Revisiting the Role for HIF Stabilizers in Bronchopulmonary Dysplasia.
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ABSTRACT:
SUBMITTER: Boucherat O
PROVIDER: S-EPMC7560795 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo quantify and compare levels of potential biomarkers in neonates with (i) Bronchopulmonary dysplasia (BPD); (ii) BPD-associated pulmonary hypertension (BPD-PH); (iii) PH without BPD; and (iv) neonates without lung disease at ~36 weeks postmenstrual age.Study designMultiple potential biomarkers were measured in plasma samples of 90 patients using a multi-spot enzyme-linked immunosorbent assay. Statistical tests done included one-way ANOVA to compare levels of biomarkers between different groups.ResultsHigher levels of ICAM-1 were present in infants with BPD and correlated with its severity. Infants with BPD have significantly higher levels of ANG-2 and lower levels of ANG-1. Infants with PH have higher levels of: IL-6, IL-8, IL-10, and TNF-α. Infants with BPD-PH have significantly lower levels of MCP-1 and higher levels of IL-1β than infants with PH without BPD.ConclusionICAM-1 may be used as a specific biomarker for diagnosis of BPD and its severity.
| S-EPMC7664991 | biostudies-literature
Project description:Bronchopulmonary dysplasia (BPD) remains the most common respiratory complication of prematurity as younger and smaller infants are surviving beyond the immediate neonatal period. The recognition that oxidative stress (OS) plays a key role in BPD pathogenesis has been widely accepted since at least the 1980s. In this article, we examine the interplay between OS and genetic regulation and review 'omics' data related to OS in BPD. Data from animal models (largely models of hyperoxic lung injury) and from human studies are presented. Epigenetic and transcriptomic analyses have demonstrated several genes related to OS to be differentially expressed in murine models that mimic BPD as well as in premature infants at risk of BPD development and infants with established lung disease. Alterations in the genetic regulation of antioxidant enzymes is a common theme in these studies. Data from metabolomics and proteomics have also demonstrated the potential involvement of OS-related pathways in BPD. A limitation of many studies includes the difficulty of obtaining timely and appropriate samples from human patients. Additional 'omics' studies could further our understanding of the role of OS in BPD pathogenesis, which may prove beneficial for prevention and timely diagnosis, and aid in the development of targeted therapies.
| S-EPMC9774798 | biostudies-literature
Project description:Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.
| S-EPMC7979539 | biostudies-literature
Project description:The objective of this study is to review the candidate gene and genome-wide association studies relevant to bronchopulmonary dysplasia, and to discuss the emerging understanding of the complexities involved in genetic predisposition to bronchopulmonary dysplasia and its outcomes. Genetic factors contribute much of the variance in risk for BPD. Studies to date evaluating single or a few candidate genes have not been successful in yielding results that are replicated in GWAS, perhaps due to more stringent p-value thresholds. GWAS studies have identified only a single gene (SPOCK2) at genome-wide significance in a European White and African cohort, which was not replicated in two North American studies. Pathway gene-set analysis in a North American cohort confirmed involvement of known pathways of lung development and repair (e.g., CD44 and phosphorus oxygen lyase activity) and indicated novel molecules and pathways (e.g., adenosine deaminase and targets of miR-219) involved in genetic predisposition to BPD. The genetic basis of severe BPD is different from that of mild/moderate BPD, and the variants/pathways associated with BPD vary by race/ethnicity. A pilot study of whole exome sequencing identified hundreds of genes of interest, and indicated the overall feasibility as well as complexity of this approach. Better phenotyping of BPD by severity and pathophysiology, and careful analysis of race/ethnicity is required to gain a better understanding of the genetic basis of BPD. Future translational studies are required for the identification of potential genetic predispositions (rare variants and dysregulated pathways) by next-generation sequencing methods in individual infants (personalized genomics).
| S-EPMC4644695 | biostudies-literature
Project description:Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5-/-) and conditional smooth muscle (smooth muscle/adh5-/-) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5-/- mice were protected from all three aspects of BPD, whereas smooth muscle/adh5-/- mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.
| S-EPMC8320118 | biostudies-literature
Project description: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.
| S-EPMC9417039 | biostudies-literature
Project description:There are limited data on the effect of bronchopulmonary dysplasia (BPD) on sleep disordered breathing (SDB). We hypothesized that both the severity of prematurity and BPD would increase the likelihood of SDB in early childhood. Our secondary aim was to evaluate the association of demographic factors on the development of SDB.This is a retrospective study of patient factors and overnight polysomnogram (PSG) data of children enrolled in our BPD registry between 2008 and 2015. Association between PSG results and studied variables was assessed using multiple linear regression analysis.One-hundred-forty children underwent at least one sleep study on room air. The mean respiratory disturbance index (RDI) was elevated at 9.9 events/hr (SD: 10.1). The mean obstructive apnea-hypopnea index (OAHI) was 6.5 (9.1) events/hr and the mean central event rate of 3.0 (3.7) events/hr. RDI had decreased by 22% or 1.5 events/hour (95%CI: 0.6, 1.9) with each year of age (P?=?0.005). Subjects with more severe respiratory disease had 38% more central events (P?=?0.02). Infants exposed to secondhand smoke had 2.4% lower (P?=?0.04) oxygen saturation nadirs and a pattern for more desaturation events. Non-white subjects were found to have 33% higher OAHI (P?=?0.05), while white subjects had a 61% higher rate of central events (P?<?0.001).RDI was elevated in a selected BPD population compared to norms for non-preterm children. BPD severity, smoke exposure, and race may augment the severity of SDB. RDI improved with age but was still elevated by age 4, suggesting that this population is at risk for the sequelae of SDB.
| S-EPMC5693767 | biostudies-literature
Project description:OBJECTIVE:To identify single-nucleotide polymorphisms (SNPs) and pathways associated with bronchopulmonary dysplasia (BPD) because O2 requirement at 36 weeks' postmenstrual age risk is strongly influenced by heritable factors. STUDY DESIGN:A genome-wide scan was conducted on 1.2 million genotyped SNPs, and an additional 7 million imputed SNPs, using a DNA repository of extremely low birth weight infants. Genome-wide association and gene set analysis was performed for BPD or death, severe BPD or death, and severe BPD in survivors. Specific targets were validated via the use of gene expression in BPD lung tissue and in mouse models. RESULTS:Of 751 infants analyzed, 428 developed BPD or died. No SNPs achieved genome-wide significance (P < 10(-8)), although multiple SNPs in adenosine deaminase, CD44, and other genes were just below P < 10(-6). Of approximately 8000 pathways, 75 were significant at false discovery rate (FDR) <0.1 and P < .001 for BPD/death, 95 for severe BPD/death, and 90 for severe BPD in survivors. The pathway with lowest FDR was miR-219 targets (P = 1.41E-08, FDR 9.5E-05) for BPD/death and phosphorous oxygen lyase activity (includes adenylate and guanylate cyclases) for both severe BPD/death (P = 5.68E-08, FDR 0.00019) and severe BPD in survivors (P = 3.91E-08, FDR 0.00013). Gene expression analysis confirmed significantly increased miR-219 and CD44 in BPD. CONCLUSIONS:Pathway analyses confirmed involvement of known pathways of lung development and repair (CD44, phosphorus oxygen lyase activity) and indicated novel molecules and pathways (adenosine deaminase, targets of miR-219) involved in genetic predisposition to BPD.
| S-EPMC4344889 | biostudies-literature
Project description:Purpose of reviewBronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in premature infants. Twin studies have shown strong heritability underlying this disease; however, the genetic architecture of BPD remains unclear.Recent findingsA number of studies employed different approaches to characterize the genetic aberrations associated with BPD, including candidate gene studies, genome-wide association studies, exome sequencing, integrative omics analysis, and pathway analysis. Candidate gene studies identified a number of genes potentially involved with the development of BPD, but the etiological contribution from each gene is not substantial. Copy number variation studies and three independent genome-wide association studies did not identify genetic variations significantly and consistently associated with BPD. A recent exome-sequencing study pointed to rare variants implicated in the disease. In this review, we summarize these studies' methodology and findings, and suggest future research directions to better understand the genetic underpinnings of this potentially life-long lung disease.SummaryGenetic factors play a significant role in the development of BPD. Recent studies suggested that rare variants in genes participating in lung development pathways could contribute to BPD susceptibility.
| S-EPMC4853271 | biostudies-literature
Project description:Bronchopulmonary dysplasia (BPD) is the most common respiratory disorder among infants born extremely preterm. The pathogenesis of BPD involves multiple prenatal and postnatal mechanisms affecting the development of a very immature lung. Their combined effects alter the lung's morphogenesis, disrupt capillary gas exchange in the alveoli, and lead to the pathological and clinical features of BPD. The disorder is ultimately the result of an aberrant repair response to antenatal and postnatal injuries to the developing lungs. Neonatology has made huge advances in dealing with conditions related to prematurity, but efforts to prevent and treat BPD have so far been only partially effective. Seeing that BPD appears to have a role in the early origin of chronic obstructive pulmonary disease, its prevention is pivotal also in long-term respiratory outcome of these patients. There is currently some evidence to support the use of antenatal glucocorticoids, surfactant therapy, protective noninvasive ventilation, targeted saturations, early caffeine treatment, vitamin A, and fluid restriction, but none of the existing strategies have had any significant impact in reducing the burden of BPD. New areas of research are raising novel therapeutic prospects, however. For instance, early topical (intratracheal or nebulized) steroids seem promising: they might help to limit BPD development without the side effects of systemic steroids. Evidence in favor of stem cell therapy has emerged from several preclinical trials, and from a couple of studies in humans. Mesenchymal stromal/stem cells (MSCs) have revealed a reparatory capability, preventing the progression of BPD in animal models. Administering MSC-conditioned media containing extracellular vesicles (EVs) have also demonstrated a preventive action, without the potential risks associated with unwanted engraftment or the adverse effects of administering cells. In this paper, we explore these emerging treatments and take a look at the revolutionary changes in BPD and neonatology on the horizon.
| S-EPMC7290764 | biostudies-literature