Bronchopulmonary Dysplasia Patients Research Articles

Deficiency of Secreted Phosphoprotein 1 Alleviates Hyperoxia-induced Bronchopulmonary Dysplasia in Neonatal Mice.

Bronchopulmonary dysplasia (BPD) is a common chronic lung disorder characterized by impaired proximal airway and bronchoalveolar development in premature births. Secreted phosphoprotein 1 (SPP1) is involved in lung development and lung injury events, while its role was not explored in BPD. For establishing the in vivo models of BPD, a mouse model of hyperoxia-induced lung injury was generated by exposing neonatal mice to hyperoxia for 7days after birth. Alveolar myofibroblasts (AMYFs) were treated with hyperoxia to establish the in vitro models of BPD. Based on the scRNA-seq analysis of lungs of mice housed under normoxia or hyperoxia conditions, mouse macrophages and fibroblasts were main different cell clusters between the two groups, and differentially expressed genes in fibroblasts were screened. Further GO and KEGG enrichment analysis revealed that these differentially expressed genes were mainly enriched in the pathways related to cell proliferation, apoptosis as well as the PI3K-AKT and ERK/MAPK pathways. SPP1 was found up-regulated in the lung tissues of hyperoxia mice. We also demonstrated the up-regulation of SPP1 in the BPD patients, the mouse model of hyperoxia-induced lung injury, and hyperoxia-induced cells. SPP1 deficiency was revealed to reduce the hyperoxia-induced apoptosis, oxidative stress and inflammation and increase the viability of AMYFs. In the mouse model of hyperoxia induced lung injury, SPP1 deficiency was demonstrated to reverse the hyperoxia-induced alveolar growth disruption, oxidative stress and inflammation. Overall, SPP1 exacerbates BPD progression in vitro and in vivo by regulating oxidative stress and inflammatory response via the PI3K-AKT and ERK/MAPK pathways, which might provide novel therapeutic target for BPD therapy.

Hedgehog Pathway regulates Alveolar Type II Cells in Human Lung Development

Rationale: The Hedgehog (HH) pathway plays an important role in human lung branching morphogenesis, yet its role in human alveologenesis remains understudied. Bronchopulmonary Dysplasia (BPD) patients exhibit simplified alveolar structures, accompanied with increased expression of HH components. Therefore, we hypothesize that HH pathway regulation is crucial for alveologenesis, specifically for proximo-distal patterning and AT2 cell differentiation. Methods: Human fetal lung explants aged 18-22 weeks gestation (WG) were cultured in CKDCI media to induce alveolar marker expression, in the presence or absence of HH activator (SAG). AT2 progenitor cells (HTII280+/CD31-/CD45-) were isolated from fresh human lung tissues (18-22 WG) and plated in Matrigel for 14 days to form organoids. A subset of organoids was treated with SAG for 7 days while in matrigel, while others were lifted to air-liquid interface (ALI) culture and treated for 14 days. RT-qPCR, fluorescent in situ hybridization (FISH), and immunofluorescence staining (IF) were carried out at various steps to assess cell fate. Results: SAG treated human fetal lung explants displayed gross morphological differences compared to the control, e.g. enlarged distal cysting. HH pathway upregulation resulted in a significant decrease of AT2 markers expression ( ABCA3, LAMP3; p<0.05) and increased expression of proximal markers ( TP63, SCGB3A2; p<0.01) as compared to control. FISH for SFTPC (AT2 marker) showed a 3-fold decrease ( p<0.05) following HH pathway activation accompanied by a loss of SOX9+ cells (2.5-fold vs control, p<0.05). The loss of SFTPC+ cells was confirmed by IF ( p<0.05). A decrease in KRT8+, a marker of intermediate AT2 cells, was also observed (1.5-fold vs control, p<0.05). Similarly, in organoid cultures, we found decreased SFTPC+, SOX9+ and KRT8+ cells (1.5-; 2- and 1.5-fold vs control, p<0.05). Furthermore, SAG treatment resulted in the formation of fewer and smaller-sized organoids (1-fold and 1.5-fold vs control, p<0.05). Staining on ALI cultures revealed fewer SFTPC+ cells and more TP63+ cells (1.5-fold vs control, p<0.05). Tight junction proteins (ZO1 and Claudin18) were compromised on ALI membranes demonstrating that HH pathway activation results in larger and fewer tight junctions, as indicated by the TIJOR score (2-fold vs control, p<0.01). Conclusion: In our alveologenesis-like model, HH pathway activation reduces AT2 markers, favoring a proximal fate, ultimately suggesting that the HH pathway regulates late human lung development. Understanding the role of the HH pathway in regulating alveologenesis is essential in pediatric conditions like BPD and could facilitate translational discoveries. CIRM EDUC4-12837 (BR) NIH/NHLBI R01HL141856 (DA). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Induction of TNFα by flavin adenine dinucleotide (FADH) protects neonatal C57Bl6 lungs from high oxygen induced lung injury

Background: Bronchopulmonary dysplasia (BPD) is a serious lung disease caused by oxidative stress, predominately affecting premature infants that require prolonged oxygen support. The co-factor flavin adenine dinucleotide (FADH) facilitates glutathione reductase (GR) enzymatic activity and increases the bioavailability of the antioxidant glutathione (GSH). As such, we hypothesized that intranasal delivery of FADH can improve redox homeostasis and attenuate lung injury following chronic high oxygen supplementation (0.85% FiO2) by altering pro-inflammatory signal transduction pathways in a C57Bl6 newborn mouse model for BPD. Methods: We used a prolonged hyperoxia-induced lung injury rodent model to recapitulate the clinical and histological changes present in BPD. Newborn mice were housed in FiO2 85% (hyperoxic) or 21% O2 (normoxic) from day of birth until post-natal day (PN) 14. FADH (7 μM) or saline (control) treatments were administered daily via intranasal insufflation on PN 14-21 in a final volume of 1.5μL/g body weight. BALF and lung tissue samples were collected and evaluated for redox stress, lung injury/development, and inflammation using standard immunohistological techniques, morphometric analysis, and standard molecular assays. BALF cytokines were measured using a flow cytometric approach (BioLegend). Two-dimensional cell migration assays were tracked via microscopy daily until 100% confluence reached; the ½ maximal peak values were evaluated to compare rate of wound closure following very low (2.5 ng/mL) TNFα or IL12 treatment. Transepithelial resistance and potential differences were measured using an EVOM device (World Precision Instrument) across human small airway epithelial cells, and equivalent short circuit currents (Isc) calculated in accordance with Ohm’s Law, where V=IR. Single data comparisons were performed using paired Student’s t-tests. Multiple comparisons were performed using ANOVA followed by post-hoc testing in Sigma Plot. Results: FADH protected neonatal lungs from high oxygen induced oxidative stress: GSH/GSSG Eh (a measure of oxidative stress) improved from -168.77 mV ± 3.64 mV to -179.10 mV ± 1.85 mV (n=5 BALF measurements). FADH also improved lung injury scores from 0.187±0.038 to 0.03±0.014 (p=0.005), decreased neutrophil migration (p<0.001), and increased macrophages (p<0.001) when compared to age-matched untreated pups. FADH-mediated increase in TNFα (and not IL12) significantly increased the rate of lung epithelial cell wound closure from [2.27±0.07 to 1.97±0.1 average days for ½ complete wound closure, n=6, p=0.01] and increased Isc from 6.5±.21 to 9.2±1.0 μA/cm2, n=3, p=0.03. Conclusions: Our findings indicate that FADH protects the preterm lung from hyperoxic injury by 1) increasing the bioavailability of GSH and 2) via TNFα signaling to increase the rate of wound closure and repair of epithelial cell function. Significances: The mechanisms identified through this study could be targeted as a potential adjunct therapy for BPD patients to attenuate high oxygen induced lung injury. Funding: Supported by R01HL137033 (MH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Investigation of the miRNA-mRNA Regulatory Circuits and Immune Signatures Associated with Bronchopulmonary Dysplasia.

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. 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. 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. 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.

Retrospective study of serial polysomnograms of bronchopulmonary dysplasia patients with oxygen dependence.

This retrospective study describes characteristics of serial polysomnograms (PSGs) of BPD patients on home oxygen therapy and describes PSG parameters associated with discontinuation of supplemental oxygen. A single-center study was performed at Children's Hospital Los Angeles, where serial PSGs for 44 patients with BPD infants discharged on home oxygen therapy were extracted for maximum of five PSGs or until oxygen discontinuation. Clinical and polysomnography data was collected. Characteristics of PSG1 were compared amongst the patients who were weaned from oxygen after PSG2 and PSG3. Of 44 patients, 68.2% of patients were males with median birth gestational age of 26 weeks (IQR: 24.6-28.1), median birthweight of 777.5 g(IQR: 632.5-1054 g) and 77.3% of the cohort had severe BPD. A total of 138 PSGs were studied between all 44 patients serially. When comparing PSG1 and PSG2 parameters, statistically significant improvement was noted in multiple parameters. Median baseline SpO2, peak RR, and average PETCO2 were found to be potential predictors of prolonged oxygen use. Gestational age and birth weight were not associated with prolonged oxygen use after PSG3. The median age of oxygen discontinuation was calculated to be about 2 years of age. The severity of hypoxia and tachypnea on initial infant PSG are associated with prolonged oxygen therapy past 2 years of age. Growth and development of lungs with maturation of control of breathing help improve these parameters over time regardless of BPD severity. The study may inform discussions between providers and parents for patients discharged home on oxygen therapy.

Atrial septal defect closure is associated with improved clinical status in patients ≤ 10 kg with bronchopulmonary dysplasia.

Patients with bronchopulmonary dysplasia (BPD) have shown clinical improvement after secundum atrial septal defect (ASD) closure. We sought to determine if this post-ASD closure improvement is secondary to the expected course in BPD patients or related to the closure itself. A novel BPD-ASD score was created to assess patients' clinical status (higher score = worse disease) and applied to 10 BPD-ASD inpatients weighing ≤ 10 kg who underwent ASD closure. The score and its subcomponents were retrospectively calculated serially ranging from 8 weeks pre- to 8 weeks post-intervention, and pre- and post-intervention score slopes were created. These slopes were compared using mixed regression modeling with an interaction term. There was a significant difference in pre- versus post-intervention slope with the most score drop the first week post-intervention (-2.1 + /- 0.8, p = 0.014). The mean score also dropped through weeks 2 (slope -0.8 + /- 0.8, p = 0.013) and 4 (slope -1.0 + /- 0.5, p = 0.001) post-intervention. There was a significant difference in pre- and post-intervention slopes for diuretics (p = 0.018) and the combined score of respiratory support, FiO2 need, and respiratory symptoms (p = 0.018). This study demonstrated significant improvement in BPD-ASD score, diuretic need, and respiratory status after ASD closure in BPD-ASD patients ≤ 10 kg that was outside of the natural course of BPD. Our study was limited by its small, single-center, retrospective nature. Future studies should be performed in a larger multicenter population to both validate the scoring system and compare to non-intervention infants.

Assessment of Vascular Indices by Abdominal Aortic Ultrasonography in Preterm Neonates with Bronchopulmonary Dysplasia.

Preterm infants with bronchopulmonary dysplasia (BPD) frequently encounter systemic hypertension, yet the underlying cause remains elusive. Given the absence of prior investigations concerning the correlation between systemic hypertension and aortic thickness, we undertook this study to assess and juxtapose diverse vascular indices amidst preterm neonates with BPD, preterm neonates lacking BPD, and healthy neonates, utilizing abdominal aorta ultrasonography. This cross-sectional study encompassed 20 preterm neonates, 20 preterm neonates with BPD, and 20 healthy neonates, meticulously matched for sex and postnatal age. Comprehensive demographic, anthropometric, and clinical evaluation data were documented. The neonates underwent abdominal aortic ultrasonography for comparative evaluation of aortic wall thickness and vasomotor function across the three groups. The study revealed that neonates with BPD exhibited a notably higher average systolic blood pressure than preterm and term neonates (P < 0.05). Conversely, echocardiographic parameters such as input impedance, and arterial wall stiffness index displayed no substantial variance among the three groups (P > 0.05). The mean (SD) aortic intima-media thickness (aIMT) for preterm neonates with BPD, preterm neonates, and term neonates were 814 (193.59) μm, 497.50 (172.19) μm, and 574.00 (113.20) μm, correspondingly (P < 0.05). Furthermore, the mean (SD) pulsatile diameter for preterm neonates with BPD, preterm neonates, and term neonates were 1.52 (0.81) mm, 0.91 (0.55) mm, and 1.34 (0.51) mm, respectively (P < 0.05). Following adjustment for birth weight, sex, and gestational age at birth, the study identified a noteworthy correlation between aIMT and BPD. The investigation concluded that the mean aortic intima-media thickness (aIMT) was significantly elevated in preterm neonates with BPD, signifying a potential early indicator of atherosclerosis and predisposition to future heightened blood pressure and cardiovascular ailments. Consequently, the study postulates that aIMT could be a consistent and well-tolerated marker for identifying BPD patients at risk of developing these health complications.

Variables related to bronchopulmonary dysplasia severity: a Six-Year retrospective study

Objectives This was a retrospective observational study conducted in a tertiary neonatal intensive care unit, in order to investigate factors which influenced the severity of bronchopulmonary dysplasia under NICHD new classification. Methods Six years of clinical data with different grades of bronchopulmonary dysplasia patients were collected and analyzed, bivariate ordinal logistic regression model and multivariable ordinal logistic regression model were used with sensitivity analyses. Results We identified seven variables were associated with the severity of BPD via a bivariate ordinal logistic regression model, including the level of referral hospital (OR 0.273；95% CI 0.117, 0.636), method of caffeine administration (OR 00.418；95% CI 0.177, 0.991), more than two occurrences of reintubation (OR 4.925；95% CI 1.878, 12.915), CPAP reapplication (OR 2.255；95% CI 1.059, 4.802), presence of positive sputum cultures (OR 2.574；95% CI 1.200, 5.519), the cumulative duration of invasive ventilation (OR 1.047；95% CI 1.017, 1.078), and postmenstrual age at the discontinuation of oxygen supplementation (OR 1.190；95% CI 1.027, 1.38). These seven variables were further analyzed via all multivariable ordinal logistic regression models, and we found that tertiary hospital birth and early administration of caffeine could reduce the severity of BPD by approximately 70% (OR 0.263；95% CI 0.090, 0.770) and 60% (OR 0.371；95% CI 0.138, 0.995), respectively. In contrast, multiple reintubations were related to higher BPD severity with an OR of 3.358 (95% CI 1.002, 11.252). Conclusion Improving perinatal care in level II hospitals, standardized caffeine administration, and optimized extubation strategy could potentially decrease the severity of BPD.

Abstract P3002: Role Of Vascular Fibroblast Growth Factor Signaling In Group 3 Hypoxia-induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a debilitating disease characterized by pathologic changes in the pulmonary vasculature that increases pulmonary vascular resistance and leads to right heart failure. Group 3 PH is caused by lung disease and/or hypoxia, including bronchopulmonary dysplasia (BPD) and chronic obstructive lung disease (COPD), and is the second largest cause of mortality in PH patients. PH further increases the morbidity and mortality in both COPD and BPD patients. Fibroblast Growth Factor 2 (FGF2) and FGF Receptor 1 (FGFR1) expression is elevated in lung tissue of PH patients. To study the role of FGF signaling in the pathogenesis of group 3 PH, we developed a physiologically relevant mouse model in which mice are challenged with 10% hypoxia for 2 weeks. Following hypoxia exposure, cardiac catheterization is used to measure right ventricular (RV) pressure that mimics Group 3 PH. Lung tissue is then analyzed for histological and molecular changes. Our initial work showed that inactivation of FGFRs in endothelial cells (EC) worsened hypoxia-induced PH while expression of a constitutively active FGFR1 (caFGFR1) in ECs protected against hypoxia-induced PH. Here we hypothesize that FGF signaling may also affect the pathogenic response to hypoxia of vascular smooth muscle (VSMC), potentially by limiting vascular muscularization in response to hypoxia. We show that in vitro inhibition of FGF2 signaling in human pulmonary artery VSMCs reduced hypoxia-induced proliferation while promoting a contractile phenotype, and in vivo inactivation of FGFRs 1 and 2 worsened hypoxia-induced vascular remodeling. These data suggest the potential for a dual beneficial effect of activation of FGF signaling, both in regulating EC-VSMC interactions and directly preventing VSMC remodeling.

Bronchopulmonary Dysplasia: A Five-Year Retrospective Cohort Study on Differences in Clinical Characteristics and Morbidities According to Severity Grading.

Bronchopulmonary dysplasia (BPD) is the most common complication associated with extreme prematurity. Although several criteria defining severity were developed over time, there are a few studies describing the differences in BPD phenotype and neonatal morbidities and complications between severity groups. We aimed to describe these differences in BPD patients of a neonatal intensive care unit (NICU). We conducted an observational retrospective cohort study through a medical record review over a five-year period. Participants were newborns admitted to an NICU who were diagnosed with BPD. We performed a descriptive statistical analysis of gestational complications and the use of antenatal corticosteroid therapy, birth-related data, and complications throughout the NICU stay, as well as the respiratory support used. We also compared different severity groups across these variables. The patients were divided into severe and non-severe BPD using the severity criteria of the 2001 NICHD/NHLBI/ORD consensus workshop. A total of 101 newborns with BPD participated in the study and 73 had data on BPD severity. The median gestational age was 27 weeks, ranging from 23 to 32 weeks. Of these 73 newborns, 36 had mild BPD (49.3%), 10 had moderate BPD (13.7%), and 27 had severe BPD (37.0%). When comparing severe and non-severe BPD, we found that extreme prematurity, extremely low birth weight, and small size for gestational age were more frequent in the severe BPD group (p-value=0.012, p-value<0.001, and p-value=0.012, respectively). Infants with severe BPD had a longer duration of invasive ventilation than those with mild or moderate BPD (p-value<0.001). Late sepsis, necrotizing enterocolitis, severe brain injury, and retinopathy of prematurity were more frequent in severe BPD (p-value=0.017, p-value=0.045, p-value=0.033, p-value=0.003, respectively). Previously published evidence describing causal links between BPD development and comorbidities exists but data on their impact on BPD severity are scarce. In our study, severe BPD seemed to be associated with a higher frequency of comorbidities and complications. Further studies are needed to ascertain the impact of each morbidity on the severity of BPD and if measures to prevent them could lead to potentially milder BPD disease.

Obstructive sleep apnea is associated with use of assisted ventilation among children with bronchopulmonary dysplasia hospitalized with respiratory illness: A nationwide inpatient cohort

Objective (s)Children with bronchopulmonary dysplasia (BPD) are at higher risk of respiratory insufficiency during respiratory illness. We aimed to investigate whether obstructive sleep apnea (OSA) is associated with increased morbidity among children with BPD hospitalized with acute respiratory illnesses. Study designHospital discharge records were obtained from the Kid's Inpatient Database for children <21 years of age with BPD hospitalized for acute respiratory illness between 1997 and 2012. Acute respiratory illnesses included bacterial and/or viral pneumonia, bronchiolitis, acute upper respiratory tract infections, aspiration pneumonia, or asthma exacerbation. The primary exposure was OSA. The primary outcome was invasive mechanical ventilation (IMV), and secondary outcomes were noninvasive mechanical ventilation (NIMV), length of hospital stay (LOS), and inflation-adjusted cost of hospitalization (IACH). Multivariable regression was conducted to ascertain the associations between OSA and primary and secondary outcomes accounting for BPD-associated comorbidities. ResultsAmong 33,640 hospitalizations of children with BPD for acute respiratory illness, there were 607 (1.8%) cases with comorbid OSA vs. 33,033 (98.2%) controls without OSA. Patients with OSA were more likely to have aspiration pneumonia, central sleep apnea, obesity, laryngeal stenosis, congenital airway, and skull/face/jaw anomalies. Multivariable regression showed that OSA was associated with IMV (OR 1.45, 95% CI 1.09–1.94, p = 0.012) and NIMV (OR 2.61, 95% CI 1.71–3.98, p < 0.001), but not LOS or IACH. ConclusionsIn BPD patients hospitalized with acute respiratory illness, having OSA is associated with increased risks for respiratory insufficiency requiring noninvasive or invasive mechanical ventilation. Clinicians should consider OSA, along with other BPD-associated comorbidities, in the management of this population.

Evaluation of preterm infants having bronchopulmonary dysplasia with echocardiography and serum biomarkers.

Pulmonary hypertension is frequent in infants with bronchopulmonary dysplasia. Echocardiography is easy to perform, non-invasive, and recommended by guidelines even though solely it is not enough. Catheterisation is gold standard but invasive, expensive, and not cost effective. Therefore, we aimed to assess to find out the role of biomarkers besides echocardiography in the diagnosis of pulmonary hypertension in preterm with bronchopulmonary dysplasia. This study is done during the time period January 2016-2017. The diagnosis of pulmonary hypertension was assessed by echocardiography at 36 weeks later repeated at 3rd and 6th months. We also repeated biomarkers at 3rd and 6th months. The infants born ≤ 28 weeks in Erciyes University hospital who were diagnosed bronchopulmonary dysplasia were included. Infants with genetic syndromes, structural lung, and CHDs were excluded. Patients without bronchopulmonary dysplasia but having pulmonary hypertension due to other reasons and patients having echocardiograms without adequate images were excluded. At initial, 21/59 patients had bronchopulmonary dysplasia-pulmonary hypertension (Group 1), 21/59 had no bronchopulmonary dysplasia-pulmonary hypertension (Group 2), and 17/59 had bronchopulmonary dysplasia without pulmonary hypertension (Group 3). Systolic pulmonary artery pressure and pulmonary vascular resistance were found high in Group 1 (36 mmHg; p <0.001, 1.25 Woods Unit; p < 0.0017, respectively). Tricuspid annular plane systolic excursion values of Group 1 were low. Median serum kallistatin levels of Group 1 were lower than the other groups (230.5 (114.5-300.5) µg/ml; p < 0.005). During the study period, pulmonary hypertension of 14/21 bronchopulmonary dysplasia-pulmonary hypertension resolved, six patients in Group 3 developed pulmonary hypertension. However, there was no difference in the biomarkers of these six patients. In the diagnosis and the follow-up of pulmonary hypertension in bronchopulmonary dysplasia patients, besides echocardiography kallistatin, gelsolin, NT-probrain natriuretic peptide, homocysteine, and cystatin-C levels can be used. Further studies were required with large sample sizes.

Identification and immunological characterization of endoplasmic reticulum stress-related molecular subtypes in bronchopulmonary dysplasia based on machine learning.

Introduction: Bronchopulmonary dysplasia (BPD) is a life-threatening lung illness that affects premature infants and has a high incidence and mortality. Using interpretable machine learning, we aimed to investigate the involvement of endoplasmic reticulum (ER) stress-related genes (ERSGs) in BPD patients. Methods: We evaluated the expression profiles of endoplasmic reticulum stress-related genes and immune features in bronchopulmonary dysplasia using the GSE32472 dataset. The endoplasmic reticulum stress-related gene-based molecular clusters and associated immune cell infiltration were studied using 62 bronchopulmonary dysplasia samples. Cluster-specific differentially expressed genes (DEGs) were identified utilizing the WGCNA technique. The optimum machine model was applied after comparing its performance with that of the generalized linear model, the extreme Gradient Boosting, the support vector machine (SVM) model, and the random forest model. Validation of the prediction efficiency was done by the use of a calibration curve, nomogram, decision curve analysis, and an external data set. Results: The bronchopulmonary dysplasia samples were compared to the control samples, and the dysregulated endoplasmic reticulum stress-related genes and activated immunological responses were analyzed. In bronchopulmonary dysplasia, two distinct molecular clusters associated with endoplasmic reticulum stress were identified. The analysis of immune cell infiltration indicated a considerable difference in levels of immunity between the various clusters. As measured by residual and root mean square error, as well as the area under the curve, the support vector machine machine model showed the greatest discriminative capacity. In the end, an support vector machine model integrating five genes was developed, and its performance was shown to be excellent on an external validation dataset. The effectiveness in predicting bronchopulmonary dysplasia subtypes was further established by decision curves, calibration curves, and nomogram analyses. Conclusion: We developed a potential prediction model to assess the risk of endoplasmic reticulum stress subtypes and the clinical outcomes of bronchopulmonary dysplasia patients, and our work comprehensively revealed the complex association between endoplasmic reticulum stress and bronchopulmonary dysplasia.

Genome-wide exploration of a pyroptosis-related gene module along with immune cell infiltration patterns in bronchopulmonary dysplasia.

Pyroptosis plays a crucial role in bronchopulmonary dysplasia (BPD) and is associated with various lung injury illnesses. However, the function of pyroptosis-related genes (PRGs) in BPD remains poorly understood. The gene expression omnibus (GEO) database was searched for information on genes associated with BPD. Twenty-five BPD-related DE-PRGs were identified, all of which were closely associated with pyroptosis regulation and immunological response. LASSO and SVM-RFE algorithms identified CHMP7, NLRC4, NLRP2, NLRP6, and NLRP9 among the 25 differentially expressed PRGs as marker genes with acceptable diagnostic capabilities. Using these five genes, we also generated a nomogram with excellent predictive power. Annotation enrichment analyses revealed that these five genes may be implicated in BPD and numerous BPD-related pathways. In addition, the ceRNA network showed an intricate regulatory link based on the marker genes. In addition, CIBERSORT-based studies revealed that alterations in the immunological microenvironment of BPD patients may be associated with the marker genes. We constructed a diagnostic nomogram and gave insight into the mechanism of BPD. Its diagnostic value for BPD must be evaluated in further research before it can be used in clinical practice.

Quality of life of patients and caregivers affected by bronchopulmonary dysplasia: a systematic review.

To synthesize evidence on the impact of bronchopulmonary dysplasia (BPD) on the Quality of Life (QoL) of affected individuals from three perspectives: (i) QoL of caregiver; (ii) caregiver's perception of BPD patient's QoL; and (iii) BPD patient's self-reported QoL. Quantitative studies (case-control, cohort, and case series) on the QoL of BPD patients or their caregivers were considered. We conducted a systematic literature search of 6 databases (PubMed, Embase, World of Science, CINAHL, PsycINFO, and Chinese National Knowledge Infrastructure) for relevant studies. All databases were searched from the date of inception of the databases to 31 March 2022. Populations of interest were caregivers with preterm babies with BPD, or children/adults who were born premature and diagnosed with BPD. The main outcome measures were total and subdomain QoL scores, and factors affecting QoL. A total of 1078 articles were found; 10 were eligible for analysis, which included 247 caregivers and 1632 patients with BPD. The QoL of patients differed by domains-some were poorer or similar, but none of the QoL domains was better than QoL of healthy controls. Poor sleep and acute care needs of BPD patients negatively affected caregiver's QoL, while increasing illness acuity negatively affected the QoL of BPD patients. The QoL of BPD patients and their caregivers was most adversely affected during the immediate post-discharge period and tended to improve with time. The physical QoL of BPD patients was similar to that of preterm babies without BPD when assessed during late childhood and early adulthood. QoL assessment should be performed as an outcome measure and incorporated in the care plan for BPD patients and their caregivers. Systematic Review Registration PROSPERO CRD42021292253.

Relationship between bronchopulmonary dysplasia phenotypes with high-resolution computed tomography score in early preterm infants.

ObjectiveTo assess the relationship between high-resolution computed tomography (HRCT) abnormalities and clinical phenotypes of bronchopulmonary dysplasia (BPD).MethodsA retrospective, single-center study was carried out at the Children’s Hospital of Fudan University between 2013 and 2020. Preterm infants born at ≤ 32 weeks’ gestation who were diagnosed with BPD and had HRCT between 40 and 50 weeks postmenstrual age (PMA)were included in the study. HRCT images from six pulmonary lobes were scored based on seven types of pulmonary lesions from two categories: hyperaeration lesions and parenchymal lesions. The hyperaeration score (HS) included scores of decreased attenuation, mosaic attenuation, and bulla/bleb, while the parenchymal score (PS) included those of linear lesion, consolidation, bronchial wall thickening, and bronchiectasis. All seven scores were summed up to create the total score (TS). One-way ANOVA testing or Kruskal-Wallis testing was adopted for the comparison of HRCT scores with BPD severity and clinical phenotypes. The correlation between HRCT scores and clinical phenotypes was evaluated by Spearman’s correlation analysis.ResultsA total of 81 cases were included in the study. Cases with more severe BPD had a higher TS (p = 0.01), HS (p = 0.02), PS (p = 0.02), mosaic attenuation score (p = 0.03), bulla/Bleb score (p = 0.03), and linear density score (p = 0.01). TS (r = 0.28), PS (r = 0.35), linear density (r = 0.34), and consolidation (r = 0.24) were correlated with pulmonary hypertension (PH). However, no HRCT score was significantly different between the patients with or without tracheobronchomalacia (TBM). BPD patients with a combination of lung parenchymal disease, PH, and TBM had the highest TS and HS.ConclusionHRCT scores correlated with BPD severity and PH in our study. HS might be a useful tool in the assessment of BPD severity while linear densities and consolidation might be helpful in predicting PH.

Diaphragmatic Thickness and Excursion in Preterm Infants With Bronchopulmonary Dysplasia Compared With Term or Near Term Infants: A Prospective Observational Study

Diaphragmatic atrophy associated with mechanical ventilation is reported in pediatric and adult patients, but a similar association has not been described in preterm infants with bronchopulmonary dysplasia (BPD). Does BPD impact the diaphragm thickness (DT) and diaphragm excursion (DE) in infants born before 32weeks' gestation compared with healthy late preterm or term infants? In this prospective observational case-control study, DT at end of expiration (DTexp), DT at end of inspiration (DTins), DT fraction (DTF), and DE (DE) were assessed using bedside ultrasound. Two groups were compared: infants with BPD (patients) and healthy, postmenstrual age-matched infants (control participants). To account for variations in body size between groups, diaphragmatic measurements were expressed as a ratio of body surface area (BSA). Statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Inc.). We enrolled 111 infants, including 56 preterm infants with BPD (mean ± SD study age, 37.7 ± 1.7weeks) and 55 healthy control participants (mean ± SD study age, 38.1 ± 1.5weeks). DTexp and DTexp to BSA ratio were significantly lower in the BPD group compared with the healthy control group (mean ± SD, 1.3 ± 0.4mm vs1.5 ± 0.4mm [P= .01] and 7.1 ± 1.4mm/m2 vs7.8 ± 1.8mm/m2 [P= .03]). DTF and DE were significantly higher in the BPD group vsthe healthy control group (mean ± SD, 61.8 ± 26.0 vs43.3 ± 19.7 [P< .01] and 6.0 ± 1.7mm vs4.4 ± 1.6mm [P< .01], respectively). In infants with BPD, DTexp was significantly lower, whereas DTF and DE were significantly higher, compared with healthy, age-matched control participants. Future studies are required and should focus on describing the evolution of diaphragmatic dimensions in preterm infants with and without BPD. ClinicalTrials.gov; No.: NCT04941963; URL: www. gov.

Microbial and metabolic profiles of bronchopulmonary dysplasia and therapeutic effects of potential probiotics Limosilactobacillus reuteri and Bifidobacterium bifidum.

Bronchopulmonary dysplasia (BPD) is a common respiratory disease in newborns; however, there is no effective treatment. We aimed to investigate the effects of the potential probiotics Limosilactobacillus reuteri and Bifidobacterium bifidum on BPD using 16S rDNA sequencing and metabolomics methods. Faecal samples were collected from 10 BPD patients and 10 healthy subjects. 16S rDNA sequencing results showed that microbial diversity was decreased and compositions were affected in BPD. Escherichia-Shigella and Clostridium_sensu_stricto_1 were increased in the BPD group, and Enterobacteriaceae, Megamonas, Blautia, Lactobacillus (Limosilactobacillus), [Eubacterium]_coprostanoligenes_group, Phascolarctobacterium and Bifidobacterium were reduced. Metabolomics analysis identified 129 differentiated metabolites that were changed in BPD patients, and they were associated with a preference for carbohydrate metabolism in translation and metabolism during genetic information processing. Correlation analysis revealed a remarkable relationship between gut microbiota and metabolites. Subsequently, a BPD cell model was constructed to test the effect of the potential probiotics. Cell function experiments verified that treatment with the potential probiotics L. reuteri and B. bifidum promoted proliferation and inhibited apoptosis of hyperoxia-induced MLE-12 cells. In addition, treatment with the potential probiotics L. reuteri and B. bifidum reduced inflammation and oxidative stress damage. Treatment with the potential probiotics L. reuteri and B. bifidum could alleviate BPD and reduce inflammation and oxidative stress damage. This study was the first to report positive roles for the potential probiotics L. reuteri and B. bifidum in BPD. The potential probiotics L. reuteri and B. bifidum were shown to reduce inflammation and oxidative stress damage in BPD. This study provided new insights on the pathogenesis and treatment of BPD.

Lef1 is transcriptionally activated by Klf4 and suppresses hyperoxia-induced alveolar epithelial cell injury

Purpose Bronchopulmonary dysplasia (BPD) is a long-term respiratory condition. More than a quarter of extremely premature newborns are harmed by BPD. At present, there are no apparent effective drugs or treatments for the condition. In this study, we aimed to investigate the functional role and mechanism of lymphoid enhancer-binding factor 1 (Lef1) in BPD in vitro. Materials and Methods Blood samples from BPD patients and healthy volunteers were gathered, and an in vitro model of BPD was developed in alveolar epithelial cells (AECs) MLE-12 induced by hyperoxia. Then expression of krüppel-like factor 4 (KLF4/Klf4) and LEF1/Lef1 were evaluated. After Lef1 overexpressing plasmid and the vector were transfected into hyperoxia-induced MLE-12 cells, cell proliferation assays were carried out. Cell apoptosis was investigated by a flow cytometry assay, and apoptosis related proteins Bcl-2, cleaved-caspase 3 and 9 were analyzed by a western blot assay. The binding between Klf4 and Lef1 promoter predicted on the JASPAR website was verified using luciferase and ChIP assays. For further study of the mechanism of Klf4 and Lef1 in BPD, gain-of-function experiments were performed. Results The mRNA levels of KLF4/Klf4 and LEF1/Lef1 were diminished in clinical BPD serum samples and hyperoxia-induced MLE-12 cells. Overexpression of Lef1 stimulated AEC proliferation and suppressed AEC apoptosis induced by hyperoxia. Mechanically, Klf4 bound to Lef1’s promoter region and aids transcription. Moreover, the results of gain-of-function experiments supported that Klf4 could impede AEC damage induced by hyperoxia via stimulating Lef1. Conclusion Klf4 and Lef1 expression levels were declined in hyperoxia-induced AECs, and Lef1 could be transcriptionally activated by Klf4 and protect against hyperoxia-induced AEC injury in BPD. As a result, Lef1 might become a prospective therapeutic target for BPD.

Pharmacometabolomics Profiling of Preterm Infants Validates Patterns of Metabolism Associated With Response to Dexamethasone Treatment for Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is one of the most common health complications of premature birth. Corticosteroids are commonly used for treatment of BPD, but their use is challenging due to variability in treatment response. Previous pharmacometabolomics study has established patterns of metabolite levels with response to dexamethasone. We obtained additional patient samples for metabolomics analysis to find associations between the metabolome and dexamethasone response in a validation cohort. A total of 14 infants provided 15 plasma and 12 urine samples. The measure of treatment response was the calculated change in respiratory severity score (deltaRSS) from pre-to-post treatment. Each metabolite was assessed with paired analysis of pre and post-treatment samples using Wilcoxon signed rank test. Correlation analysis was conducted between deltaRSS and pre-to-post change in metabolite level. Paired association analysis identified 20 plasma and 26 urine metabolites with significant level difference comparing pre to post treatment samples (p < 0.05). 4 plasma and 4 urine metabolites were also significant in the original study. Pre-to-post treatment change in metabolite analysis identified 4 plasma and 8 urine metabolites significantly associated with deltaRSS (p < 0.05). Change in urine citrulline levels showed a similar correlation pattern with deltaRSS in the first study, with increasing level associated with improved drug response. These results help validate the first major findings from pharmacometabolomics of BPD including key metabolites within the urea cycle and trans-4-hydroxyproline as a potential marker for lung injury. Ultimately, this study furthers our understanding of the mechanisms of steroid response in BPD patients and helps to design future targeted metabolomics studies in this patient population.