Early Detection of Pulmonary Vascular Dysfunction in Neonatal Bronchopulmonary Dysplasia.
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ABSTRACT:
SUBMITTER: Hassoun PM
PROVIDER: S-EPMC6938142 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Early Detection of Pulmonary Vascular Dysfunction in Neonatal Bronchopulmonary Dysplasia.
American journal of respiratory and critical care medicine 20200101 1
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Project description:A naturally occurring single nucleotide polymorphism (SNP), (R213G), in extracellular superoxide dismutase (SOD3), decreases SOD3 matrix binding affinity. Humans and mature mice expressing the R213G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this SNP on the neonatal lung at baseline or with injury is unknown. Wild type and homozygous R213G mice were injected with intraperitoneal bleomycin or phosphate buffered saline (PBS) three times weekly for three weeks and tissue harvested at 22 days of life. Vascular and alveolar development were evaluated by morphometric analysis and immunostaining of lung sections. Pulmonary hypertension (PH) was assessed by right ventricular hypertrophy (RVH). Lung protein expression for superoxide dismutase (SOD) isoforms, catalase, vascular endothelial growth factor receptor 2 (VEGFR2), endothelial nitric oxide synthase (eNOS) and guanosine triphosphate cyclohydrolase-1 (GTPCH-1) was evaluated by western blot. SOD activity and SOD3 expression were measured in serum. In R213G mice, SOD3 lung protein expression decreased, serum SOD3 protein expression and SOD serum activity increased compared to wild type (WT) mice. Under control conditions, R213G mice developed pulmonary vascular remodeling (decreased vessel density and increased medial wall thickness) and PH; alveolar development was similar between strains. After bleomycin injury, in contrast to WT, R213G mice were protected from impaired alveolar development and their vascular abnormalities and PH did not worsen. Bleomycin decreased VEGFR2 and GTPCH-1 only in WT mice. R213G neonatal mice demonstrate impaired vascular development and PH at baseline without alveolar simplification, yet are protected from bleomycin induced lung injury and worsening of pulmonary vascular remodeling and PH. These results show that vessel bound SOD3 is essential in normal pulmonary vascular development, and increased serum SOD3 expression and SOD activity prevent lung injury in experimental bronchopulmonary dysplasia (BPD) and PH.
| S-EPMC5874528 | biostudies-literature
Project description:Rationale: Patients with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) have increased morbidity and mortality. Noninvasive assessment relies on echocardiograms (echos), which are technically challenging in this population. Improved assessment could augment decisions regarding PH therapies.Objectives: We hypothesized that neonatal cardiac magnetic resonance imaging (MRI) will correlate with BPD severity and predict short-term clinical outcomes, including need for PH therapies for infants with BPD.Methods: A total of 52 infants (31 severe BPD, 9 moderate BPD, and 12 with either mild or no BPD) were imaged between 39 and 47 weeks postmenstrual age on a neonatal-sized, neonatal ICU-sited 1.5-T magnetic resonance (MR) scanner. MR left ventricular eccentricity index (EI), main pulmonary artery-to-aorta (PA/AO) diameter ratio, and pulmonary arterial blood flow were determined. Echos obtained for clinical indications were reviewed. MRI and echo indices were compared with BPD severity and clinical outcomes, including length of stay (LOS), duration of respiratory support, respiratory support at discharge, and PH therapy.Measurements and Main Results: PA/AO ratio increased with BPD severity. Increased PA/AO ratio, MR-EI, and echo-EIs were associated with increased LOS and duration of respiratory support. No correlation was seen between pulmonary arterial blood flow and BPD outcomes. Controlling for gestational age, birth weight, and BPD severity, MR-EI was associated with LOS and duration of respiratory support. Increased PA/AO ratio and MR-EI were associated with PH therapy during hospitalization and at discharge.Conclusions: MRI can provide important image-based measures of cardiac morphology that relate to disease severity and clinical outcomes in neonates with BPD.
| S-EPMC6938152 | biostudies-literature
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) 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.
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Project description:BackgroundBradycardia and oxygen desaturation episodes are common among preterm very low birth weight (VLBW) infants in the Neonatal Intensive Care Unit (NICU), and their association with adverse outcomes such as bronchopulmonary dysplasia (BPD) is unclear.MethodsFor 502 VLBW infants we quantified bradycardias (HR < 100 for ≥ 4 s) and desaturations (SpO2 < 80% for ≥ 10 s), combined bradycardia and desaturation (BD) events, and percent time in events in the first 4 weeks after birth (32 infant-years of data). We tested logistic regression models of clinical risks (including a respiratory acuity score incorporating FiO2 and level of respiratory support) to estimate the risks of BPD or death and secondary outcomes. We then tested the additive value of the bradycardia and desaturation metrics for outcomes prediction.ResultsBPD occurred in 187 infants (37%). The clinical risk model had ROC area for BPD of 0.874. Measures of desaturation, but not bradycardia, significantly added to the predictive model. Desaturation metrics also added to clinical risks for prediction of severe intraventricular hemorrhage, retinopathy of prematurity and prolonged length of stay in the NICU.ConclusionsOxygen desaturations in the first month of the NICU course are associated with risk of BPD and other morbidities in VLBW infants.
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Project description:Bronchopulmonary dysplasia (BPD) is a common complication of prematurity with a multifactorial etiology, influenced by both genetic susceptibility and environmental factors on the immature lung. Fibroblast growth factor receptor-3 and -4 (FGFR-3 and FGFR-4) are abundantly expressed in both the epithelium and mesenchyme in the developing mammalian lung. FGFR-4 may play a role in developing BPD as it is associated with airway inflammation and remodeling; studies showed a link between BPD and a polymorphism in the FGFR-4 gene. The aim of this study was to study the significance of FGFR-4 in developing BPD and to investigate the correlation between its serum level and its genetic polymorphism in relation to development of BPD in preterms. This case-control study was performed on 80 preterm neonates (<32 weeks) divided into two groups: group I included 50 preterms with respiratory distress syndrome (RDS) who developed BPD and group II included 30 preterms with RDS only. The mean serum level of FGFR-4 was significantly lower in group I than in group II ( p -value < 0.05). There was no significant correlation between the serum levels of FGFR-4 and the degree of severity of BPD. Allele variation in the FGFR-4 gene was similar in both groups. The serum level of FGFR-4 was significantly lower in preterms with BPD, although the gene polymorphism was not significantly different in the studied groups.
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Project description:ObjectiveTo demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants.Methods and resultsProteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic®, Olink-Proteomics®) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease.ConclusionWhile successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD.Trial registrationDeutsches Register Klinische Studien (DRKS) No. 00004600; https://www.drks.de .ImpactThe urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD.
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Project description:BackgroundThe association between the presence of common pathogens in the maternal cervicovaginal tract as well as neonatal gastric fluid and adverse outcomes in preterm newborns remains uncertain.MethodsCervicovaginal swabs were collected from 98 mothers, and gastric fluid specimens were obtained from 121 premature infants with gestational ages of ≤ 32 weeks within 24 h of birth. Thirteen pathogens were tested using suspension microarray. Neonatal outcomes were monitored until either death or discharge. RESULTS UREAPLASMA: was the predominant species identified in both maternal cervicovaginal swabs and neonatal gastric fluid. Preterm newborns with Ureaplasma in gastric fluid at birth exhibited a smaller gestational age (P < 0.001), a lower 1-min Apgar score (P = 0.01), an increased requirement for pulmonary surfactant (P = 0.029), and a higher incidence of bronchopulmonary dysplasia (BPD) (P = 0.02) compared to those who tested negative for Ureaplasma. Similarly, pregnant women with Ureaplasma colonization in the genital tract were more likely to deliver babies with a smaller gestational age (P = 0.002), a higher rate of tracheal intubation after birth (P = 0.013), a lower proportion of small for gestational age (SGA) infants (P = 0.018), and an increased occurrence of BPD (P = 0.048) than mothers without the agent. Furthermore, the presence of Ureaplasma in the gastric fluid of premature infants was identified as a risk factor for BPD, with an odds ratio (OR) of up to 6, alongside gestational age and SGA as independent predictors of BPD.ConclusionsThese findings suggest that antenatal exposure to Ureaplasma is correlated with the occurrence of BPD in premature infants, which has potential clinical implications.
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Project description:ObjectiveTo evaluate the association of ibuprofen exposure with the risk of bronchopulmonary dysplasia (BPD) in extremely premature infants.Study designThis was a retrospective study of all extremely premature infants admitted to a tertiary unit from 2016 to 2018.ResultsA total of 203 extremely premature infants were included in this study. The rate of BPD was significantly higher in infants with early exposure to ibuprofen (42.5%) compared to infants with no exposure (21.6%, P = 0.001). After adjusting for covariates, the risk of BPD was associated independently with ibuprofen exposure (odds ratios (OR) 2.296, 95% confidence interval (CI): 1.166-4.522, p = 0.016). Further analysis showed a trend towards higher risk of BPD in infants with successful patent ductus arteriosus (PDA) closure after ibuprofen treatment (32.3%) compared to non-treated infants (20.2%, p = 0.162).ConclusionOur findings suggest that ibuprofen exposure may contribute to the occurrence of BPD in extremely preterm infants.
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Project description:This study evaluated whether early pulmonary hypertension (PH) in extremely preterm infants (EPIs) at 22-27 weeks of gestation detected clinically with echocardiography at 4-7 postnatal days (PND) is a risk factor for death before 36 weeks post-menstrual age (PMA) or late PH in moderate or severe (m/s) bronchopulmonary dysplasia (BPD) (BPD-PH). We analyzed risk factors for death before 36 weeks PMA or BPD-PH. Among 247 EPIs enrolled, 74 (30.0%) had early PH. Twenty-one (28.4%) infants with early PH and 18 (10.4%) without early PH died before 36 weeks PMA; 14 (18.9%) infants with early PH and 9 (5.2%) without early PH had BPD-PH at 36-38 weeks PMA. Multivariate analysis revealed that early PH (adjusted odds ratio, 6.55; 95% confidence interval, 3.10-13.82, P < 0.05), clinical chorioamnionitis (2.50; 1.18-5.31), intraventricular hemorrhage (grade 3-4) (3.43; 1.26-9.37), and late sepsis (6.76; 3.20-14.28) independently increased the risk of development of death before 36 weeks PMA or BPD-PH. Subgroup analysis among m/s BPD patients revealed that early PH (4.50; 1.61-12.58) and prolonged invasive ventilator care (> 28 days) (4.91; 1.02-23.68) increased the risk for late PH independently. In conclusion, EPIs with early PH at 4-7 PND should be monitored for BPD-associated late PH development.
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