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Bronchopulmonary dysplasia: "A vascular hypothesis"
... Bronchopulmonary dysplasia (BPD) is a chronic disease that develops in premature newborns following ventilation and oxygen treatment for acute respiratory failure due to their shortened gestation (1). BPD results in disrupted lung development characterized by alveolar simplification -enlarged alveoli with reduced septation, and vascular rarefaction -reduced and dysmorphic vasculature (1). ...
... Bronchopulmonary dysplasia (BPD) is a chronic disease that develops in premature newborns following ventilation and oxygen treatment for acute respiratory failure due to their shortened gestation (1). BPD results in disrupted lung development characterized by alveolar simplification -enlarged alveoli with reduced septation, and vascular rarefaction -reduced and dysmorphic vasculature (1). Historically, much of the focus has been on the epithelium and mesenchyme as the target cells that underlie BPD pathology (2). ...
... Historically, much of the focus has been on the epithelium and mesenchyme as the target cells that underlie BPD pathology (2). However, limited studies propose the vasculature as a main player in the pathogenesis of BPD, something known as the "vascular hypothesis" (1). Recent studies have explored the transcriptomic changes in mouse models of BPD using single-cell RNA-sequencing (scRNA-seq) (3)(4)(5); however, the endothelialspecific contributions remain unexplored. ...
Bronchopulmonary dysplasia (BPD), a prevalent and chronic lung disease affecting premature newborns, results in vascular rarefaction and alveolar simplification. Although the vasculature has been recognized as a main player in this disease, the recently found capillary heterogeneity and cellular dynamics of endothelial subpopulations in BPD remain unclear. Here, we show Cap2 cells are damaged during neonatal hyperoxic injury, leading to their replacement by Cap1 cells which, in turn, significantly decline. Single-cell RNA-seq identifies the activation of numerous p53 target genes in endothelial cells, including Cdkn1a (p21) . While global deletion of p53 results in worsened vasculature, endothelial-specific deletion of p53 reverses the vascular phenotype and improves alveolar simplification during hyperoxia. This recovery is associated with the emergence of a transitional EC state, enriched for oxidative stress response genes and growth factors. These findings implicate the p53 pathway in EC type transition during injury-repair and highlights the endothelial contributions to BPD.
... The conserved pattern of histological and vascular signaling abnormalities in new BPD led to the hypothesis that ECs and aberrant signaling drive disease (Abman, 2001). A common preclinical model for investigating BPD is the rodent hyperoxia-induced lung injury model, where newborn animals are exposed to hyperoxia to impair lung development. ...
... VEGF is central to the vascular hypothesis of BPD and may have a potential role in treatment (Abman, 2001). In hyperoxiachallenged mice, administration of anti-angiogenic agents impaired angiogenesis and alveolarization (Tang et al., 2012;Wallace et al., 2018), while over-expression of VEGF attenuated the adverse effects of hyperoxia on alveolarization (Alvira, 2016). ...
... In another study in hyperoxia-exposed Sprague-Dawley rats, recombinant human VEGF treatment reversed the BPD phenotype and accelerated EC-mediated vessel growth and alveolarization (Kunig et al., 2005). In lung development, growth factors released from the niche coordinate epithelial cell growth and are critical for mediating the development of distal airspace structures (Abman, 2001). Furthermore VEGFR2 signaling promotes differentiation of alveolar type II epithelial cells (AT2) and stimulates secretion of surfactant, which are critical in BPD (Cross et al., 2003). ...
Lung endothelial cells comprise the pulmonary vascular bed and account for the majority of cells in the lungs. Beyond their role in gas exchange, lung ECs form a specialized microenvironment, or niche, with important roles in health and disease. In early development, progenitor ECs direct alveolar development through angiogenesis. Following birth, lung ECs are thought to maintain their regenerative capacity despite the aging process. As such, harnessing the power of the EC niche, specifically to promote angiogenesis and alveolar regeneration has potential clinical applications. Here, we focus on translational research with applications related to developmental lung diseases including pulmonary hypoplasia and bronchopulmonary dysplasia. An overview of studies examining the role of ECs in lung regeneration following acute lung injury is also provided. These diseases are all characterized by significant morbidity and mortality with limited existing therapeutics, affecting both young children and adults.
... The prevalent narrative linking in-utero events such as utero-placental insufficiency (UPI) with 'subsequent' respiratory sequela such as BPD is through the involvement of pulmonary parenchyma and somatic growth. While the pathophysiology of BPD is multifactorial, the vascular hypothesis behind it is increasingly being explored [12][13], The Barker Hypothesis, or the Developmental Origins of Health and Disease Hypothesis, in its original proposition, explained fetal/developmental priming of the cardiovascular system [14][15]. However, the underlying principles are equally relevant to the developing pulmonary vasculature [16]. ...
... Impairments in angiogenic signalling during critical fetal periods can reduce pulmonary vascular density, making them particularly susceptible to pulmonary vascular injury [13,[18][19][20][21]. In essence, early-life vascular disorders may impact alveolar development [12,22]. A wide variety of prenatal conditions have been associated with impaired pulmonary vascular development; these include FGR-fetal hypoxia, pre-eclampsia, chorioamnionitis and exposure to intrauterine toxins produced by maternal smoking. ...
... In a retrospective cohort study of 247 mother-neonatal pairs, pre-eclampsia was associated with BPD, in part mediated by FGR [95]. Abnormal vascular endothelial growth factor signalling might play a critical role as it has been described in the pathogenesis of pre-eclampsia [96] and in the 'vascular hypothesis' of BPD [12][13]97]. Third trimester fetal blood flow patterns might inform childhood respiratory health. ...
Bronchopulmonary dysplasia (BPD) is the most common respiratory sequela of prematurity, and infants born with fetal growth restriction (FGR) are disproportionately represented in BPD statistics, as factors which affect somatic growth may also affect pulmonary growth. Effects of in-utero hypoxia underlying FGR on lung parenchymal architecture predisposing to BPD are well documented, but the pulmonary vascular constructs are not well appreciated. Disruption of angiogenesis during critical periods of lung growth impairs alveolarization, contributing to BPD pathogenesis. Pulmonary artery thickness/stiffness has been noted in FGR in the initial postnatal weeks, and also in well-grown infants with established BPD. The lack of waveform cushioning by the major arteries exposes the pulmonary resistance vessels to higher pulsatile stress, thereby accelerating microvascular disease. Reactive oxygen species, increased sympathetic activity and endothelial dysfunction are common mediators in FGR and BPD; each putative targets for prevention and/or therapeutics using interleukin (IL)-1 receptor antagonist (IL-1Ra), melatonin or inhibition of renin–angiotensin–aldosterone system. While BPD is the archetypal respiratory disease of infancy, effects of FGR on pulmonary function are long-term, extending well into childhood. This narrative links FGR in very/extremely preterm infants with BPD through the vascular affliction as a mechanistic and potentially, therapeutic pathway. Our objectives were to depict the burden of disease for FGR and BPD amongst preterm infants, portray vascular involvement in the placenta in FGR and BPD cohorts, provide high resolution vascular ultrasound information in both cohorts with a view to address therapeutic relevance, and lastly, link this information with paediatric age-group lung diseases.
... The pathology of the lungs at postmortem examination demonstrated diffuse fibroproliferative lung disease [2]. More recently, researchers have demonstrated a contribution of abnormal pulmonary vascular development to the pathogenesis of BPD [3][4][5][6][7]. Despite major advances in neonatal care and more conservative strategies for mechanical ventilation, up to 40% of premature infants still progress to the development of this chronic lung disease [8]. ...
... We suggest the discordant results could be attributed to different sample sizes, wider ranges of gestational ages, different definitions of HDP and/or severity of BPD as well as omission of the potential interaction between gestational age and HDP. The pathophysiology of BPD is characterized by an arrest of both alveolarization and of pulmonary vascular development, secondary to multiple antenatal and perinatal insults when infants are born at the late canalicular stage of lung growth [3][4][5][6][7]. Preeclampsia also has links with dysregulation of angiogenic function that starts early in pregnancy with an imbalance in circulating angiogenic factors [37]. ...
Objective
Determine the association between severe hypertensive disease of pregnancy (HDP) with moderate-severe bronchopulmonary dysplasia (BPD) in preterm infants (< 31 weeks’ gestation).
Study Design
Preterm birth cohort study of 693 mother-infant dyads. Severe HDP was defined as severe preeclampsia, HELLP syndrome or eclampsia. The outcome was moderate-severe BPD classified at 36 weeks corrected gestational age, per the NICHD Consensus statement.
Results
225 (32%) mothers developed severe HDP and 234 (34%) infants had moderate-severe BPD. There was an interaction between severe HDP and gestational age (p = 0.03). Infants born at < 25 weeks gestation to mothers with HDP had increased odds for moderate-severe BPD compared to infants of normotensive mothers delivering at the same gestational age. Infants born > 28 weeks to mothers with severe HDP had decreased odds for the outcome, though not statistically significant.
Conclusions
Severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age.
... (2) More recently, researchers have demonstrated a contribution of abnormal pulmonary vascular development to the pathogenesis of BPD. (3)(4)(5)(6)(7) Despite major advances in neonatal care and more conservative strategies for mechanical ventilation, up to 40% of premature infants still progress to the development of this chronic lung disease. (8) Preeclampsia, HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome, and eclampsia are hypertensive diseases of pregnancy (HDP) associated with abnormal vascular growth within the uteroplacental interface resulting in dysfunctional placentation. ...
... The pathophysiology of BPD is characterized by an arrest of both alveolarization and of pulmonary vascular development, secondary to multiple antenatal and perinatal insults when infants are born at the late canalicular stage of lung growth. (3)(4)(5)(6)(7) Preeclampsia also has links with dysregulation of angiogenic function that starts early in pregnancy with an imbalance in circulating angiogenic factors. (37) We hypothesize from the results of our study that altered levels of angiogenic factors may impact pulmonary vascular development in the fetus, in a maturational or gestational age dependent manner. ...
Objective: Determine the association between severe hypertensive disease of pregnancy (HDP) with moderate-severe bronchopulmonary dysplasia (BPD) in preterm infants (< 31 weeks’ gestation).
Study Design: Preterm birth cohort study of 693 mother-infant dyads. Severe HDPwas defined as severe preeclampsia, HELLP syndrome or eclampsia. The outcome was moderate-severe BPD classified at 36 weeks corrected gestational age, based on the NICHD Consensusstatement.
Results: 225 (32%) mothers developed severe HDP and 234 (34%) infants hadmoderate-severe BPD. There was an interaction between severe HDP and gestational age (p=0.03). Infants born at earlier gestational ages to mothers with HDP had increased odds for moderate-severe BPD compared to infants of normotensive mothers delivering at the same gestational age. Infants born at later gestational ages to mothers with severe HDP had decreased odds for the outcome.
Conclusions: Severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age.
... In 2001, Steven Abman introduced the "vascular hypothesis": that angiogenesis drives the alveolarization process and that impaired vascular growth may lead to the stunted alveolarization seen in BPD (7). This hypothesis was supported by previous studies that reported decreased expression of proangiogenic factors in the lungs of infants with respiratory failure, BPD, and pulmonary hypertension (8,9). ...
... Together, the results of this study strongly support the concept of the vascular hypothesis. The idea of this hypothesis is that, in normal lung development, vascularization drives alveolarization and that, in BPD, injury to the more susceptible vasculature causes aberrant alveolarization and hypoplasia (7). Previous studies demonstrated the adverse effects of inhibited angiogenesis on alveolarization (10)(11)(12)(13)(14)(15)(16), which is in line with the results of the present study. ...
Bronchopulmonary dysplasia (BPD), the most common sequela of preterm birth, is a severe disorder of the lung that is often associated with long-lasting morbidity. A hallmark of BPD is the disruption of alveolarization whose pathogenesis is incompletely understood. Here, we tested the vascular hypothesis that disordered vascular development precedes the decreased alveolarization associated with BPD. Neonatal mouse pups were exposed to 7, 14 or 21 days of normoxia (21% O2) or hyperoxia (85% O2) with n=8-11 for each group. The right lungs were fixed by vascular perfusion and investigated by design-based stereology or three-dimensional (3D) reconstruction of data sets obtained by serial block-face scanning electron microscopy. The alveolar capillary network of hyperoxia-exposed mice was characterized by rarefaction, partially altered geometry and widening of capillary segments as shown by 3D reconstruction. Stereology revealed that the development of alveolar epithelium and capillary endothelium was decreased in hyperoxia-exposed mice, however, the time course of these effects was different. That the surface area of the alveolar epithelium was smaller in hyperoxia-exposed mice first became evident at day 14.In contrast, the surface area of the endothelium was reduced in hyperoxia-exposed mouse pups at day 7. The thickness of the air-blood barrier decreased during postnatal development in normoxic mice whereas it increased in hyperoxic mice. The endothelium and the septal connective tissue made appreciable contributions to the thickened septa. In conclusion, the present study provides clear support for the idea that the stunted alveolarization follows the disordered microvascular development, thus supporting the vascular hypothesis of BPD.
... Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development with severe impairment in vascular development and alveolarization [1]. Despite recent advances in perinatal care, BPD remains a leading cause of morbidity in premature neonates [2,3]. ...
Background
Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.
Methods
Wild-type and miR-30a −/− neonatal mice were exposed to hyperoxia [95% FiO 2 , postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a −/− mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a −/− male and female lung transcriptome data.
Results
Significantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a −/− mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a −/− female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand–receptor interaction. Gene expression signature in the miR-30a −/− female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium.
Conclusions
miR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.
... Increasing evidence hints to the "vascular hypothesis" of BPD, where errand microvascular development is thought to be a pivotal precondition for pathological changes in alveolar structure. 16 In human BPD patients, 17,18 preterm infants, 7 and baboon BPD models, 19,20 alveolar capillary networks (ACNs) were conspicuously dysmorphic. In mice, capillary changes seem to become apparent before impaired alveolarization. ...
Bronchopulmonary dysplasia (BPD) is a developmental disorder of infants born prematurely, characterized by disrupted alveolarization and microvascular maturation. However, the sequence of alveolar and vascular alterations is currently not fully understood. Therefore, we used a rabbit model to evaluate alveolar and vascular development under preterm birth and hyperoxia, respectively. Pups were born by cesarean section 3 days before term and exposed for 7 days to hyperoxia (95% O2) or normoxia (21% O2). In addition, term-born rabbits were exposed to normoxia for 4 days. Rabbit lungs were fixed by vascular perfusion and prepared for stereological analysis. Normoxic preterm rabbits had a significantly lower number of alveoli than term rabbits. The number of septal capillaries was lower in preterm rabbits but less pronounced than the alveolar reduction. In hyperoxic preterm rabbits, the number of alveoli was similar to that in normoxic preterm animals; however, hyperoxia had a severe additional negative effect on the capillary number. In conclusion, preterm birth had a strong effect on alveolar development, and hyperoxia had a more pronounced effect on capillary development. The data provide a complex picture of the vascular hypothesis of BPD which rather seems to reflect the ambient oxygen concentration than the effect of premature birth.
... The development of lung alveoli is dependent on pulmonary vascular development, and any disruption of vascular growth and signaling leads to reduction in alveolar development. 15,16 Studies have also indicated that postnatal imbalance between pro-and antiangiogenic factors triggered by inflammation, and oxidative and hypoxic stressors also contribute to the development of BPD-PH. [17][18][19] While maternal pre-eclampsia, chorioamnionitis, and small for GA are identified as the predominant risk factors for developing BPD-PH 17,20 and could potentially predict its development, these are also factors are also key drivers of development of sBPD. ...
Pulmonary hypertension associated with bronchopulmonary dysplasia is a severe complication of preterm birth resulting in high mortality of up to 50% within the first 2 years of life. There is a direct relationship between bronchopulmonary dysplasia severity and incidence of associated pulmonary hypertension. However, it is challenging to clinically characterize severe bronchopulmonary dysplasia with and without pulmonary hypertension and there is need for better understanding of the two entities. Our main objective is to identify markers to help understand biological processes and characterize infants with pulmonary hypertension associated with bronchopulmonary dysplasia using tracheal aspirates. We conducted an unbiased multiomic analysis of tracheal aspirates via microRNA (miRNA) polymerase chain reaction arrays, RNA sequencing, and mass spectrometry proteomics in preterm infants with severe bronchopulmonary dysplasia with and without pulmonary hypertension (n = 46). Our pilot study analysis revealed 12 miRNAs (hsa-miR-29a, has-miR-542-3p, has-miR-624, has-miR-183, hsa-miR-501-3p, hsa-miR-101, hsa-miR-3131, hsa-miR-3683, hsa-miR-3193, hsa-miR-3672, hsa-miR-3128, and hsa-miR-1287), 6 transcripts (IL6, RPL35P5, HSD3B7, RNA5SP215, OR2A1-AS1, and RNVU1-19), and 5 proteins (CAPS, AAT, KRT5, SFTPB, and LGALS3BP) with significant differential expression in preterm infants with severe lung disease with pulmonary hypertension when compared with infants with severe lung disease but no pulmonary hypertension. Pathway analysis of the integrated multiomic expression signatures revealed NFkB, VEGF, SERPINA1, IL6, and ERK1/2 as target molecules and cellular development, cellular growth and proliferation, and cellular movement as key affected molecular functions. Our multiomic analysis of tracheal aspirates revealed a comprehensive thumbprint of miRNAs, mRNAs, and proteins that could help endotype infants with severe lung disease and pulmonary hypertension.
... Oxidant stress secondary to such hyperoxia exposure is a significant cause of impaired lung development and increased pulmonary fibrosis that results in bronchopulmonary dysplasia (BPD), which is a significant morbidity experienced by ELBW infants that continues to remain highly prevalent despite advances in their medical care (1)(2)(3). ...
Mitochondrial dysfunction at birth predicts bronchopulmonary dysplasia (BPD) in extremely low birth weight (ELBW) infants. Recently, nebulized thyroid hormone (TH), given as triiodothyronine (T3) was noted to decrease pulmonary fibrosis in adult animals through improved mitochondrial function. We hypothesized that TH may have similar effects on hyperoxia-induced neonatal lung injury and mitochondrial dysfunction. To determine whether intranasal T3 decreases neonatal hyperoxic lung injury in newborn mice, T3 improves mitochondrial function in lung homogenates, neonatal murine lung fibroblasts (NMLF) and umbilical cord-derived mesenchymal stem cells (MSCs) obtained from ELBW infants, and whether neonatal hypothyroxinemia is associated with BPD in ELBW infants. Inhaled T3 (given intranasally) attenuated hyperoxia-induced lung injury and mitochondrial dysfunction in newborn mice. T3 also reduced bioenergetic deficits in UC-MSCs obtained both from infants with no/mild BPD and those with moderate/severe BPD. T3 also increased PGC1α content in lung homogenates of mice exposed to hyperoxia as well as mitochondrial potential in both NMLF and UC-MSCs. ELBW infants who died or developed moderate/severe BPD had lower TT4 compared to survivors with no/mild BPD. TH signaling and function may play a critical role in neonatal lung injury and inhaled T3 supplementation may be useful as a therapeutic strategy for BPD.
... Due to the complex array of contributing factors, the prevention, clinical diagnosis, and effective management of BPD-PH are challenging. The development of lung alveoli is dependent on pulmonary vascular development, and any disruption of vascular growth and signaling leads to reduction in alveolar development (15,16). Studies have also indicated that postnatal imbalance between pro-and antiangiogenic factors triggered by inflammation, and oxidative and hypoxic stressors also contribute to the development of BPD-PH (17)(18)(19). ...
Rationale: Pulmonary hypertension associated with bronchopulmonary dysplasia is a severe complication of preterm birth resulting in high mortality of up to 50% within the first 2 years of life. There is a direct relationship between bronchopulmonary dysplasia severity and incidence of associated pulmonary hypertension. However, it is challenging to clinically characterize severe bronchopulmonary dysplasia with and without pulmonary hypertension and there is need for better understanding of the two entities.
Objectives: To identify markers to help understand biological processes and endotype characterization of infants with pulmonary hypertension associated with bronchopulmonary dysplasia in tracheal aspirates.
Methods: We conducted multi-omic analysis of tracheal aspirates via miRNA PCR arrays, RNA sequencing and mass spectrometry proteomics in preterm infants with severe bronchopulmonary dysplasia with (n=21) and without (n=25) pulmonary hypertension.
Results: Our study analysis revealed 12 miRNAs (hsa-miR-29a, has-miR-542-3p, has-miR-624, has-miR-183, hsa-miR-501-3p, hsa-miR-101, hsa-miR-3131, hsa-miR-3683, hsa-miR-3193, hsa-miR-3672, hsa-miR-3128, and hsa-miR-1287); 6 transcripts (IL6, RPL35P5, HSD3B7, RNA5SP215, OR2A1-AS1, and RNVU1-19), and 5 proteins (CAPS, AAT, KRT5, SFTPB, and LGALS3BP) with significant differential expression in preterm infants with severe lung disease with pulmonary hypertension when compared to infants with severe lung disease but no pulmonary hypertension. Pathway analysis of the integrated multi-omic expression signatures revealed NFkB, VEGF, SERPINA1, IL6 and ERK12 as target molecules for miRNAs, and angiogenesis and hyperoxia stress as recurrent pathways of individual markers.
Conclusion: Our multi-omic analysis of tracheal aspirates revealed a comprehensive thumbprint of miRNAs, mRNAs and proteins that could help endotype infants with severe lung disease and pulmonary hypertension.
... Although cross-talk between epithelial and endothelial cells plays important roles in lung injury and repair, accumulating evidence supports the vascular hypothesis of BPD, in which lung endothelial cell dysfunction drive the disease [13][14][15]. Therefore, targeting dysfunctional endothelial cells could provide new therapeutic options for BPD. ...
Background
Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants that may cause long-term lung dysfunction. Accumulating evidence supports the vascular hypothesis of BPD, in which lung endothelial cell dysfunction drives this disease. We recently reported that endothelial carnitine palmitoyltransferase 1a (Cpt1a) is reduced by hyperoxia, and that endothelial cell-specific Cpt1a knockout mice are more susceptible to developing hyperoxia-induced injury than wild type mice. Whether Cpt1a upregulation attenuates hyperoxia-induced endothelial cell dysfunction and lung injury remains unknown. We hypothesized that upregulation of Cpt1a by baicalin or l- carnitine ameliorates hyperoxia-induced endothelial cell dysfunction and persistent lung injury.
Methods
Lung endothelial cells or newborn mice (< 12 h old) were treated with baicalin or l -carnitine after hyperoxia (50% and 95% O 2 ) followed by air recovery.
Results
We found that incubation with l -carnitine (40 and 80 mg/L) and baicalin (22.5 and 45 mg/L) reduced hyperoxia-induced apoptosis, impaired cell migration and angiogenesis in cultured lung endothelial cells. This was associated with increased Cpt1a gene expression. In mice, neonatal hyperoxia caused persistent alveolar and vascular simplification in a concentration-dependent manner. Treatment with l -carnitine (150 and 300 mg/kg) and baicalin (50 and 100 mg/kg) attenuated neonatal hyperoxia-induced alveolar and vascular simplification in adult mice. These effects were diminished in endothelial cell-specific Cpt1a knockout mice.
Conclusions
Upregulating Cpt1a by baicalin or l -carnitine ameliorates hyperoxia-induced lung endothelial cell dysfunction, and persistent alveolar and vascular simplification. These findings provide potential therapeutic avenues for using l -carnitine and baicalin as Cpt1a upregulators to prevent persistent lung injury in premature infants with BPD.
... [42][43][44][45] The phenotype of BPD evolved from a fibrocystic disease secondary to ventilator trauma and oxygen injury to impairment of parenchymal development and pulmonary vascular growth dysregulation. 15,46,47 Previous clinical studies have supported the essential role of VEGF in BPD development. 10,48,49 The effect of anti-VEGF agents in immature lungs was explored previously in preclinical studies. ...
Background
Intravitreal bevacizumab (IVB), an anti-vascular endothelial growth factor (anti-VEGF) antibody, is a widely adopted treatment for retinopathy of prematurity (ROP). Although animal studies have demonstrated that IVB inhibits alveologenesis in neonatal rat lung, the clinical influence of IVB on respiratory outcomes has never been studied.
Research question
Would intravitreal bevacizumab affect the respiratory outcome in preterm infants with bronchopulmonary dysplasia?
Study design and methods
We retrospectively assessed very low birth weight (VLBW) preterm infants admitted to our neonatal intensive care unit between January 2016 and June 2021. Furthermore, we evaluated the short-term respiratory outcomes after IVB therapy in VLBW preterm infants requiring ventilatory support at a postmenstrual age (PMA) of 36 weeks.
Results
One hundred and seventy-four VLBW preterm infants with bronchopulmonary dysplasia were recruited. There were 88 infants with ROP onset before ventilator-free and 78 infants with the most severe ROP diagnosed before ventilator-free. Among them, 32 were diagnosed with type-1 ROP and received IVB treatment. After adjusting for gestational age, birth bodyweight, and baseline respiratory status, we discovered that IVB is significantly associated with prolonged ventilatory support and a lower likelihood of ventilator-free (HR = 0.53, P = 0.03).
Interpretation
IVB may have a short-term respiratory adverse effect in patients requiring ventilatory support at PMA of 36 weeks. Therefore, long-term follow up for respiratory outcomes may be considered in VLBW infants with IVB treatment.
... 1,2 Various perinatal factors may affect BPD development, including lung damage and impaired alveolar and vascular development. [1][2][3] Efforts have been made to predict the occurrence of BPD soon after birth 4 and to prevent BPD in preterm infants using various ventilator strategies 5 and the early caffeine use. 6 However, the incidence of BPD has not decreased over the past 10 years in infants born at ...
Background:
This meta-analysis was performed to examine the association between maternal hypertension during pregnancy (HDP) and neonatal bronchopulmonary dysplasia (BPD).
Methods:
We systematically searched PubMed, EMBASE, the Cochrane Library, and the KoreaMed database for relevant studies. We used the Newcastle-Ottawa Scale for quality assessment of all included studies. The meta-analysis was performed using Comprehensive Meta-Analysis software (version 3.3).
Results:
We included 35 studies that fulfilled the inclusion criteria; the total number of infants evaluated came to 97,399 through review process. Maternal HDP was not significantly associated with any definition of BPD, i.e., oxygen dependency at 36 weeks of gestation (odds ratio [OR], 1.162; 95% confidence interval [CI], 0.991-1.362; P = 0.064) in pooled analysis of 29 studies or oxygen dependency at 28 days of age (OR, 1.084; 95% CI, 0.660-1.780; P = 0.751) in pooled analysis of 8 studies. Maternal HDP was significantly associated only with severe BPD (OR, 2.341; 95% CI, 1.726-3.174; P < 0.001). BPD was not associated with HDP in the overall analysis (OR, 1.131; 95% CI, 0.977-1.309; P = 0.100) or subgroup analysis according to the definition of HDP.
Conclusion:
Maternal HDP was not associated with neonatal BPD defined by the duration of oxygen dependency (at either 36 weeks of gestation or 28 days of life) but was associated with severe BPD.
... This effect is consistent with the findings of other series in which oligohydramnios was associated with parenchymal pulmonary compromise, pulmonary vascular alterations [39][40][41], and pulmonary hypertension [42]. The correlation between impaired pulmonary vascular development and the emergence of BPD is widely discussed in the literature [43], with some authors suggesting it is one of the etiopathogenic mechanisms behind BPD (vascular theory of BPD) in which the impaired development of pulmonary vessels would dictate any alteration in distal airspace growth [44,45]. ...
GEIDIS is a national-based research-net registry of patients with bronchopulmonary dysplasia (BPD) from public and private Spanish hospitals. It was created to provide data on the clinical characterization and follow-up of infants with BPD until adulthood. The purpose of this observational study was to analyze the characteristics and the impact of perinatal risk factors on BPD severity. The study included 1755 preterm patients diagnosed with BPD. Of the total sample, 90.6% (n = 1591) were less than 30 weeks of gestation. The median gestational age was 27.1 weeks (25.8–28.5) and median birth weight 885 g (740–1,070 g). A total of 52.5% (n = 922) were classified as mild (type 1), 25.3% (n = 444) were moderate (type 2), and 22.2% (n = 389) were severe BPD (type 3). In patients born at under 30 weeks’ gestation, most pre-and postnatal risk factors for type 2/3 BPD were associated with the length of exposure to mechanical ventilation (MV). Independent prenatal risk factors were male gender, oligohydramnios, and intrauterine growth restriction. Postnatal risk factors included the need for FiO2 of > 0.30 in the delivery room, nosocomial pneumonia, and the length of exposure to MV. Conclusion: In this national-based research-net registry of BPD patients, the length of MV is the most important risk factor associated with type 2/3 BPD. Among type 3 BPD patients, those who required an FiO2 > .30 at 36 weeks’ postmenstrual age had a higher morbidity, during hospitalization and at discharge, compared to those with nasal positive pressure but FiO2 < .30.
What is Known:
• BPD is a highly complex multifactorial disease associated with preterm birth.
What is New:
• The length of exposure to mechanical ventilation is the most important postnatal risk factor associated to bronchopulmonary severity which modulate the effect of most pre and postnatal risk factors.
• Among patients with BPD, the requirement for FiO2 >.30% at 36 weeks of postmenstrual age is associated with greater morbidity during hospitalization and at discharge.
... Shennan and colleagues introduced the idea that infants who required respiratory support at 36 weeks' postmenstrual age (PMA) were more likely to have abnormal pulmonary outcomes in the first 2 years of life [2]. Later, to capture the changing BPD phenotypes seen after the advent of surfactant and antenatal steroids, a severity-based classification was proposed in a 2001 National Institute of Child Health and Human Development (NICHD) Workshop [3,4]. Challenges emerged in applying the 2001 NICHD BPD definition as newer therapies, such as high-flow nasal cannula and non-invasive mechanical ventilation, sometimes without supplemental oxygen, were more widely used [5][6][7][8]. ...
To compare three bronchopulmonary dysplasia (BPD) definitions against hospital outcomes in a referral-based population.
Data from the Children’s Hospitals Neonatal Consortium were classified by 2018 NICHD, 2019 NRN, and Canadian Neonatal Network (CNN) BPD definitions. Multivariable models evaluated the associations between BPD severity and death, tracheostomy, or length of stay, relative to No BPD references.
Mortality was highest in 2019 NRN Grade 3 infants (aOR 225), followed by 2018 NICHD Grade 3 (aOR 145). Infants with lower BPD grades rarely died (<1%), but Grade 2 infants had aOR 7–21-fold higher for death and 23–56-fold higher for tracheostomy.
Definitions with 3 BPD grades had better discrimination and Grade 3 2019 NRN had the strongest association with outcomes. No/Grade 1 infants rarely had severe outcomes, but Grade 2 infants were at risk. These data may be useful for counseling families and determining therapies for infants with BPD.
... BPD, the chronic lung disease that follows preterm birth, is characterized by an arrest of vascular and alveolar growth and high risk for PH, yet mechanisms contributing to its pathogenesis and early strategies to prevent BPD are poorly understood. In addition to its impact on developing PH, preclinical and clinical studies suggest that early disruption of angiogenesis during critical periods of lung vascular growth impairs alveolarization or growth of the distal airspace (the "vascular hypothesis" of BPD) [25,26]. Past studies demonstrate that early disruption of lung vascular growth due to hemodynamic stress in utero or by treatment with antiangiogenesis agents during the early postnatal period causes PH and impairs alveolarization [27][28][29]. ...
Despite growing awareness of the clinical importance of pulmonary hypertension (PH) in preterm infants, uncertainty persists regarding the different clinical settings in which abnormalities of pulmonary vascular growth, function, and structure contribute to high morbidity and mortality, and potential interventions to improve outcomes are uncertain. A major gap for improving outcomes of preterm infants with PH has been the limited characterization of the distinct settings of PH and related disease-specific mechanisms in preterm infants that represent diverse pulmonary vascular phenotypes of prematurity. In comparison with term newborns, preterm infants have a higher risk for developing hypoxemia due to suprasystemic levels of PH in preterm infants shortly after birth or persistent pulmonary hypertension of the newborn (PPHN). Variable and milder levels of PH have also been demonstrated in preterm infants without evidence of severe hypoxemic respiratory failure, suggesting delayed vascular transition of the lung which is associated with higher risks of mortality and developing bronchopulmonary dysplasia (BPD). In addition, early echocardiographic signs of PH at day 7 are strongly associated with the subsequent diagnosis of BPD, late PH, and respiratory disease throughout early childhood. In infants with evolving or established BPD, PH that persists beyond the first few months of life in preterm infants is associated with high mortality. Recent data further show that PVD can persist and cause PH in prematurely born adults. Overall, more precise characterization and studies of diverse pulmonary vascular phenotypes in preterm infants will be likely to improve the development of therapeutic strategies to optimize care of preterm infants with PH.
Background
Bronchopulmonary dysplasia (BPD) has become a major cause of morbidity and mortality in preterm infants worldwide, yet its pathogenesis and underlying mechanisms remain poorly understood. The present study sought to explore microRNA-mRNA regulatory networks and immune cells involvement in BPD through a combination of bioinformatic analysis and experimental validation.
Methods
MicroRNA and mRNA microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed microRNAs (DEMs) were identified in BPD patients compared to control subjects, and their target genes were predicted using miRWalk, miRNet, miRDB, and TargetScan databases. Subsequently, protein-protein interaction (PPI) and functional enrichment analyses were conducted on the target genes. 30 hub genes were screened using the Cytohubba plugin of the Cytoscape software. Additionally, mRNA microarray data was utilized to validate the expression of hub genes and to perform immune infiltration analysis. Finally, real-time PCR (RT-PCR), immunohistochemistry (IHC), and flow cytometry were conducted using a mouse model of BPD to confirm the bioinformatics findings.
Results
Two DEMs (miR-15b-5p and miR-20a-5p) targeting genes primarily involved in the regulation of cell cycle phase transition, ubiquitin ligase complex, protein serine/threonine kinase activity, and MAPK signaling pathway were identified. APP and four autophagy-related genes (DLC1, PARP1, NLRC4, and NRG1) were differentially expressed in the mRNA microarray dataset. Analysis of immune infiltration revealed significant differences in levels of neutrophils and naive B cells between BPD patients and control subjects. RT-PCR and IHC confirmed reduced expression of APP in a mouse model of BPD. Although the proportion of total neutrophils did not change appreciably, the activation of neutrophils, marked by loss of CD62L, was significantly increased in BPD mice.
Conclusion
Downregulation of APP mediated by miR-15b-5p and miR-20a-5p may be associated with the development of BPD. Additionally, increased CD62L⁻ neutrophil subset might be important for the immune-mediated injury in BPD.
Interrupted lung angiogenesis is a hallmark of bronchopulmonary dysplasia (BPD); however, druggable targets that can rescue this phenotype remain elusive. Thus, our investigation focused on amphiregulin (Areg), a growth factor that mediates cellular proliferation, differentiation, migration, survival, and repair. While Areg promotes lung branching morphogenesis, its effect on endothelial cell (EC) homeostasis in developing lungs is understudied. Therefore, we hypothesized that Areg promotes the proangiogenic ability of the ECs in developing murine lungs exposed to hyperoxia. Lung tissues were harvested from neonatal mice exposed to normoxia or hyperoxia to determine Areg expression. Next, we performed genetic loss-of-function and pharmacological gain-of-function studies in normoxia- and hyperoxia-exposed fetal murine lung ECs. Hyperoxia increased Areg mRNA levels and Areg+ cells in whole lungs. While Areg expression was increased in lung ECs exposed to hyperoxia, the expression of its signaling receptor, epidermal growth factor receptor, was decreased, indicating that hyperoxia reduces Areg signaling in lung ECs. Areg deficiency potentiated hyperoxia-mediated anti-angiogenic effects. In contrast, Areg treatment increased extracellular signal-regulated kinase activation and exerted proangiogenic effects. In conclusion, Areg promotes EC tubule formation in developing murine lungs exposed to hyperoxia.
The early childhood period, encompassing prenatal and early stages, assumes a pivotal role in shaping cardiovascular risk factors. We conducted a narrative review, presenting a non-systematic summation and analysis of the available literature, focusing on cardiovascular risk from prenatal development to the first 1000 days of life. Elements such as maternal health, genetic predisposition, inadequate fetal nutrition, and rapid postnatal growth contribute to this risk. Specifically, maternal obesity and antibiotic use during pregnancy can influence transgenerational risk factors. Conditions at birth, such as fetal growth restriction and low birth weight, set the stage for potential cardiovascular challenges. To consider cardiovascular risk in early childhood as a dynamic process is useful when adopting a personalized prevention for future healthcare and providing recommendations for management throughout their journey from infancy to early adulthood. A comprehensive approach is paramount in addressing early childhood cardiovascular risks. By targeting critical periods and implementing preventive strategies, healthcare professionals and policymakers can pave the way for improved cardiovascular outcomes. Investing in children’s health during their early years holds the key to alleviating the burden of cardiovascular diseases for future generations.
Congenital diaphragmatic hernia (CDH) is a neonatal anomaly that includes pulmonary hypoplasia and hypertension. We hypothesized that microvascular endothelial cell (EC) heterogeneity is different in CDH lungs and related to lung underdevelopment and remodeling. To test this, we evaluated rat fetuses at E21.5 in a nitrofen model of CDH to compare lung transcriptomes among healthy controls (2HC), nitrofen-exposed controls (NC) and nitrofen-exposed subjects with CDH. Single-cell RNA sequencing with unbiased clustering revealed 3 distinct microvascular EC clusters: a general population (mvEC), a proliferative population and a population high in hemoglobin. Only the CDH mvEC cluster had a distinct inflammatory transcriptomic signature as compared to the 2HC and NC endothelial cells, e.g. greater activation and adhesion of inflammatory cells and production of reactive oxygen species. Furthermore, CDH mvECs had downregulated Ca4, Apln and Ednrb gene expression. Those genes are markers for ECs important to lung development, gas exchange and alveolar repair (mvCa4+). mvCa4+ ECs were reduced in CDH (2HC [22.6%], NC [13.1%] and CDH [5.3%], p < 0.0001). Overall, these findings identify transcriptionally distinct microvascular endothelial cell clusters in CDH, including the distinctly inflammatory mvEC cluster and the depleted group of mvCa4+ ECs, which together may contribute to pathogenesis.
Bronchopulmonary dysplasia (BPD) is characterized by abnormal development of the blood vessels and alveoli in lungs, which largely occurs in premature infants. Exosomes (EXO) from very preterm infants (VPI) with BPD (BPD-EXO) impair angiogenic activities of human umbilical vein endothelial cells (HUVECs) via EXO-miRNAs cargo. This study aimed to determine whether and how BPD-EXO affect the development of BPD in a mouse model. We showed that treating BPD mice with BPD-EXO chronically and irreversibly aggravated lung injury. BPD-EXO up-regulated 139 and down-regulated 735 genes in the mouse lung tissue. These differentially expressed genes were enriched to the MAPK pathway (e.g., Fgf9 and Cacna2d3), which is critical to angiogenesis and vascular remodeling. BPD-EXO suppressed expression of Fgf9 and Cacna2d3 in HUVECs and inhibited migration, tube formation, and increased cell apoptosis in HUVECs. These data demonstrate that BPD-EXO aggravate lung injury in BPD mice and impair lung angiogenesis, plausibly leading to adverse outcomes of VPI with BPD. These data also suggest that BPD-EXO could serve as promising targets for predicting and treating BPD.
The impact of placental dysfunction and placental injury on the fetus and newborn infant has become a topic of growing interest in neonatal disease research. However, the use of placental pathology in directing or influencing neonatal clinical management continues to be limited for a wide range of reasons, some of which are historical and thus easily overcome today. In this review, we summarize the most recent literature linking placental function to neonatal outcomes, focusing on clinical placental pathology findings and the most common neonatal diagnoses that have been associated with placental dysfunction. We discuss how recent technological advances in neonatal and perinatal medicine may allow us to make a paradigm shift, in which valuable information provided by the placenta could be used to guide neonatal management more effectively, and to ultimately enhance neonatal care in order to improve our patient outcomes. We propose new avenues of clinical management in which the placenta could serve as a diagnostic tool toward more personalized neonatal intensive care unit management.
The past decades have seen markedly improved survival of increasingly immature preterm infants, yet major health complications persist. This is particularly true for bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, which has become the most common sequelae of prematurity and a significant predictor of respiratory morbidity throughout childhood as well as adult life, neurodevelopmental disability, cardiovascular disease, and even death. The need for novel approaches to reduce BPD and related complications of prematurity has never been more critical. Thus, despite major advances in the use of antenatal steroids, surfactant therapy, and improvements in respiratory support, there is a persistent need for developing therapeutic strategies that more specifically reflect our growing understanding of BPD in the post-surfactant age, or the "new BPD." In contrast with the severe lung injury leading to marked fibroproliferative disease from the past, the "new BPD" is primarily characterized by an arrest of lung development as related to more extreme prematurity. This distinction and the continued high incidence of BPD and related sequelae suggest the need to identify therapies that target critical mechanisms that support lung growth and maturation in conjunction with treatments to improve respiratory outcomes across the lifespan. As the prevention of BPD and its severity remains a primary goal, we highlight the concept from preclinical and early clinical observations that insulin-like growth factor 1 (IGF-1) can potentially support the natural sequence of lung growth as a replacement therapy after preterm birth. Data supporting this hypothesis are robust and include observations that low IGF-1 levels persist after extremely preterm birth in human infants and strong preclinical data from experimental models of BPD highlight the therapeutic benefit of IGF-1 in reducing disease. Importantly, phase 2a clinical data in extremely premature infants where replacement of IGF-1 with a human recombinant human IGF-1 complexed with its main IGF-1 binding protein 3, significantly reduced the most severe form of BPD, which is strongly associated with multiple morbidities that have lifelong consequences. As physiologic replacement therapy of surfactant heralded the success of reducing acute respiratory distress syndrome in preterm infants, the paradigm has the potential to become the platform for discovering the next generation of therapies like IGF-1, which becomes deficient after extremely premature birth where endogenous production by the infant is not sufficient to maintain the physiologic levels adequate to support normal organ development and maturation.
Pulmonary hypertension (PH) is associated with significant morbidities and high mortality in preterm infants, yet mechanisms contributing to the pathogenesis of PH, the impact of early pulmonary vascular disease (PVD) on the risk for BPD, the role for PH-targeted drug therapies, and long-term pulmonary vascular sequelae remain poorly understood. PVD is not a homogeneous disease, rather, PVD in the setting of prematurity includes various phenotypes as based on underlying pathophysiology, the severity of associated PH, the timing of disease onset, its contribution to hemodynamic and respiratory status, late outcomes, and other features. As with term newborns, severe hypoxemia with acute respiratory failure (HRF) in preterm infants can be due to marked elevation of pulmonary artery pressure with extrapulmonary shunt, traditionally referred to as persistent pulmonary hypertension of the newborn (PPHN). Transient and less severe levels of PH can also be observed during the early transition after birth without evidence of severe HRF, representing physiologic PH or delayed pulmonary vascular transition in preterm infants. Importantly, echocardiographic evidence of early PH has been strongly associated with the subsequent development of bronchopulmonary dysplasia (BPD), late PH, and chronic respiratory disease during infancy and early childhood. Late PH beyond the first postnatal months in preterm in neonates with established BPD is further associated with poor outcomes, especially as related to BPD severity. In addition, echocardiographic signs of PVD can further persist throughout childhood and may lead to chronic PH of variable severity and cardiac maldevelopment in prematurely born young adults. This review discusses the importance of characterizing diverse pulmonary vascular phenotypes in preterm infants to better guide clinical care and research, and to enhance the development of more precise therapeutic strategies to optimize early and late outcomes of preterm infants.
Bronchopulmonary dysplasia (BPD) is a multifactorial disease occurring as a consequence of premature birth, as well as antenatal and postnatal injury to the developing lung. BPD morbidity and severity depend on a complex interplay between prenatal and postnatal inflammation, mechanical ventilation, and oxygen therapy as well as associated prematurity-related complications. These initial hits result in ill-explored aberrant immune and reparative response, activation of pro-fibrotic and anti-angiogenic factors, which further perpetuate the injury. Histologically, the disease presents primarily by impaired lung development and an arrest in lung microvascular maturation. Consequently, BPD leads to respiratory complications beyond the neonatal period and may result in premature aging of the lung. While the numerous prenatal and postnatal stimuli contributing to BPD pathogenesis are relatively well known, the specific cell populations driving the injury, as well as underlying mechanisms are still not well understood. Recently, an effort to gain a more detailed insight into the cellular composition of the developing lung and its progenitor populations has unfold. Here, we provide an overview of the current knowledge regarding perinatal origin of BPD and discuss underlying mechanisms, as well as novel approaches to study the perturbed lung development.
Circular RNA (circRNA) is a newly discovered noncoding RNA that regulates gene transcription, binds to RNA-related proteins, and encodes protein microRNAs (miRNAs). The development of molecular biomarkers such as circRNAs holds great promise in the diagnosis and prognosis of clinical disorders. Importantly, circRNA-mediated maternal-fetus risk factors including environmental (high altitude), maternal (preeclampsia, smoking, and chorioamnionitis), placental, and fetal (preterm birth and low birth weight) factors are the early origins and likely to contribute to the occurrence and progression of developmental and pediatric cardiopulmonary disorders. Although studies of circRNAs in normal cardiopulmonary development and developmental diseases have just begun, some studies have revealed their expression patterns. Here, we provide an overview of circRNAs’ biogenesis and biological functions. Furthermore, this review aims to emphasize the importance of circRNAs in maternal-fetus risk factors. Likewise, the potential biomarker and therapeutic target of circRNAs in developmental and pediatric lung diseases are explored.
This review has been prepared by the Early Career Members and Chairs of the European Respiratory Society (ERS) Assembly 7: Paediatrics. We here summarise the highlights of the advances in paediatric respiratory research presented at the ERS International Congress 2022. The eight scientific Groups of this Assembly cover a wide range of research areas, including respiratory physiology and sleep, asthma and allergy, cystic fibrosis (CF), respiratory infection and immunology, neonatology and intensive care, respiratory epidemiology, bronchology, and lung and airway developmental biology. Specifically, we report on abstracts presented at the congress on the effect of high altitude on sleep, sleep disorders, the hypoxic challenge test, and measurements of ventilation inhomogeneity. We discuss prevention of preschool wheeze and asthma, and new asthma medications. In children with CF, we describe how to monitor the effect of CF transmembrane conductance regulator modulator therapy. We present respiratory manifestations and chronic lung disease associated with common variable immunodeficiency. Furthermore, we discuss how to monitor respiratory function in neonatal and paediatric intensive care units. In respiratory epidemiology, we present the latest news from population-based and clinical cohort studies. We also focus on innovative and interventional procedures for the paediatric airway, such as cryotherapy. Finally, we stress the importance of better understanding the molecular mechanisms underlying normal and abnormal lung development.
Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are increased in the lungs of rat pups raised in hyperoxia, an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in hyperoxia rat pups. We treated Sprague-Dawley rat pups with tunicamycin or hyperoxia to determine this relationship. ER stress was detected using immunofluorescence, transcriptomic, proteomic, and electron microscopic analyses. Immunofluorescence observed increased ER stress in the lungs of hyperoxic rat BPD and human BPD. Proteomic and morphometric studies showed that tunicamycin directly increased ER stress of rat lungs and decreased lung complexity with a BPD phenotype. Previously, we showed that hyperoxia initiates a cycle of destruction that we hypothesized starts from increasing OS through MPO accumulation and then increases ER stress to cause BPD. To inhibit ER stress, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO, we used N-acetyl-lysyltyrosylcysteine amide (KYC). The fact that TUDCA improved lung complexity in tunicamycin- and hyperoxia-treated rat pups supports the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of tunicamycin- and hyperoxia-treated rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC’s inhibition of ER stress in the tunicamycin-treated rat pup’s lung provides additional support for the idea that MPO-induced ER stress plays a causal role in the BPD phenotype. ER stress appears to expand our proposed cycle of destruction . Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impair growth and development. The encouraging effect of TUDCA indicates that this compound has the potential for treating BPD.
OBJECTIVE
To characterize different phenotypes of early pulmonary hypertension (PH) in preterm infants and their respective associations with bronchopulmonary dysplasia (BPD) and survival.
STUDY design
A prospective cohort study in a tertiary University Medical Centre from June 2016 until March 2019. Infants with a gestational age <30 weeks and/or a birth weight <1000 grams were included. Echocardiographic assessment for PH was performed 3-10 days after birth. Subsequent development of BPD at 36 weeks postmenstrual age and mortality were assessed.
RESULTS
Early-PH was identified in 55% of 104 included infants: 21% with persistent PH of the newborn (PPHN), 61% with flow-associated PH and 18% PH without-shunt. Only PPHN was associated with placental fetal vascular malperfusion, lower gestational age and low Apgar-scores. Both PPHN and flow-PH were associated with the development of BPD. Early-PH was associated with poorer survival, driven by PPHN.
CONCLUSIONS
Early-PH is highly prevalent (55%) in preterm infants and associated with the development of BPD, independent of the phenotype of PH. Infants with PPHN had the poorest survival. Early-PH presents in various phenotypes that are characterized by different etiology, pathophysiology, and associated long-term sequelae.
Introduction
Ibuprofen is one of the most common non-steroidal anti-inflammatory drugs used to close patent ductus arteriosus (PDA) in preterm infants. PDA is associated with bronchopulmonary dysplasia (BPD), while PDA closure by ibuprofen did not reduce the incidence of BPD or death. Previous studies have indicated an anti-angiogenesis effect of ibuprofen. This study investigated the change of angiogenic factors after ibuprofen treatment in preterm infants.
Methods
Preterm infants with hemodynamically significant PDA (hsPDA) were included. After confirmed hsPDA by color doppler ultrasonography within 1 week after birth, infants received oral ibuprofen for three continuous days. Paired plasma before and after the ibuprofen treatment was collected and measured by ELISA to determine the concentrations of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor A (VEGF-A), and hypoxia-inducible factor-2α (HIF-2α).
Results
17 paired plasma from infants with hsPDA were collected. The concentration of PDGF-BB and VEGF-A significantly decreased after ibuprofen treatment (1,908 vs. 442 pg/mL for PDGF-BB, 379 vs. 174 pg/mL for VEGF-A). HIF-2α level showed a tendency to decrease after ibuprofen treatment, although the reduction was not statistically significant ( p = 0.077).
Conclusion
This study demonstrated decreased vascular growth factors after ibuprofen exposure in hsPDA infants.
Oxygen supplementation in preterm infants disrupts alveolar epithelial type 2 (AT2) cell proliferation through poorly understood mechanisms. Here, newborn mice are used to understand how hyperoxia stimulates an early aberrant wave of AT2 cell proliferation that occurs between postnatal days (PND) 0-4. RNA-seq analysis of AT2 cells isolated from PND4 mice revealed hyperoxia stimulates expression of mitochondrial-specific methylenetetrahydrofolate dehydrogenase (Mthfd) 2 and other genes involved in mitochondrial one-carbon coupled folate metabolism and serine synthesis. The same genes were induced when AT2 cells normally proliferate on PND7 and when they proliferate in response to the mitogen fibroblast growth factor 7 (FGF7). However, hyperoxia selectively stimulated their expression via the stress responsive activating transcription factor 4 (ATF4). Administration of the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia suppressed ATF4 and thus early AT2 cell proliferation, but it had no effect on normative AT2 cell proliferation seen on PND7. Since ATF4 and MTHFD2 are detected in hyperplastic AT2 cells of preterm infant humans and baboons with bronchopulmonary dysplasia, dampening mitochondrial oxidative stress and ATF4 activation may provide new opportunities for controlling excess AT2 cell proliferation in neonatal lung disease.
The role of the β-adrenoceptors (β-ARs) in hypoxia-driven diseases has gained visibility after the demonstration that propranolol promotes the regression of infantile hemangiomas and ameliorates the signs of retinopathy of prematurity (ROP). Besides the role of β2-ARs, preclinical studies in ROP have also revealed that β3-ARs are upregulated by hypoxia and that they are possibly involved in retinal angiogenesis. In a sort of figurative round trip, peculiarities typical of ROP, where hypoxia drives retinal neovascularization, have been then translated to cancer, a disease equally characterized by hypoxia-driven angiogenesis. In this step, investigating the role of β3-ARs has taken advantage of the assumption that cancer growth uses a set of strategies in common with embryo development. The possibility that hypoxic induction of β3-ARs may represent one of the mechanisms through which primarily embryo (and then cancer, as an astute imitator) adapts to grow in an otherwise hostile environment, has grown evidence. In both cancer and embryo, β3-ARs exert similar functions by exploiting a metabolic shift known as the Warburg effect, by acquiring resistance against xenobiotics, and by inducing a local immune tolerance. An additional potential role of β3-AR as a marker of stemness has been suggested by the finding that its antagonism induces cancer cell differentiation evoking that β3-ARs may help cancer to grow in a nonhospital environment, a strategy also exploited by embryos. From cancer, the round trip goes back to neonatal diseases for which new possible interpretative keys and potential pharmacological perspectives have been suggested.
Pediatric pulmonary hypertension (PPH) is a multifactorial disease with diverse etiologies and presenting features. Pulmonary hypertension (PH), defined as elevated pulmonary artery pressure, is the presenting feature for several pulmonary vascular diseases. It is often a hidden component of other lung diseases, such as cystic fibrosis and bronchopulmonary dysplasia. Alterations in lung development and genetic conditions are an important contributor to pediatric pulmonary hypertensive disease, which is a distinct entity from adult PH. Many of the causes of pediatric PH have prenatal onset with altered lung development due to maternal and fetal conditions. Since lung growth is altered in several conditions that lead to PPH, therapy for PPH includes both pulmonary vasodilators and strategies to restore lung growth. These strategies include optimal alveolar recruitment, maintaining physiologic blood gas tension, nutritional support, and addressing contributing factors, such as airway disease and gastroesophageal reflux. The outcome for infants and children with PH is highly variable and largely dependent on the underlying cause. The best outcomes are for neonates with persistent pulmonary hypertension (PPHN) and reversible lung diseases, while some genetic conditions such as alveolar capillary dysplasia are lethal. © 2021 American Physiological Society. Compr Physiol 11:2135-2190, 2021.
Introduction
Although chronic pulmonary hypertension (cPH) secondary to chronic neonatal lung disease is associated with increased mortality and respiratory and neurodevelopmental morbidities, late diagnosis (typically ≥36 weeks postmenstrual age, PMA) and the use of qualitative echocardiographic diagnostic criterion (flat interventricular septum in systole) remain significant limitations in clinical care. Our objective in this study is to evaluate the utility of relevant quantitative echocardiographic indices to identify cPH in preterm neonates, early in postnatal course and to develop a diagnostic test based on the best combination of markers.
Methods and analysis
In this ongoing international prospective multicentre observational diagnostic accuracy study, we aim to recruit 350 neonates born <27 weeks PMA and/or birth weight <1000 g and perform echocardiograms in the third week of age and at 32 weeks PMA (early diagnostic assessments, EDA) in addition to the standard diagnostic assessment (SDA) for cPH at 36 weeks PMA. Predefined echocardiographic markers under investigation will be measured at each EDA and examined to create a scoring system to identify neonates who subsequently meet the primary outcome of cPH/death at SDA. Diagnostic test characteristics will be defined for each EDA. Pulmonary artery acceleration time and tricuspid annular plane systolic excursion are the primary markers of interest.
Ethics and dissemination
Ethics approval has been received by the Mount Sinai Hospital Research Ethics Board (REB) (#16-0111-E), Sunnybrook Health Sciences Centre REB (#228-2016), NHS Health Research Authority (IRAS 266498), University of Iowa Human Subjects Office/Institutional Review Board (201903736), Rotunda Hospital Research and Ethics Committee (REC-2019-008), and UBC Children’s and Women’s REB (H19-02738), and is under review at Boston Children’s Hospital Institutional Review Board. Study results will be disseminated to participating families in lay format, presented to the scientific community at paediatric and critical care conferences and published in relevant peer-reviewed journals.
Trail registration number
NCT04402645 .
Background
Premature infants who require oxygen therapy for respiratory distress syndrome often develop bronchopulmonary dysplasia, a chronic lung disease characterized by interrupted alveologenesis. Disrupted angiogenesis inhibits alveologenesis; however, the mechanisms through which disrupted angiogenesis affects lung development are poorly understood. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple oxygen-sensitive genes, including those encoding for vascular endothelial growth factor (VEGF). However, the HIF modulation of angiogenesis in hyperoxia-induced lung injury is not fully understood. Therefore, we explored the effects of roxadustat, an HIF stabilizer that has been shown to promote angiogenesis, in regulating pulmonary angiogenesis upon hyperoxia exposure.
Methods
C57BL6 mice pups reared in room air and 85% O2 were injected with phosphate-buffered saline or 5 mg/kg or 10 mg/kg roxadustat. Their daily body weight and survival rate were recorded. Their lungs were excised for histology and angiogenic factor expression analyses on postnatal Day 7.
Results
Exposure to neonatal hyperoxia reduced body weight; survival rate; and expressions of von Willebrand factor, HIF-1α, phosphor mammalian target of rapamycin, VEGF, and endothelial nitric oxide synthase and increased the mean linear intercept values in the pups. Roxadustat administration reversed these effects.
Conclusion
Hyperoxia suppressed pulmonary vascular development and the expression of proangiogenic factors. Roxadustat promoted pulmonary angiogenesis upon hyperoxia exposure by stabilizing HIF-1α and upregulating the expression of proangiogenic factors, indicating its potential in clinical and therapeutic applications.
Bronchopulmonary dysplasia (BPD) still carries a heavy burden of morbidity and mortality in survivors of extreme prematurity. The disease is characterized by simplification of the alveolar structure, involving a smaller number of enlarged alveoli due to decreased septation and a dysmorphic pulmonary microvessel growth. These changes lead to persistent abnormalities mainly affecting the smaller airways, lung parenchyma and pulmonary vasculature, that can be assessed with lung function tests and imaging techniques. Several longitudinal lung function studies have demonstrated that most preterm‐born subjects with BPD embark on a low lung function trajectory, never achieving their full airway growth potential. They are consequently at higher risk of developing a chronic obstructive pulmonary disease(COPD)‐like phenotype later in life. Studies based on computer tomography and magnetic resonance imaging, have also shown that in these patients there is a persistence of lung abnormalities like emphysematous areas, bronchial wall thickening, interstitial opacities and mosaic lung attenuation also in adult age.
This review aims to outline the current knowledge on pulmonary and vascular growth in survivors of BPD and the evidence of their lung function and imaging up to adulthood.
This article is protected by copyright. All rights reserved.
Bronchopulmonary dysplasia (BPD) is the most common morbidity following preterm birth, and there are an estimated 13,000 new cases each year in the United States. The approach to the patient with BPD and particularly the more severe forms of BPD requires a chronic care mentality that includes a multidisciplinary approach. The lung physiology that characterizes BPD is very different from that seen with RDS. The goal of this chapter is to characterize the epidemiology, pulmonary, and cardiovascular pathophysiology of severe BPD, especially in ventilator-dependent infants, and to discuss therapeutic strategies for their management as based on the underlying physiology.
Emerging evidence indicates that early life events can increase the risk for developing chronic obstructive pulmonary disease (COPD). Using an inducible transgenic mouse model for NF-κB activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage [postnatal day (PN)3 - PN5] but not alveolar stage (PN10 - PN12) of lung development disrupts elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progresses through 24 months of age. Neutrophil depletion prevented disruption of elastic fiber assembly and restored normal lung development. Mechanistic studies uncovered a role for neutrophil elastase (NE) in downregulating expression of critical elastic fiber assembly components, particularly fibulin-5 and elastin. Further, both purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation down-regulated elastin and fibulin-5 expression by saccular stage mouse lung fibroblasts. Together, our studies define a critical developmental window for assembling the elastin scaffold in the distal lung, which is required to support lung structure and function throughout the lifespan. While neutrophils play a well-recognized role in COPD development in adults, neutrophilic inflammation may also contribute to early life predisposition to COPD.
Bronchopulmonary Dysplasia (BPD) is a pulmonary disease affecting newborns, commonly those with prematurity or low birth weight. Its pathogenesis involves underdevelopment of lung tissue with subsequent limitations in ventilation and oxygenation, resulting in impaired postnatal alveolarization. Despite advances in care with improved survival, BPD remains a prevalent comorbidity of prematurity. In severe cases, management may involve mechanical ventilation via tracheostomy. BPD's demand for multidisciplinary care compounds the challenges in management of this condition.
Here, we review existing literature: the history of disease, criteria for diagnosis, pathogenesis, and modes of treatment with a focus on the severe subtype: that which is associated with pulmonary hypertension (PAH) for which tracheostomy is often required to facilitate long-term mechanical ventilation. We review the current recommendations for tracheostomy and decannulation.
The endothelial cell-specific vascular endothelial growth factor (VEGF) and its cellular receptors Flt-1 and Flk-1 have been implicated in the formation of the embryonic vasculature. This is suggested by their colocalized expression during embryogenesis and the impaired vessel formation in Flk-1 and Flt-1 deficient embryos. However, because Flt-1 also binds placental growth factor, a VEGF homologue, the precise role of VEGF was unknown. Here we report that formation of blood vessels was abnormal, but not abolished, in heterozygous VEGF-deficient (VEGF+/-) embryos, generated by aggregation of embryonic stem (ES) cells with tetraploid embryos (T-ES) and even more impaired in homozygous VEGF-deficient (VEGF-/-) T-ES embryos, resulting in death at mid-gestation. Similar phenotypes were observed in F1-VEGF+/- embryos, generated by germline transmission. We believe that this heterozygous lethal phenotype, which differs from the homozygous lethality in VEGF-receptor-deficient embryos, is unprecedented for a targeted autosomal gene inactivation, and is indicative of a tight dose-dependent regulation of embryonic vessel development by VEGF.
Exposure to high levels of inspired oxygen leads to respiratory failure and death in many animal models. Endothelial cell death is an early finding, before the onset of respiratory failure. Vascular endothelial growth factor (VEGF) is highly expressed in the lungs of adult animals. In the present study, adult Sprague-Dawley rats were exposed to >95% FiO2 for 24 or 48 hours. Northern blot analysis revealed a marked reduction in VEGF mRNA abundance by 24 hours, which decreased to less than 50% of control by 48 hours. In situ hybridization revealed that VEGF was highly expressed in distal airway epithelial cells in controls but disappeared in the oxygen-exposed animals. Immunohistochemistry and Western blot analyses demonstrated that VEGF protein was decreased at 48 hours. TUNEL staining demonstrated the presence of apoptotic cells coincident with the decline in VEGF. Abundance of VEGF receptor mRNAs (Flt-1 and KDR/Flk) decreased in the late time points of the study (48 hours), possibly secondary to the loss of endothelial cells. We speculate that VEGF functions as a survival factor in the normal adult rat lung, and its loss during hyperoxia contributes to the pathophysiology of oxygen-induced lung damage.
In this work we have undertaken a comparative study of human umbilical vein endothelial cells (HUVECs) and human saphenous vein endothelial cells (HSVECs) with respect to functional and antigenic tissue factor (TF), tissue factor pathway inhibitor (TFPI), and TF mRNA. Monolayers of each cell type (passage 2, except where specified) were grown to confluence and then activated for 4 h with either 50 U/mL IL-1-alpha or 10 microg/mL tumor necrosis factor-alpha. Activated factor X appearing in supernatant was measured using a chromogenic assay, and both Northern blots and quantitative RT-PCR were performed to assess concentrations of TF mRNA accompanying activation. The role of TFPI was separately determined by ELISA for supernatant TFPI antigen, and by measurements of production of activated factor X in the presence of 0, 5, 15, or 50 microg/mL of an antibody directed against TFPI. To address a non-TF pathway endothelial cell function, antigenic concentrations of tissue plasminogen activator for both cell types was also determined by ELISA. HUVECs were found to produce 2.4- to 3.5-fold more functional TF. No significant HUVEC-HSVEC differences were detected in TF antigen, supernatant TFPI, anti-TFPI affinity for endothelial cell-associated TFPI, TF mRNA or its amplification products, and tissue plasminogen activator. Immunostaining for TF antigen, however, may have failed to detect a modest HUVEC-HSVEC difference. Our finding with respect to functional TF indicates that HUVECs and HSVECs are not equivalent in terms of models for endothelial cell function in small children versus adults.