Hydrogen gas inhalation ameliorates LPS-induced BPD by inhibiting inflammation via regulating the TLR4-NFκB-IL6/NLRP3 signaling pathway in the placenta.

INTRODUCTION: Hydrogen (H2) is regarded as a novel therapeutic agent against several diseases owing to its inherent biosafety. Bronchopulmonary dysplasia (BPD) has been widely considered among adverse pregnancy outcomes, without effective treatment. Placenta plays a role in defense, synthesis, and immunity, which provides a new perspective for the treatment of BPD. This study aimed to investigate if H2 reduced the placental inflammation to protect the neonatal rat against BPD damage and potential mechanisms. METHODS: We induced neonatal BPD model by injecting lipopolysaccharide (LPS, 1 µg) into the amniotic fluid at embryonic day 16.5 as LPS group. LPS + H2 group inhaled 42% H2 gas (4 h/day) until the samples were collected. We primarily analyzed the neonatal outcomes and then compared inflammatory levels from the control group (CON), LPS group and LPS + H2 group. HE staining was performed to evaluate inflammatory levels. RNA sequencing revealed dominant differentially expressed genes. Bioinformatics analysis (GO and KEGG) of RNA-seq was applied to mine the signaling pathways involved in protective effect of H2 on the development of LPS-induced BPD. We further used qRT-PCR, Western blot and ELISA methods to verify differential expression of mRNA and proteins. Moreover, we verified the correlation between the upstream signaling pathways and the downstream targets in LPS-induced BPD model. RESULTS: Upon administration of H2, the inflammatory infiltration degree of the LPS-induced placenta was reduced, and infiltration significantly narrowed. Hydrogen normalized LPS-induced perturbed lung development and reduced the death ratio of the fetus and neonate. RNA-seq results revealed the importance of inflammatory response biological processes and Toll-like receptor signaling pathway in protective effect of hydrogen on BPD. The over-activated upstream signals [Toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), Caspase1 (Casp1) and NLR family pyrin domain containing 3 (NLRP3) inflammasome] in LPS placenta were attenuated by H2 inhalation. The downstream targets, inflammatory cytokines/chemokines [interleukin (IL)-6, IL-18, IL-1ß, C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1)], were decreased both in mRNA and protein levels by H2 inhalation in LPS-induced placentas to rescue them from BPD. Correlation analysis displayed a positive association of TLR4-mediated signaling pathway both proinflammatory cytokines and chemokines in placenta. CONCLUSION: H2 inhalation ameliorates LPS-induced BPD by inhibiting excessive inflammatory cytokines and chemokines via the TLR4-NFκB-IL6/NLRP3 signaling pathway in placenta and may be a potential therapeutic strategy for BPD.

Quercetin alleviates hyperoxia-induced bronchopulmonary dysplasia by inhibiting ferroptosis through the MAPK/PTGS2 pathway: Insights from network pharmacology, molecular docking, and experimental evaluations.

Quercetin, a bioactive natural compound renowned for its potent anti-inflammatory, antioxidant, and antiviral properties, has exhibited therapeutic potential in various diseases. Given that bronchopulmonary dysplasia (BPD) development is closely linked to inflammation and oxidative stress, and quercetin, a robust antioxidant known to activate NRF2 and influence the ferroptosis pathway, offers promise for a wide range of age groups. Nonetheless, the specific role of quercetin in BPD remains largely unexplored. This study aims to uncover the target role of quercetin in BPD through a combination of network pharmacology, molecular docking, computer analyses, and experimental evaluations.

Long-term impact of late pulmonary hypertension requiring medication in extremely preterm infants with severe bronchopulmonary dysplasia.

This study investigated whether late pulmonary hypertension (LPH) independently increases the risk of long-term mortality or neurodevelopmental delay (NDD) in extremely preterm infants (EPIs) with severe bronchopulmonary dysplasia (BPD). Using prospectively collected data from the Korean Neonatal Network, we included EPIs with severe BPD born at 22-27 weeks' gestation between 2013 and 2021. EPIs having severe BPD with LPH (LPH, n = 124) were matched 1:3 with those without pulmonary hypertension (PH) as controls (CON, n = 372), via propensity score matching. LPH was defined as PH with the initiation of medication after 36 weeks' corrected age (CA). Long-term mortality after 36 weeks' CA or NDD at 18-24 months' CA was analyzed. NDD was assessed using composite scores based on various neurodevelopmental assessment modalities. LPH had significantly higher long-term mortality or NDD (45.2% vs. 23.1%, P < 0.001), mortality (24.2% vs. 4.84%, P < 0.001), and NDD (68.4% vs. 37.8%, P = 0.001), respectively than CON, even after adjusting for different demographic factors. Multivariable regression demonstrated that LPH independently increased the risk of mortality or NDD (adjusted odds ratio, 1.95; 95% confidence intervals, 1.17-3.25). When LPH occurs in EPIs with severe BPD, special monitoring and meticulous care for long-term survival and neurodevelopment are continuously needed.

The impact of combined administration of surfactant and intratracheal budesonide compared to surfactant alone on bronchopulmonary dysplasia (BPD) and mortality rate in preterm infants with respiratory distress syndrome: a single-blind randomized clinical trial.

BACKGROUND: Respiratory distress syndrome (RDS) is one of the most important and common disorders among premature infants. OBJECTIVE: This study aimed to compare the effect of the combination of surfactant and budesonide with surfactant alone on Bronchopulmonary dysplasia (BPD) and mortality rate among premature infants with RDS. METHOD: An outcome assessor-blind randomized clinical trial was conducted on 134 premature infants with RDS who were born in Ayatollah Mousavi Hospital, Zanjan, Iran in 2021. The covariate adaptive randomization method was utilized to allocate participants into two groups (surfactant alone and a combination of surfactant and budesonide). The primary outcomes were BPD and Mortality rate from admission to hospital discharge. The data in this study were analyzed using SPSS software version 18. RESULTS: Overall the comparison of mortality rate and BPD between the two groups did not show a significant difference(p > 0.05). The subgroup results showed that administering surfactant with budesonide to infants under 30 weeks of age significantly reduced the number of deaths compared to using surfactant alone (5 vs. 17). Similar positive effects were observed for the occurrence of Pulmonary Hemorrhage, the need for a second dose of surfactant, oxygen index, mean blood pressure and mean arterial pressure (MAP) in infants under 34 weeks of age compared to more than 34 weeks (p < 0.05). CONCLUSION: These findings suggest that the combination therapy of surfactant and budesonide may be beneficial, particularly in preterm infants with less than 34 weeks gestational age and 1500 birth weight. However, further studies with larger sample sizes and longer follow-up periods are needed to confirm these results and assess long-term outcomes. TRIAL REGISTRATION: The study was registered at the Iranian Registry of Clinical Trials website under the code IRCT20201222049802N1. https://en.irct.ir/user/trial/48117/view . REGISTRATION DATE: 28/02/2021. PUBLIC REPOSITORY: DATA SET: This research data set link is displayed on the Zanjan-Iran Medical Sciences website: https://repository.zums.ac.ir/cgi/users/login? target=https%3 A%2 F/repository.zums.ac.ir/id/eprint .

Corticosteroids for the prevention and treatment of bronchopulmonary dysplasia: an overview of systematic reviews.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD, explaining the rationale for investigating postnatal corticosteroids. Multiple systematic reviews (SRs) have summarised the evidence from numerous randomised controlled trials (RCTs) investigating different aspects of administrating postnatal corticosteroids. Besides beneficial effects on the outcome of death or BPD, potential short- and long-term harms have been reported. OBJECTIVES: The primary objective of this overview was to summarise and appraise the evidence from SRs regarding the efficacy and safety of postnatal corticosteroids in preterm infants at risk of developing BPD. METHODS: We searched the Cochrane Database of Systematic Reviews, MEDLINE, Embase, CINAHL, and Epistemonikos for SRs in April 2023. We included all SRs assessing any form of postnatal corticosteroid administration in preterm populations with the objective of ameliorating pulmonary disease. All regimens and comparisons were included. Two review authors independently checked the eligibility of the SRs comparing corticosteroids with placebo, and corticosteroids with different routes of administration and regimens. The included outcomes, considered key drivers in the decision to administer postnatal corticosteroids, were the composite outcome of death or BPD at 36 weeks' postmenstrual age (PMA), its individual components, long-term neurodevelopmental sequelae, sepsis, and gastrointestinal tract perforation. We independently assessed the methodological quality of the included SRs by using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) and ROBIS (Risk Of Bias In Systematic reviews) tools. We assessed the certainty of the evidence using GRADE. We provided a narrative description of the characteristics, methodological quality, and results of the included SRs. MAIN RESULTS: We included nine SRs (seven Cochrane, two non-Cochrane) containing 87 RCTs, 1 follow-up study, and 9419 preterm infants, investigating the effects of postnatal corticosteroids to prevent or treat BPD. The quality of the included SRs according to AMSTAR 2 varied from high to critically low. Risk of bias according to ROBIS was low. The certainty of the evidence according to GRADE ranged from very low to moderate. Early initiated systemic dexamethasone (< seven days after birth) likely has a beneficial effect on death or BPD at 36 weeks' PMA (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.81 to 0.95; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 41; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA (RR 0.72, 95% CI 0.63 to 0.82; NNTB 13, 95% CI 9 to 21; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence). Early initiated systemic hydrocortisone may also have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.90, 95% CI 0.82 to 0.99; NNTB 18, 95% CI 9 to 594; I2 = 43%; 9 studies; 1376 infants; low-certainty evidence). However, these benefits are likely accompanied by harmful effects like cerebral palsy or neurosensory disability (dexamethasone) or gastrointestinal perforation (both dexamethasone and hydrocortisone). Late initiated systemic dexamethasone (≥ seven days after birth) may have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; NNTB 5, 95% CI 4 to 9; I2 = 61%; 12 studies; 553 infants; low-certainty evidence), mostly contributed to by a beneficial effect on BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; NNTB 6, 95% CI 4 to 13; I2 = 14%; 12 studies; 553 infants; low-certainty evidence). No harmful side effects were shown in the outcomes chosen as key drivers to the decision to start or withhold late systemic dexamethasone. No effects, either beneficial or harmful, were found in the subgroup meta-analyses of late hydrocortisone studies. Early initiated inhaled corticosteroids probably have a beneficial effect on death and BPD at 36 weeks' PMA (RR 0.86, 95% CI 0.75 to 0.99; NNTB 19, 95% CI not applicable; I2 = 0%; 6 studies; 1285 infants; moderate-certainty evidence), with no apparent adverse effects shown in the SRs. In contrast, late initiated inhaled corticosteroids do not appear to have any benefits or harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier likely has a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.60, 95% CI 0.49 to 0.74; NNTB 4, 95% CI 3 to 6; I2 = 0%; 2 studies; 381 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA. No evidence of harmful effects was found. There was little evidence for effects of different starting doses or timing of systemic corticosteroids on death or BPD at 36 weeks' PMA, but potential adverse effects were observed for some comparisons. Lowering the dose might result in a more unfavourable balance of benefits and harms. Moderately early initiated systemic corticosteroids, compared with early systemic corticosteroids, may result in a higher incidence of BPD at 36 weeks' PMA. Pulse dosing instead of continuous dosing may have a negative effect on death and BPD at 36 weeks' PMA. We found no differences for the comparisons of inhaled versus systemic corticosteroids. AUTHORS' CONCLUSIONS: This overview summarises the evidence of nine SRs investigating the effect of postnatal corticosteroids in preterm infants at risk for BPD. Late initiated (≥ seven days after birth) systemic administration of dexamethasone is considered an effective intervention to reduce the risk of BPD in infants with a high risk profile for BPD, based on a favourable balance between benefits and harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is a promising intervention, based on the beneficial effect on desirable outcomes without (so far) negative side effects. Pending results of ongoing large, multicentre RCTs investigating both short- and long-term effects, endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is not appropriate for clinical practice at present. Early initiated (< seven days after birth) systemic dexamethasone and hydrocortisone and late initiated (≥ seven days after birth) hydrocortisone are considered ineffective interventions, because of an unfavourable balance between benefits and harms. No conclusions are possible regarding early and late inhaled corticosteroids, as more research is needed.

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OBJECTIVES: To investigate the effects of different angles of pulmonary surfactant (PS) administration on the incidence of bronchopulmonary dysplasia and intracranial hemorrhage in preterm infants. METHODS: A prospective study was conducted on 146 preterm infants (gestational age <32 weeks) admitted to the Department of Neonatology, Provincial Hospital Affiliated to Anhui Medical University from January 2019 to May 2023. The infants were randomly assigned to different angles for injection of pulmonary surfactant groups: 0° group (34 cases), 30° group (36 cases), 45° group (38 cases), and 60° group (38 cases). Clinical indicators and outcomes were compared among the groups. RESULTS: The oxygenation index was lower in the 60° group compared with the other three groups, with shorter invasive ventilation time and oxygen use time, and a lower incidence of bronchopulmonary dysplasia than the other three groups (P<0.05). The incidence of intracranial hemorrhage was lower in the 60° group compared to the 0° group (P<0.05). The cure rate in the 60° group was higher than that in the 0° group and the 30° group (P<0.05). CONCLUSIONS: The clinical efficacy of injection of pulmonary surfactant at a 60° angle is higher than other angles, reducing the incidence of intracranial hemorrhage and bronchopulmonary dysplasia in preterm infants.

Lactobacillus plantarum L168 improves hyperoxia-induced pulmonary inflammation and hypoalveolarization in a rat model of bronchopulmonary dysplasia.

Alteration of gut microbiota can affect chronic lung diseases, such as asthma and chronic obstructive pulmonary disease, through abnormal immune and inflammatory responses. Previous studies have shown a feasible connection between gut microbiota and bronchopulmonary dysplasia (BPD) in preterm infants. However, whether BPD can be ameliorated by restoring the gut microbiota remains unclear. In preterm infants with BPD, we found variance in the diversity and structure of gut microbiota. Similarly, BPD rats showed gut dysbiosis, characterized by a deficiency of Lactobacillus, which was abundant in normal rats. We therefore explored the effect and potential mechanism of action of a probiotic strain, Lactobacillus plantarum L168, in improving BPD. The BPD rats were treated with L. plantarum L168 by gavage for 2 weeks, and the effect was evaluated by lung histopathology, lung function, and serum inflammatory markers. Subsequently, we observed reduced lung injury and improved lung development in BPD rats exposed to L. plantarum L168. Further evaluation revealed that L. plantarum L168 improved intestinal permeability in BPD rats. Serum metabolomics showed altered inflammation-associated metabolites following L. plantarum L168 intervention, notably a marked increase in anti-inflammatory metabolites. In agreement with the metabolites analysis, RNA-seq analysis of the intestine and lung showed that inflammation and immune-related genes were down-regulated. Based on the information from RNA-seq, we validated that L. plantarum L168 might improve BPD relating to down-regulation of TLR4 /NF-κB /CCL4 pathway. Together, our findings suggest the potential of L. plantarum L168 to provide probiotic-based therapeutic strategies for BPD.

Nesfatin-1 alleviates hyperoxia-induced bronchopulmonary dysplasia (BPD) via the nuclear factor-κB (NF-κB) p65 signaling pathway.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease in newborns, which severely influences the health of infants and lacks effective clinical treatment strategies. The pathogenesis of BPD is correlated to enhanced inflammation and activated oxidative stress (OS). The application of antioxidants and anti-inflammatory treatment could be hot spots for BPD treatment. Nesfatin-1, a peptide with a suppressive property against inflammation, was tested herein for its potential therapeutic value in BPD. Neonatal SD rats were stimulated with hyperoxia, followed by being intraperitoneally administered with 20 µg/kg/day Nesfatin-1 for 2 weeks. Decreased RAC value in lung tissues, increased wet weight/dry weight (W/D) pulmonary ratio and bronchoalveolar lavage fluid (BALF) proteins, elevated cytokine release in BALF, increased malondialdehyde (MDA) content, and declined superoxide dismutase (SOD) activity were observed in BPD rats, all of which were sharply mitigated by Nesfatin-1. Rat epithelial type II cells (AECIIs) were handled with hyperoxia, and then cultured with 1 and 10 nM Nesfatin-1. Reduced cell viability, elevated lactate dehydrogenase production, elevated cytokine secretion, elevated MDA content, and decreased SOD activity were observed in hyperoxia-handled AECIIs, all of which were markedly alleviated by Nesfatin-1. Furthermore, activated nuclear factor-κB (NF-κB) signaling observed in both BPD rats and hyperoxia-handled AECIIs were notably repressed by Nesfatin-1. Collectively, Nesfatin-1 alleviated hyperoxia-triggered BPD by repressing inflammation and OS via the NF-κB signaling pathway.

The effect of bethanechol on tracheobronchomalacia in preterm infants with bronchopulmonary dysplasia: a retrospective cohort study.

OBJECTIVE: Bethanechol has demonstrated improvement in trachealis tone in animal models, but no trials have studied efficacy in infants. This study aimed to examine if bethanechol improves a standardized pulmonary severity score (PSS) in infants with severe bronchopulmonary dysplasia with a diagnosis of tracheobronchomalacia (TBM). STUDY DESIGN: This retrospective cohort study evaluated cases treated with bethanechol matched with controls who did not receive bethanechol. TBM was diagnosed by dynamic computography. Daily PSS was recorded for each infant from 40 to 55 weeks post-menstrual age. RESULTS: Cases' mean PSS change was 21% lower than the controls' mean PSS change pre- and post-bethanechol (95% CI -40%, -2%) by paired t-test (p = 0.03). Matched differences (controls' PSS - cases' PSS) demonstrated greater mean PSS difference post-bethanechol compared to pre-bethanechol 0.17, (95% CI 0.05, 0.29) by paired t-test (p = 0.009). CONCLUSION: Infants with TBM treated with bethanechol compared to those not treated had a lower PSS reflecting improved respiratory status.

The beneficial effect of prophylactic hydrocortisone treatment in extremely preterm infants improves upon adjustment of the baseline characteristics.

BACKGROUND: Prophylactic low-dose hydrocortisone (HC) was found to improve survival without bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, appropriately adjusting for baseline risks of BPD or death might substantially increase the precision of the HC effect size. METHODS: We conducted a secondary analysis of the PREMILOC trial. The treatment effect was evaluated on the primary endpoint through a covariance analysis ANCOVA, adjusting for the baseline covariates using a mixed linear model. Several sensitivity analyses were conducted to assess the potential heterogeneity of the treatment effect across centers and subpopulations. RESULTS: The interaction between treatment group and baseline risk for BPD or death was not statistically significant (p = 0.498). After adjusting for the patient's probability of BPD-free survival using baseline predictors alone, the HC treatment exhibited a highly significant effect (OR [95% CI] = 2.053 [1.602-2.501], p = 0.002), with a number needed to treat NNT [95% CI] = 5.8 [4.1-23.0]. Despite a weak interaction with sex, we found a lack of heterogeneity in the treatment effect across specific subpopulations. CONCLUSIONS: In the PREMILOC trial, the beneficial effect of prophylactic HC versus placebo on BPD-free survival in extremely preterm neonates was found to be greater when adjusted to baseline risks of BPD or death. REGISTRATION NUMBERS: EudraCT number 2007-002041-20, ClinicalTrial.gov number NCT00623740. IMPACT: Prophylactic low-dose hydrocortisone (HC) provided past evidence of a beneficial effect in improving survival without BPD in infants born extremely preterm. Adjustment for baseline risks of BPD or death might substantially increase the precision of the HC effect size. The beneficial effect of prophylactic HC vs placebo on BPD-free survival in extremely preterm neonates was found to be greater when adjusted to baseline risks of BPD or death. We evidenced a lack of heterogeneity in the treatment effect in specific subpopulations despite some weak interaction with sex.

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia.

OBJECTIVE: Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Based on our single-dose pharmacokinetic study, we evaluated the ability of a multi-dose enteral L-citrulline strategy to achieve a target trough steady-state L-citrulline plasma concentration and its tolerability in premature infants. STUDY DESIGN: Plasma L-citrulline concentrations were measured in six premature infants receiving 60 mg/kg L-citrulline every 6 h for 72 h before the first and last L-citrulline doses. L-citrulline concentrations were compared to concentration-time profiles from our previous study. RESULTS: Target trough plasma L-citrulline concentrations were achieved in 2/6 subjects. No serious adverse events occurred. CONCLUSIONS: Multi-dose L-citrulline was well tolerated. These results will assist in the design of phase II RCTs evaluating L-citrulline dosage strategies to achieve target plasma L-citrulline concentrations in infants at risk for BPD-PH. CLINICAL TRIALS: gov ID: NCT03542812.

Neurodevelopment at 24 months corrected age in extremely preterm infants treated with dexamethasone alternatives during the late postnatal period: a cohort study.

The administration of dexamethasone has been associated with suboptimal neurodevelopment. We aimed to compare the development of extremely premature infants treated or not with alternatives to dexamethasone: betamethasone, hydrocortisone hemisuccinate. This retrospective cohort study included infants born before 29 weeks of gestational age, treated or not with late (day ≥ 7) postnatal steroids (betamethasone, hydrocortisone hemisuccinate). The neurodevelopment outcome was evaluated at 24 months corrected age, after adjustment on comorbidities of extreme prematurity. In order to analyse their overall development, data about growth and respiratory outcomes were collected. Among the 192 infants included, 59 (30.7%) received postnatal steroids. Suboptimal neurodevelopment concerned 37/59 (62.7%) postnatal steroid-treated and 43/133 (38.1%; p = 0.002) untreated infants. However, in multivariable analysis, only severe neonatal morbidity (p = 0.007) and male gender (p = 0.027) were associated with suboptimal neurodevelopment outcome at 24 months.  Conclusions: Betamethasone or hydrocortisone hemisuccinate treatment was not an independent risk for suboptimal neurological development, growth and respiratory outcomes assessed at 24 months corrected age in extremely premature infants.  Registration number: The study was registered on the ClinicalTrials.gov register: NCT05055193. What is Known: • Late postnatal steroids are used to treat bronchopulmonary dysplasia • Meta-analyses warned against the neurological risk of dexamethasone use during neonatal period. Early or late hydrocortisone hemisuccinate has been evaluated in multiple studies, none of which have reported an adverse effect on neurodevelopment at least to 2 years. Data about the use of betamethasone are scarce. What is New: • The risk of suboptimal neurodevelopment was higher among extremely premature infants who received postnatal steroids when compared to those who did not. • Betamethasone and hydrocortisone hemisuccinate treatment was not an independent risk factor for suboptimal neurodevelopment at 24 months corrected age.

Effect of Systemic Hydrocortisone on Brain Abnormalities and Regional Brain Volumes in Ventilator-dependent Infants Born Preterm: Substudy of the SToP-BPD Study.

OBJECTIVE: To evaluate whether a high cumulative dose of systemic hydrocortisone affects brain development compared with placebo when initiated between 7 and 14 days after birth in ventilated infants born preterm. STUDY DESIGN: A double-blind, placebo-controlled, randomized trial was conducted in 16 neonatal intensive care units among infants born at <30 weeks of gestation or with a birth weight of <1250 g who were ventilator-dependent in the second week after birth. Three centers performed MRI at term-equivalent age. Brain injury was assessed on MRI using the Kidokoro scoring system and compared between the 2 treatment groups. Both total and regional brain volumes were calculated using an automatic segmentation method and compared using multivariable regression analysis adjusted for baseline variables. RESULTS: From the 3 centers, 78 infants participated in the study and 59 had acceptable MRI scans (hydrocortisone group, n = 31; placebo group, n = 28). Analyses of the median global brain abnormality score of the Kidokoro score showed no difference between the hydrocortisone and placebo groups (median, 7; IQR, 5-9 vs median, 8, IQR, 4-10, respectively; P = .92). In 39 infants, brain tissue volumes were measured, showing no differences in the adjusted mean total brain tissue volumes, at 352 ± 32 mL in the hydrocortisone group and 364 ± 51 mL in the placebo group (P = .80). CONCLUSIONS: Systemic hydrocortisone started in the second week after birth in ventilator-dependent infants born very preterm was not found to be associated with significant differences in brain development compared with placebo treatment. TRIAL REGISTRATION: The SToP-BPD study was registered with the Netherlands Trial Register (NTR2768; registered on 17 February 2011; https://www.trialregister.nl/trial/2640) and the European Union Clinical Trials Register (EudraCT, 2010-023777-19; registered on 2 November 2010; https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023777-19/NL).

Diuretic Tolerance to Repeated-Dose Furosemide in Infants Born Very Preterm with Bronchopulmonary Dysplasia.

OBJECTIVES: To assess the presence and timing of furosemide diuretic tolerance in infants with bronchopulmonary dysplasia (BPD), and to determine if tolerance is modified by thiazide co-administration. STUDY DESIGN: We performed a retrospective cohort study among infants born very preterm with BPD exposed to repeated-dose furosemide for 72 hours, measuring net fluid balance (total intake minus total output) as a surrogate of diuresis in the 3 days before and after exposure. The primary comparison was the difference in fluid balance between the first and third 24 hours of furosemide exposure. We fit a general linear model for within-subject repeated measures of fluid balance over time, with thiazide co-administration as an interaction variable. Secondary analyses included an evaluation of weight trajectories over time. RESULTS: In 83 infants, median fluid balance ranged between + 43.6 and + 52.7 ml/kg/d in the 3 days prior to furosemide exposure. Fluid balance decreased to a median of + 29.1 ml/kg/d in the first 24 hours after furosemide, but then increased to +47.5 ml/kg/d by the third 24-hour interval, consistent with tolerance (P < .001). Thiazides did not modify the change in fluid balance during furosemide exposure for any time-period. Weight decreased significantly in the first 24 hours after furosemide and increased thereafter (P < .001). CONCLUSIONS: The net fluid balance response to furosemide decreases rapidly during repeated-dose exposures in infants with BPD, consistent with diuretic tolerance. Clinicians should consider this finding in the context of an infant's therapeutic goals. Further research efforts to identify safe and effective furosemide dosage strategies are needed.

Common Clinical Scenarios of Systemic Hypertension in the NICU.

Hypertension affects ∼1% to 3% of newborns in the NICU. However, the identification and management of hypertension can be challenging because of the lack of data-driven diagnostic criteria and management guidelines. In this review, we summarize the most recent approaches to diagnosis, evaluation, and treatment of hypertension in neonates and infants. We also identify common clinical conditions in neonates in whom hypertension occurs, such as renal vascular and parenchymal disease, bronchopulmonary dysplasia, and cardiac conditions, and address specific considerations for the evaluation and treatment of hypertension in those conditions. Finally, we discuss the importance of ongoing monitoring and long-term follow-up of infants diagnosed with hypertension.

Factors associated with the response to postnatal dexamethasone use in very low birthweight infants: a nationwide cohort study.

BACKGROUND: Dexamethasone is widely used as a systemic corticosteroid to treat and prevent bronchopulmonary dysplasia (BPD) in preterm infants. We evaluated the current epidemiology of dexamethasone use to prevent BPD and analyse the factors associated with the response to dexamethasone in very low birthweight infants using a nationwide database. METHODS: We included very low birthweight infants born between January 2013 and December 2020 with a gestational age of 23-31 weeks using data from the Korean Neonatal Network registry. Patients were grouped based on their dexamethasone use into 'Dex' or 'No Dex' groups. Clinical variables and data were collected, and the annual trends of dexamethasone use and the proportion of patients who received dexamethasone according to gestational age were analysed. Respiratory outcomes were compared between the groups. Univariate and multivariate analyses were performed to analyse factors associated with the response to dexamethasone in BPD. RESULTS: Of 11 261 eligible infants, 2313 (20.5%) received dexamethasone, and 1714 (74.1%) of them were diagnosed with moderate-to-severe BPD. The 8-year annual prevalence of dexamethasone use was 17.7-22.3%. The 'Dex' group had more moderate-to-severe BPD, more frequent invasive ventilation use at a postmenstrual age of 36 weeks and longer ventilator duration. Birth weight, 5-minute APGAR score, pulmonary hypertension within the first 28 days, surgical treatment of patent ductus arteriosus, medical treatment of patent ductus arteriosus, pathological chorioamnionitis, hydrocortisone or budesonide use, surgical management of necrotising enterocolitis and fungal sepsis were associated with BPD after dexamethasone use. CONCLUSIONS: Approximately 20.5% of preterm infants received dexamethasone, and the frequency increased as gestational age decreased. Poor response to dexamethasone was associated with antenatal and postnatal inflammation, low birth weight and early pulmonary hypertension.

Furin Regulates the Alveolarization of Neonatal Lungs in a Mouse Model of Hyperoxic Lung Injury.

Despite advances in treatment options, such as corticosteroid administration and less invasive respiratory support, bronchopulmonary dysplasia (BPD) remains an important prognostic factor in preterm infants. We previously reported that furin regulates changes in lung smooth muscle cell phenotypes, suggesting that it plays a critical role in BPD pathogenesis. Therefore, in this study, we aimed to evaluate whether it regulates the alveolarization of immature lungs through activating alveolarization-driving proteins. We first examined furin expression levels, and its functions, using an established hyperoxia-induced BPD mouse model. Thereafter, we treated mice pups, as well as primary myofibroblast cell cultures, with furin inhibitors. Finally, we administered the hyperoxia-exposed mice pups with recombinant furin. Immunofluorescence revealed the co-expression of furin with alpha-smooth muscle actin. Hyperoxia exposure for 10 d decreased alveolar formation, as well as the expression of furin and its target, IGF-1R. Hexa-D-arginine administration also significantly inhibited alveolar formation. Another furin inhibitor, decanoyl-RVKR-chloromethylketone, accumulated pro-IGF-1R, and decreased IGF-1R phosphorylation in myofibroblast primary cultures. Finally, recombinant furin treatment significantly improved alveolarization in hyperoxia-exposed mice pups. Furin regulates alveolarization in immature lungs. Therefore, this study provides novel insights regarding the involvement of furin in BPD pathogenesis, and highlights a potential treatment target for ameliorating the impact of BPD.

Self-assembled miR-134-5p inhibitor nanoparticles ameliorate experimental bronchopulmonary dysplasia (BPD) via suppressing ferroptosis.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants with increased levels of reactive oxygen species (ROS) and ferroptosis. Herein, we designed a peptide-based nanoparticle to deliver therapeutic molecules to pulmonary, thereby ameliorating BPD. The BPD-induced damages of lung tissues were detected by H&E and immunohistochemistry staining. Inflammatory cytokines, Fe2+, and ROS levels were quantified by the indicated kits, respectively. The targeting relationship was verified by luciferase reporter assay and pull-down assay. Subsequently, self-assembled miR-134-5p inhibitor nanoparticles with pulmonary epithelial cell-targeting were synthesized. The characteristics were detected by transmission electron microscopy, luminescence imaging, and dynamic light scattering. A significant ferroptosis was observed in the BPD mice. The protein level of GPX4 was decreased significantly compared to the control group. Constantly, miR-134-5p showed positive regulation on ferroptosis by targeting GPX4. The designed nanoparticles were mainly accumulated in the lung region. Besides, it ameliorated experimental bronchopulmonary dysplasia via suppressing ferroptosis, in vivo and in vitro. Our findings provided a miR-134-5p/GPX4 axis in regulating ferroptosis of BPD and prompted the potential of applying the peptide-based nanoparticle to BPD treatment.

Pharmacotherapy of BPD: Current status & future perspectives.

Bronchopulmonary dysplasia (BPD) is a disease exclusive to prematurity and has changed in its definition since Northway first described it in 1967. There have been countless clinical trials evaluating the efficacy of drugs in the treatment and prevention of BPD in human subjects, and an even larger number of animal studies. Despite these, only a handful of drugs are used at the bedside today, primarily due to the lack of consistent efficacy seen in clinical trials or due to reports of adverse effects. This review summarizes the list of the most commonly used drugs and emerging new therapies which target BPD and BPD-related pulmonary hypertension (BPD-PH), including those which have shown promise in human trials but are not yet used routinely.

Management of bronchopulmonary dysplasia in Japan: A nationwide survey.

BACKGROUND: The incidence of bronchopulmonary dysplasia (BPD) and respiratory management practices for extremely low birth weight infants (ELBWIs) widely vary among institutions and countries. AIMS: To clarify the variation and characteristics of the current practices of Japanese neonatologists managing patients with BPD. STUDY DESIGN: Questionnaire-based survey. PARTICIPANTS: Level II and III perinatal centers certified by the Japan Society of Perinatal and Neonatal Medicine. OUTCOME MEASURES: Policies of the neonatal intensive care units (NICUs) regarding respiratory care and medications for BPD prevention and treatment. RESULTS: A total of 76 % of facilities (207/274) responded to our survey. The response rates of level III and II facilities were 91 % (102/112) and 35 % (105/296), respectively. INtubation-SURfactant-Extubation and Less Invasive Surfactant Administration methods were performed in 23 % (47/206) and 1 % (3/206) of facilities, respectively. For the prophylactic purpose, systemic and inhaled steroids were administered "frequently" or "occasionally" in 14 % (28/205) and 42 % (86/204) of NICUs, respectively. For the therapeutic purpose, systemic and inhaled steroids were administered "frequently" or "occasionally" in 84 % (171/204) and 29 % (59/204) of NICUs, respectively. Approximately half of the NICUs (99/202) used volume-targeted ventilation (VTV) "frequently" or "occasionally" in progressing BPD. High-frequency oscillation ventilation (HFOV) was used for progressing BPD "frequently" and "occasionally" in 89 % (180/202) of the facilities. CONCLUSIONS: Our study provided an overview and characteristics of BPD management in Japan in recent years. Noninvasive approaches with surfactant administration remain not widely used in Japan. HFOV is a widely accepted management for progressing BPD.