BDNF was associated with increased risk of BPD, PD, and EPPD (BPD: OR 2.75; 95% CI 1.83-4.15; PD: OR 3.13; 95% CI 1.60-6.14; and EPPD: OR 7.94; 95% CI 3.70-17.04). Infants with persistently low and intermediate BDNF trajectories had higher risk of adverse pulmonary outcomes compared with those with persistently high BDNF levels. Longitudinal BDNF trajectories identify subgroups of preterm infants at differential risk for adverse respiratory outcomes. Persistently high BDNF during the first month of life may be protective and a potential target for preventive strategies. Persistently low brain-derived neurotrophic factor (BDNF) levels during the first postnatal month are associated with increased risk and severity of bronchopulmonary dysplasia (BPD) and early adverse respiratory phenotypes in extremely preterm infants. Longitudinal BDNF trajectories provide greater discrimination of respiratory risk than single time-point measurements. Infants with persistently high BDNF have the lowest risk of pulmonary deterioration, early persistent pulmonary dysfunction, and severe BPD. These findings support BDNF as a potential early biomarker of lung disease progression in preterm infants.
2026-07-03 | Inhibition of thrombospondin-1 signaling prevents experimental bronchopulmonary dysplasia.
Bronchopulmonary dysplasia (BPD) is a neonatal lung injury characterized by inflammation, and alveolar and vascular hypoplasia that currently lacks effective treatment. Thrombospondin (TSP)-1 is an angiostatic and pro-inflammatory protein, recently implicated in BPD pathogenesis, that both activates transforming growth factor (TGF)-β1 and suppresses nitric oxide (NO) signaling. In order to gain further insight into the relative importance of downstream effects of TSP-1, our objective in a neonatal rat model of hyperoxia-intermittent hypoxia (H-IH)-induced lung injury was to compare effects of inhibiting: 1) TSP-1-mediated TGF-β1 activation alone (LSKL) or 2) global TSP-1 signaling (soluble CD47 receptor ligand trap; sCD47r). From postnatal days (PND) 1-21, rat pups were exposed to air or to H-IH (PND 1-7 85% O2, PND 7-14 60% O2 and PND 14-21 air with intermittent exposure to 10% O2 for 10 min every 4 hours) while either receiving daily s.c. LSKL (20 mg/kg) or third daily sCD47r (3 mg/kg). Controls were treated with vehicle or were continuously exposed to normoxia. Exposure to H-IH increased lung contents of TSP-1 and active TGF-β1, and caused macrophage influx, alveolar and pulmonary vascular hypoplasia, and pulmonary hypertension (PH). Both strategies prevented H-IH-mediated effects on active TGF-β1 content, macrophage influx, abnormal lung morphology and PH, while only sCD47r increased lung NO content and signaling. These observations in a clinically-relevant model indicate that multiple strategies aimed at suppressing TSP-1 signaling are effective in preventing lung injury and that targeting TSP-1-mediated activation of TGF-β1 is sufficient to achieve these effects.
cell therapies
2026-08-07 | Human Umbilical Cord Mesenchymal Stem Cell-Derived Microvesicles Alleviate Bronchopulmonary Dysplasia in Preterm Rats by Inhibiting Neutrophil Extracellular Trap Formation.
Among preterm infants, bronchopulmonary dysplasia (BPD) is the most prevalent chronic pulmonary disorder. Its pathogenesis involves a complex interplay between prenatal inflammatory exposure and abnormal immune activation. Neutrophil extracellular traps (NETs) are mediators of tissue damage, but whether they bridge intrauterine inflammation and the subsequent development of BPD is not yet clear. We used a prenatal lipopolysaccharide (LPS)-exposed rat model to ask two questions: first, whether excessive NETs drive BPD pathogenesis, and second, whether human umbilical cord mesenchymal stem cell-derived microvesicles (hUCMSC-MVs) can alleviate lung injury by inhibiting this process. We established a BPD model in preterm rats via prenatal LPS exposure and assessed lung morphometry, neutrophil infiltration, and NETs markers. We then compared the therapeutic effects of hUCMSC-MVs with NET extrusion (NETosis) inhibitors in vivo and also examined direct neutrophil effects in vitro. Prenatal LPS exposure led to significantly elevated NET markers in both lung tissue and circulation, which correlated with severe alveolar simplification. Neutrophils in this model exhibited a "primed" phenotype with enhanced potential for NETs release. In vivo, hUCMSC-MVs suppressed NET formation, attenuated neutrophilic inflammation, and restored alveolar structure, matching the efficacy of conventional NETosis inhibitors. In vitro, they were internalized by neutrophils and abrogated LPS-induced NETosis. These findings point to excessive NETosis as a key mechanistic link between prenatal inflammation and postnatal lung impairment. hUCMSC-MVs directly inhibit this pathological process and alleviate BPD-like lung injury. This work advances the mechanistic understanding of BPD and supports hUCMSC-MVs as a promising cell-free therapeutic candidate.
2026-07-30 | Mitochondrial programmed cell death in bronchopulmonary dysplasia: mechanisms and therapeutic targets.
Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in preterm infants, primarily characterized by arrested alveolarization and dysregulated pulmonary microvascular development. Mitochondria are crucial for normal lung development, supporting cellular energy and homeostasis. In BPD, mitochondrial homeostasis is severely disrupted, characterized by excessive fission, suppressed fusion, deficient biogenesis, imbalanced mitophagy, a collapsed antioxidant system, and a consequent energy crisis. Following mitochondrial damage, a spectrum of mitochondria-associated programmed cell death pathways is activated in pulmonary cells, including mitophagy-dependent death, apoptosis, necroptosis, pyroptosis, and ferroptosis. Within alveolar epithelial cells, vascular endothelial cells, and other pulmonary cells, these death pathways operate both independently and through extensive crosstalk, forming a complex regulatory network. This network synergistically disrupts pulmonary cell survival, proliferation, and differentiation, ultimately arresting lung development. Therapeutic strategies aim to restore mitochondrial homeostasis, inhibit specific death pathways, and utilize regenerative approaches like exosome-based delivery. This review examines the role of mitochondrial dysfunction and interconnected cell death pathways in BPD pathogenesis and discusses emerging treatments.
2026-07-29 | Five-year follow-up of phase II trial of autologous cord blood mononuclear cells for bronchopulmonary dysplasia prevention in very preterm infants.
We previously performed a phase II clinical trial involving the intravenous infusion of autologous cord blood mononuclear cells (ACBMNCs) to prevent bronchopulmonary dysplasia in premature infants. We reported the outcomes before discharge and at 2-year follow-up of the enrolled infants. We have reported the developmental outcomes at the 5-year follow-up visit. We evaluated the 5-year long-term outcomes of ACBMNCs infusion, including growth, respiratory, and neurodevelopmental outcomes, by interviewing the parents. Children's development was assessed using scores on the Chinese version of the Ages & Stages Questionnaires (ASQ), third edition (ASQ-3), completed by the parents or guardians. The primary outcome was the neurodevelopmental outcome. The secondary outcomes were growth and respiratory outcomes. In terms of the primary endpoint, intravenously infused ACBMNCs significantly improved the scores of the fine motor and personal-social domains in the ASQ (P = .044 and P = .048, respectively). This study also showed high consistency between the motor index in the Bayley score at a 2-year follow-up with both gross and fine motor domain scores, as well as the language index with communication, problem-solving, and personal-social domain scores. Although pneumonia-related hospitalizations were similar between the two groups, the intervention group showed a lower possibility of nocturnal cough. Infants who received intravenous ACBMNC infusion had better fine motor and personal-social abilities at 5 years than those in the control group. In addition to providing reassuring safety data, the study suggested longer-term neurodevelopmental benefits of ACBMNC intervention early in the NICU course. Further randomized placebo-controlled trials are essential to confirm these findings. The trial was prospectively registered at ClinicalTrials.gov (NCT02999373), registered on December 21, 2016.
2026-07-24 | Regenerative strategies for surfactant deficiency in neonatal and pediatric lung disease: the role of mesenchymal stem cells and their extracellular vesicles.
Surfactant deficiency underlies several neonatal and pediatric lung diseases, including respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and genetic surfactant disorders. Although advances in neonatal care and surfactant replacement therapy have improved survival in preterm infants, current treatments mainly provide supportive management and do not fully address mechanisms of lung injury and impaired lung development. Regenerative approaches based on mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) have emerged as potential strategies to promote lung repair and restore alveolar homeostasis. This narrative review summarizes experimental and clinical evidence on MSC- and EV-based regenerative strategies for surfactant-related lung diseases. Relevant studies investigating MSCs or MSC-derived EVs in neonatal and pediatric lung injury were identified through searches in PubMed, Scopus and Web of Science and were qualitatively analyzed. Preclinical studies show that MSCs reduce inflammation, protect type II alveolar epithelial cells and promote alveolar development in models of immature lung injury. These effects are largely mediated by paracrine mechanisms, including the release of MSC-derived EVs, which transfer bioactive molecules to target cells and regulate inflammatory and regenerative pathways. Accordingly, EV-based therapies, as a cell-free derivative of MSCs, reproduce several beneficial effects of MSC transplantation in animal models. Early clinical studies in preterm infants at risk of BPD show encouraging safety profiles, although evidence of long-term efficacy remains limited. MSC- and EV-based regenerative approaches represent promising strategies for surfactant-related lung diseases. Further studies are needed to clarify mechanisms of action and evaluate their efficacy in well-designed clinical trials involving neonatal and pediatric populations.
2026-07-07 | Helping Underdeveloped Lungs with Cells (HULC-2): mesenchymal stromal cells in extreme preterm infants at risk of developing bronchopulmonary dysplasia - a study protocol of a phase 2 multicentre double blind randomised controlled trial in Canada.
Bronchopulmonary dysplasia (BPD) remains a major complication among extremely low gestational age (ELGA) infants, with long-term respiratory and neurodevelopmental consequences. Despite advances in neonatal care, effective therapies to prevent BPD are lacking. Mesenchymal stromal cells (MSCs), particularly those derived from umbilical cord (UC-MSC), offer promise due to their pleiotropic effects. Preclinical and early-phase clinical studies have demonstrated safety and potential efficacy of MSC in neonatal lung injury. The Helping Underdeveloped Lungs with Cells (HULC)-2 trial aims to evaluate whether multiple intravenous doses of human allogenic UC-MSC can reduce mechanical ventilation duration and improve the respiratory outcome in ELGA infants at high risk of developing BPD. HULC-2 is a multicentre, double-blind, randomised controlled Phase II trial conducted in Canadian Neonatal Intensive Care Units. ELGA infants (gestational age <28 weeks) who remain ventilator-dependent between 4 and 14 days of life will be randomised to receive either 3 weekly intravenous doses of UC-MSC (10×106 cells/kg/dose) or a sham procedure. The primary outcome is ventilation-free days (VFDs) at 120 days postrandomisation, accounting for mortality. Secondary outcomes include cell administration safety, respiratory and neurodevelopmental outcomes and complications of prematurity. A total of 168 participants will be enrolled to detect a clinically meaningful difference in VFDs. The study was approved through Clinical Trials Ontario by the Ottawa Health Science Network Research Ethics Board. Results will be disseminated via peer-reviewed publications, conferences and public engagement platforms. Parent partners are actively involved in study design and dissemination to ensure relevance and transparency. NCT07058025.
other
2026-08-31 | Downregulation of UNC5B-AS1 in Preterm Infants with Bronchopulmonary Dysplasia and Its Protective Mechanism via the miR-134-5p/IGF1 Axis.
Bronchopulmonary dysplasia (BPD) is a major chronic lung disease in preterm infants. This study was designed to elucidate the functional significance and molecular mechanism of the long non-coding RNA UNC5B-AS1 in BPD pathogenesis. This study included 50 preterm infants with BPD and 42 healthy newborns. The levels of UNC5B-AS1, miR-134-5p, IGF1, Bax, and Bcl-2 were detected by RT-qPCR. In in vitro experiments, A549 and MLE-12 cells were used to establish a hyperoxia-induced BPD model. A series of assays was performed to evaluate the cellular phenotypes, including CCK-8 for viability, flow cytometry for apoptosis, ELISA for inflammatory factors (TNF-α, IL-1β, IL-6), and SOD activity, and DCFH-DA probing for ROS levels. IGF1 protein expression was examined by Western blot. Dual-luciferase reporter assay and RIP experiments were performed to validate the targeting relationships between UNC5B-AS1 and miR-134-5p, and between miR-134-5p and IGF1. Serum levels of UNC5B-AS1 were significantly downregulated, while miR-134-5p expression was significantly upregulated in BPD infants, both showing good diagnostic value. UNC5B-AS1 directly binds to miR-134-5p. In the cellular model, the protective effect of UNC5B-AS1 overexpression against hyperoxia-induced injury was reversed by miR-134-5p overexpression. Furthermore, IGF1 was confirmed as a direct target of miR‑134‑5p, and knockdown of IGF1 abolished the protective effects achieved by miR‑134‑5p inhibition. Serum UNC5B‑AS1 is downregulated and miR‑134‑5p is upregulated in preterm BPD infants. Mechanistically, UNC5B‑AS1 may sponges miR‑134‑5p to upregulate IGF1, protecting against hyperoxia‑induced alveolar injury.
2026-07-19 | SRPRA affects hyperoxia-induced bronchopulmonary dysplasia by modulating endoplasmic reticulum stress through the CHOP pathway.
Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease among preterm infants, largely attributed to hyperoxia-induced injury to alveolar epithelial cells. Excessive endoplasmic reticulum (ER) stress plays a vital role in BPD progression. SRPRA, a subunit of the ER-localized SRP receptor, is upregulated in BPD, while its function and link with ER stress remain largely unclear. This study aimed to explore the role of SRPRA in hyperoxia-induced BPD and its underlying mechanism. A hyperoxia-exposed alveolar type II epithelial cell (AECII) model was established to mimic BPD in vitro. Cell viability, cell proliferation and apoptosis were detected by CCK-8, EdU assay and flow cytometry, respectively. The secretion of inflammatory factors was evaluated via ELISA assay. ROS levels were detected by DCFH-DA fluorescence staining. Commercial kits were used to detect MDA and SOD levels. The SRPRA mRNA level and protein expression was measured using qRT-PCR and Western blot. Expression levels of apoptosis-related proteins (Bax, Bcl2), inflammation-related proteins (iNOS, Cox2) and CHOP pathway-related proteins were assessed by western blotting. SRPRA was markedly upregulated in hyperoxia-induced alveolar epithelial cells. Hyperoxia stimulation decreased viability and proliferation, and enhanced apoptosis in AECIIs, accompanied by elevated inflammatory responses and oxidative stress. SRPRA knockdown alleviated hyperoxia-induced cell damage, inflammation and oxidative stress, and downregulated the expression of CHOP (a key mediator of ER stress). The protective effects mediated by SRPRA silencing were largely reversed by thapsigargin. SRPRA knockdown alleviates hyperoxia-induced AECII injury by attenuating CHOP-mediated ER stress. Our findings reveal the pathogenic role of SRPRA in BPD, and suggest SRPRA as a potential therapeutic target for this disease.
2025-11-09 | IRF4 exacerbates pulmonary inflammation in bronchopulmonary dysplasia mice model by regulating macrophage polarization and phagocytosis.
This study investigates the critical function of interferon regulatory factor 4 (IRF4) during bronchopulmonary dysplasia (BPD) progression by regulating alveolar macrophages (AMs) polarization and phagocytic function. We developed IRF4 knockout mice using CRISPR/Cas9 technology and established an animal model for neonatal bronchopulmonary dysplasia (BPD) by hyperoxia exposure. Lung tissue pathology was analyzed by Hematoxylin and eosin staining (HE). The concentrations of TNF-α, IL-1β, IL-10, and TGF-β were ascertained by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to investigate M1/M2 macrophage polarization in bronchoalveolar lavage fluid (BALF) and lung tissue, while Western blotting and quantitative real-time PCR (qRT-PCR) were employed to detect IRF4, iNOS, and Arg-1 protein and mRNA expression. At cellular level, we silenced IRF4 in murine alveolar macrophage cell lines using IRF4 siRNA to investigate its effect on inflammatory cytokine secretion, polarization, and phagocytic function. To assess the effect of IRF4 on alveolar macrophage phagocytosis after hyperoxia, we utilized flow cytometry to ascertain the mean fluorescence intensity of engulfed fluorescent microspheres and fluorescence microscopy to quantify phagocytic cells. Hyperoxia-exposed mice showed markedly upregulated IRF4 expression, increased M1 macrophage and iNOS levels, and decreased M2 macrophages and Arg-1 expression. This cytokine shift was characterized by a marked upregulation of inflammatory factors such as TNF-α and IL-1β, accompanied by a notable decline in anti-inflammatory factors encompassing IL-10 and TGF-β, indicating an imbalance towards a pro-inflammatory state. IRF4 knockout or siRNA-mediated silencing attenuated the inflammatory response, promoting M2 macrophage differentiation while suppressing M1 differentiation. Phagocytic assays showed that hyperoxia impaired the phagocytic activity of AMs, while transfection of IRF4 siRNA restored the phagocytic activity of macrophage. IRF4 functions as a crucial regulator in the progression of hyperoxia-induced bronchopulmonary dysplasia, exerting its effects by influencing the polarization state and phagocytic function of alveolar macrophages. Deletion of IRF4 promotes an M2-dominant anti-inflammatory response, attenuates hyperoxia-induced inflammation, and increases the phagocytosis capacity of macrophages.
2025-10-09 | TXNIP mediates ferroptosis in a bronchopulmonary dysplasia mouse model by regulating the SLC7A11/GPX4 pathway.
Bronchopulmonary dysplasia (BPD) is one of the most common respiratory diseases in preterm infants. Studies have shown that ferroptosis is involved in the pathogenesis of BPD, and thioredoxin-interacting protein (TXNIP)-mediated oxidative stress also plays a role in its development. The solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway is one of the key pathways regulating ferroptosis. This study aimed to investigate the mechanism by which TXNIP regulates SLC7A11/GPX4 pathway-mediated ferroptosis in BPD. Mice were randomly divided into ten treatment groups: Air, Hyperoxia, Hyperoxia + RSL3, Hyperoxia + Ferrostatin-1, Hyperoxia + Ad-shNC, Hyperoxia + Ad-shTXNIP, Hyperoxia + Ad-vector, Hyperoxia + Ad-TXNIP, Hyperoxia + Ad-shSLC7A11, and Hyperoxia + Ad-shTXNIP + Ad-shSLC7A11. Lung tissues were collected for hematoxylin and eosin (H&E) staining to observe pathological changes, and transmission electron microscopy (TEM) was used to examine mitochondrial morphology. Real-time quantitative polymerase chain reaction (qPCR) was performed to measure the mRNA expression of TXNIP, SLC7A11, and GPX4. Western blotting was used to analyze the protein levels of TXNIP, SLC7A11, and GPX4. GPX4 activity was determined using an enzyme-linked immunosorbent assay (ELISA). Additionally, glutathione (GSH), malondialdehyde (MDA), and ferrous iron (Fe2+) levels in lung tissues were measured using corresponding detection kits. H&E staining and TEM confirmed successful modeling of lung injury after hyperoxia. MDA and Fe2+ increased, GSH decreased, and GPX4 activity declined after hyperoxia. TXNIP mRNA and protein were upregulated by hyperoxia, while SLC7A11 and GPX4 were downregulated. Ferroptosis activation exacerbated lung injury, whereas inhibition alleviated it. TXNIP overexpression using adenovirus serotype 5 (Ad5) aggravated ferroptosis in BPD, and this was ameliorated by TXNIP knockdown. Knockdown of the upstream signal SLC7A11 increased ferroptosis in BPD, and simultaneous knockdown of TXNIP and SLC7A11 reversed the ferroptosis reduction. In conclusion, in the BPD model, TXNIP expression was increased, and TXNIP promoted ferroptosis by downregulating the SLC7A11/GPX4 pathway. These findings suggest that gene therapy targeting TXNIP knockdown using adenovirus as a vector may serve as a therapeutic strategy for BPD.
2025-09-15 | Pulmonary Hypertension Outcomes After Closure of Atrial Septal Defect in Infants With Developmental Lung Disease.
Pulmonary hypertension (PHTN) in infants with developmental lung disease, such as bronchopulmonary dysplasia (BPD), chronic lung disease of infancy (CLD), or congenital diaphragmatic hernia (CDH), can be exacerbated by atrial septal shunts secondary to atrial septal defects (ASD). While transcatheter ASD closure may reduce pulmonary overcirculation, data on post-closure hemodynamic and pharmacologic outcomes remain limited. This single-center retrospective study aimed to characterize changes in PHTN severity, respiratory support, and medication use 1 year after early transcatheter ASD closure (defined as closure at ≤ 1 year of age). Eligible patients were infants with BPD, CLD, or CDH who underwent early transcatheter ASD closure between 2021 and 2024 and had preprocedural PHTN medication use and respiratory support. Sixteen infants met the inclusion criteria. At 1 year, excluding the 3 who died, 10 of 13 infants (76.9%) showed improved PHTN severity, including 6 (60%) with complete resolution. Of the 13 infants, 6 (46.2%) weaned off all respiratory support. Average diuretic dosage (mg/kg/day) decreased by 92.9%, and vasodilator dosage declined by 47.0%. Infants with ASDs ≥ 5 mm and gestational age (GA) < 32 weeks required significantly longer diuretic therapy than those with smaller ASDs (< 5 mm) and GA ≥ 32 weeks. No similar associations were found with vasodilator weaning. These findings suggest early transcatheter ASD closure may offer therapeutic benefit in select high-risk infants, resulting in improved hemodynamics and reduced medication dependence. Although limited by small sample size and retrospective design, this study supports the potential for individualized weaning strategies and the need for prospective multicenter investigations.
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Drug Discovery Landscape
34 orphan drug designations for Bronchopulmonary dysplasia.
34 orphan drug designations for Bronchopulmonary dysplasia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Mecasermin rinfabate | proteins | EMA | Orphix Consulting GmbH | |
Human allogeneic umbilical cord mesenchymal stromal cells-derived extracellular vesicles. | cell therapies | FDA | Exo Biologics SA | |
Allogeneic umbilical cord-derived mesenchymal stem cell drug | cell therapies | FDA | — | Meribank Biotech Co. Ltd. |
azithromycin | small molecules | FDA | Iorek Pharma Limited | |
Azithromycin dihydrate | small molecules | EMA | Morningside Healthcare (Malta) Limited | |
Retinol palmitate | small molecules | EMA | Transcrip Ireland Limited | |
Allogeneic umbilical cord mesenchymal cells-derived extracellular vesicles | cell therapies | EMA | EXO Biologics | |
mecasermin rinfabate | proteins | FDA | OHB Neonatology Ltd | |
Hydrocortisone hemisuccinate | small molecules | EMA | — | Laboratoire Aguettant |
Mesenchymal Stem Cell-derived Extracellular Vesicles | cell therapies | FDA | — | Stella Kourembanas, M.D. |
N-((2S,3R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2-(4-nitrophenoxy)tetrahydro-2H-pyran-3-yl)acetamide | small molecules | FDA | — | AyuVis Research, Inc. |
Allogeneic umbilical cord tissue-derived mesenchymal stromal cells ex vivo expanded | cell therapies | EMA | — | MDTB Cells GmbH |
Retinol palmitate | small molecules | EMA | Provepharm S.A.S. | |
hydrocortisone | small molecules | FDA | LABORATOIRE AGUETTANT | |
recombinant fragment human surfactant protein-D | proteins | FDA | Trimunocor Ltd. | |
Recombinant fragment of human surfactant protein-D | proteins | EMA | Premier Research Group S.L. | |
Retinol palmitate | small molecules | FDA | Orphanix GmbH | |
vitamin A palmitate | small molecules | FDA | Advent Therapeutics, Inc. | |
Allogeneic ex-vivo-expanded human umbilical cord blood-derived mesenchymal stem cells | cell therapies | EMA | — | Ergomed B.V. |
Recombinant human club cell 10 KDa protein | proteins | EMA | RLM Consulting | |
Retinol | small molecules | EMA | Orphanix GmbH | |
recombinant human surfactant protein D | proteins | FDA | Airway Therapeutics LLC | |
Recombinant human surfactant protein D | proteins | EMA | Airway Therapeutics Spain S.L. | |
Caffeine citrate | small molecules | EMA | Viridian Pharma Ltd | |
human umbilical cord blood-derived mesenchymal stem cells | cell therapies | FDA | MEDIPOST America, Inc. | |
Water-miscible vitamin A palmitate | small molecules | FDA | Fox Pharma, Inc. | |
Lucinactant | small molecules | FDA | Lee’s Pharmaceutical (HK) Limited | |
Lucinactant | proteins | FDA | Lee’s Pharmaceutical (HK) Limited | |
Recombinant human alpha 1-antitrypsin | proteins | FDA | — | Arriva Pharmaceuticals, Inc. |
Estradiol Hemihydrate and Progesterone | combination | EMA | — | Dr Frank Pohlandt |
Nitric oxide | small molecules | FDA | Mallinckrodt Pharmaceuticals Ireland Ltd. | |
Recombinant human Clara Cell 10kDa protein | proteins | FDA | Trove Therapeutics, Inc. | |
Secretory leukocyte protease inhibitor | proteins | FDA | — | Synergen, Inc. |
Recombinant human superoxide dismutase | proteins | FDA | — | Savient Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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