Recent Advances in Bronchopulmonary Dysplasia Protection and Therapy

For preterm infants, bronchopulmonary dysplasia (BPD) is usually caused by abnormal lung development due to various factors during prenatal and postnatal process. One of the reasons for death and bad prognosis of preterm infants is to have BPD. Up to now, there are no unified strategies or drugs to treat BPD. In clinical, many intervention treatments have been applied to achieve BPD therapy, mainly including preterm protection, protective ventilation strategies, and delivery of corticosteroids, pulmonary vasodilators, and antioxidants. This review summarizes the current advances in BPD protection and treatment, and notes that gut microbiota and mesenchymal stem cells (MSCs) can be the promising strategy for protecting and treating BPD in the future.

Influence of Gut and Lung Microbiota and the Gut-Lung Axis on Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia(BPD),also known as neonatal chronic lung disease,is a common respiratory disease in preterm infants.Preterm infants with BPD often exhibit changes in gut and lung microbiota.In recent years,with the development of high-throughput sequencing technology,more and more mechanisms of the gut-lung axis have been confirmed,helping to explore new directions for the treatment of BPD using microecological agents.This paper reviews the roles of gut microbiota,lung microbiota,and the gut-lung axis in the pathogenesis of BPD in preterm infants,providing new research avenues for the prevention and treatment of BPD.

Association of Ureaplasma urealyticum Colonization with Development of Bronchopulmonary Dysplasia: A Systemic Review and Meta-analysis

There is controversy regarding the roles of Ureaplasma urealyticum （U. urealyticum） colo- nization in the development of hronchopulmonary dysplasia （BPD）. This study explored the association between U. urealyticum and bronchopulmonary dysplasia at 36 weeks post-menstrual age （BPD36）. Studies published before December 31, 2013 were searched from Medline, Embase, Ovid, Web of Sci- ence, and Cochrane databases, with the terms ＂Ureaplasma urealyticum＂, ＂chronic lung disease＂, or ＂BPD36＂ used, and English language as a limit. The association between U. urealyticum colonization and BPD36 was analyzed with RevMan 4.2.10 software, using the odds ratio （OR） and relative risk （RR） for dichotomous variables. Out of the enrolled 81 studies, 11 investigated the BPD36 in total 1193 in- fants. Pooled studies showed no association between U. urealyticum colonization and subsequent de- velopment of BPD36, with the OR and RR being 1.03 （95% CI=0.78-1.37; P=-0.84） and 1.01 （95% CI= 0.88-1.16, P=-0.84）, respectively. These findings indicated no association between U. urealyticum colo- nization and the development of BPD36.

Association of Surfactant Protein B Gene Polymorphisms (C/A-18, C/T1580, Intron 4 and A/G9306) and Haplotypes with Bronchopulmonary Dysplasia in Chinese Han Population

Summary： This study aimed to investigate the association between surfactant protein B （SP-B） pol- ymorphisms and bronchopulmonary dysplasia （BPD） in Chinese Han infants. We performed a case- control study including 86 infants with BPD and 156 matched controls. Genotyping was performed by sequence specific primer-polymerase chain reaction （PCR） and haplotypes were reconstructed by the fastPHASE software. The results showed that significant differences were detected in the geno- type distribution of C/A-18 and intron 4 polymorphisms of SP-B gene between cases and controls. No significant differences were detected in fhe genotype distribution of C/T1580 or A/G9306 be- tween the two groups. Haplotype analysis revealed that the frequency of A-del-C-A haplotype was higher in case group （0.12 to 0.05, P=0.003）, whereas the frequency of C-inv-C-A haplotype was higher in control group （0.19 to 0.05, P=0.000）. In addition, a significant difference was observed in the frequency of C-inv-T-A haplotype between the two groups. It was concluded that the polymor- phisms of SP-B intron 4 and C/A-18 could be associated with BPD in Chinese Han infants, and the del allele of intron 4 and A allele of C/A-18 might be used as markers of susceptibility in the disease. Haplotype analysis indicated that the gene-gene interactions would play an important part in deter- mining susceptibility to BPD.

Successful treatment of pulmonary hypertension in a neonate with bronchopulmonary dysplasia: A case report and literature review

BACKGROUND Pulmonary hypertension(PH)is a severe complication of bronchopulmonary dysplasia(BPD)in premature neonates and is closely related to prognosis.However,there is no effective and safe treatment for PH due to BPD in infants.Successful treatment for cases of BPD-associated PH with Tadalafil combined with bosentan is rare.This case may make a significant contribution to the literature because PH is difficult to manage as a serious complication of BPD in preterm infants.Mortality is high,especially when it is complicated by heart failure.CASE SUMMARY An extremely premature neonate with a gestational age of 26+5 wk and birth weight of 0.83 kg was diagnosed with BPD associated with PH;oral sildenafil did not improve the PH.The infant experienced sudden cardiac arrest and serious heart failure with severe PH.After a series of treatments,including cardiopulmonary resuscitation,mechanical ventilation,and inhaled nitric oxide(iNO),the respiratory and circulatory status improved but the pulmonary artery pressure remained high.Then oral sildenafil was replaced with oral tadalafil and bosentan;pulmonary artery pressure improved,and the infant recovered at our hospital.After 2 years of follow-up,she is in good condition,without any cardiovascular complications.CONCLUSION INO can effectively improve the respiratory and circulatory status of infants with PH associated with premature BPD.B-type natriuretic peptide should be routinely measured during hospitalization to evaluate the risk and prognosis of BPD-associated PH in preterm infants.Tadalafil combined with bosentan for the treatment of PH associated with premature BPD was better than sildenafil in this case.Further studies are needed to explore the efficacy and safety of different vasodilators in the treatment of PH associated with premature BPD.

Research Progress in Bronchopulmonary Dysplasia: A Narrative Review by Etiology

Background: Bronchopulmonary Dysplasia (BPD) is a chronic lung condition that primarily affects preterm infants. Genetic predispositions, environmental factors, prenatal, and postnatal risk factors have been associated with bronchopulmonary dysplasia. However, there is a lack of consensus regarding these factors. Purpose: To examine the available information on pathogenesis and summarize the points of agreement to generate concise information that can guide patient management and spur further research. Method: PubMed, Embase and Web of Science were used to search for studies that analyzed the risk factors associated with bronchopulmonary dysplasia between 2006 and 2022 with the key search terms “bronchopulmonary dysplasia, etiology, preterm birth, mechanical ventilation”. Results: This study found that the pathogenesis of bronchopulmonary dysplasia is multifactorial, involving close interactions among these major etiological factors and other minor risk factors. A combination of mechanical ventilation, intrauterine factors, inflammation, genetic predispositions, insufficient surfactants, docosahexaenoic acid, and nutrition, among other minor risk factors, was all required in one way or another to influence BPD development. Therefore, studies should continuously update and incorporate the emerging information to assist frontline healthcare workers and generate qualitative data for clinical trial design and further research. Conclusion: Bronchopulmonary Dysplasia is different from other respiratory illnesses, and the pathogenesis of bronchopulmonary is multifactorial.

Bronchopulmonary Dysplasia in Premature Infants with Very Low Birth Weight: A Single Centre Retrospective Study in China

To investigate bronchopulmonary dysplasia (BPD) and its treatment with dexamethasone (DEX) in premature infants with birth weight (BW) < 1500 g. We retrospectively reviewed the records of preterm infants admitted to the Division of Neonatology, the Second Xiangya Hospital, Central South University between September 2011 and December 2014. Patients were excluded if they needed oxygen therapy but were lost to follow-up at ≤36 weeks post-menstrual age (PMA) or <56 days after birth, or they had severe congenital anomalies. The incidence of BPD was 18% (37/212). Gestational age (GA) was <32 weeks in all BPD patients. GA, BW, and Apgar scores were lower and hospitalization duration and pulmonary surfactant (PS) use were higher in the BPD group than in the non-BPD group (P < 0.05). Risk factors for BPD included neonatal respiratory distress syndrome, neonatal pneumonia, positive sputum culture, pulmonary hemorrhage, respiratory failure. Multivariate logistic regression revealed that GA (odds ratio [OR]: 0.479, P = 0.004) and neonatal respiratory distress syndrome (OR: 6.146, P = 0.043) were independent risk factors for BPD. DEX was administered to 26 patients after the diagnosis of BPD. After one and two weeks of DEX treatment, the oxygen requirement had significantly reduced compared to the week prior to treatment (P < 0.05), while during treatment, the weight gain rate and weight gain efficiency slower significantly than that during either of the two preceding weeks (P < 0.001). These results suggest that low GA was the most important risk factor for BPD, DEX reduced oxygen dependency but decreased weight gain.

Factors affecting length of stay according to bronchopulmonary dysplasia severity:a nationwide cohort study in Korea

Background Longer hospitalizations for preterm infants with bronchopulmonary dysplasia(BPD)delay developmental outcomes,increase the risk for hospital-acquired complications,and exert a substantial socioeconomic burden.This study aimed to identify factors associated with an extended length of stay(LOS)at different levels of severity of BPD.Methods A cohort study was conducted using the Korean Neonatal Network registry of very low birth weight infants with BPD between 2013 and 2017 through retrospective analysis.Results A total of 4263 infants were diagnosed with BPD.For mild BPD,infants requiring surgical treatment for patent ductus arteriosus needed a longer LOS[eadjustedβcoefficients(adjβ)1.041;95%confidence interval(CI):0.01–0.08]and hydrocephalus(eadjβ1.094;95%CI 0.01–0.17).In moderate BPD,infants administered steroids or with intraventricular hemorrhage required a longer LOS(eadjβ1.041;95%CI 0.00–0.07 and eadjβ1.271;95%CI 0.11–0.38,respectively).In severe BPD,infants with comorbidities required a longer LOS:pulmonary hypertension(eadjβ1.174;95%CI 0.09–0.23),administrated steroid for BPD(eadjβ1.116;95%CI 0.07–0.14),sepsis(eadjβ1.062;95%CI 0.01–0.11),patent ductus arteriosus requiring surgical ligation(eadjβ1.041;95%CI 0.00–0.08),and intraventricular hemorrhage(eadjβ1.016;95%CI 0.05–0.26).Additionally,the higher the clinical risk index score,the longer the LOS needed for infants in all groups.Conclusions The factors affecting LOS differed according to the severity of BPD.Individualized approaches to reducing LOS may be devised using knowledge of the various risk factors affecting LOS by BPD severity.

Longer duration of initial invasive mechanical ventilation is still a crucial risk factor for moderate‑to‑severe bronchopulmonary dysplasia in very preterm infants:a multicentrer prospective study

Objectives We aimed to evaluate the risk factors for moderate-to-severe bronchopulmonary dysplasia(BPD)and focus on discussing its relationship with the duration of initial invasive mechanical ventilation(IMV)in very preterm neonates less than 32 weeks of gestational age(GA).Methods We performed a prospective cohort study involving infants born at 23–31 weeks of GA who were admitted to 47 different neonatal intensive care unit(NICU)hospitals in China from January 2018 to December 2021.Patient data were obtained from the Sina-northern Neonatal Network(SNN)Database.Results We identified 6538 very preterm infants,of whom 49.5%(3236/6538)received initial IMV support,and 12.6%(823/6538)were diagnosed with moderate-to-severe BPD symptoms.The median duration of initial IMV in the moderateto-severe BPD group was 26(17–41)days,while in the no or mild BPD group,it was 6(3–10)days.The incidence rate of moderate-to-severe BPD and the median duration of initial IMV were quite different across different GAs.Multivariable logistic regression analysis showed that the onset of moderate-to-severe BPD was significantly associated with the duration of initial IMV[adjusted odds ratio(AOR):1.97;95%confidence interval(CI):1.10–2.67],late-onset neonatal sepsis(LONS),and patent ductus arteriosus(PDA).Conclusion In this multicenter cohort study,the duration of initial IMV was still relatively long in very premature infants,and the longer duration of initial IMV accounts for the increased risk of moderate-to-severe BPD.

Characteristics of home oxygen therapy for preterm infants with bronchopulmonary dysplasia in China:results of a multicenter cohort

Background Home oxygen therapy(HOT)is indicated upon discharge in some preterm infants with severe bronchopulmonary dysplasia(BPD).There is a lack of evidence-based consensus on the indication for HOT among these infants.Because wide variation in the institutional use of HOT exists,little is known about the role of regional social-economic level in the wide variation of HOT.Methods This was a secondary analysis of Chinese Neonatal Network(CHNN)data from January 1,2019 to December 31,2019.Infants at gestational ages<32 weeks,with a birth weight<1500 g,and with moderate or severe BPD who survived to discharge from tertiary hospitals located in 25 provinces were included in this study.Infants with major congenital anomalies and those who were discharged against medical advice were excluded.Results Of 1768 preterm infants with BPD,474 infants(26.8%)were discharged to home with oxygen.The proportion of HOT use in participating member hospitals varied from 0 to 89%,with five of 52 hospitals’observing proportions of HOT use that were significantly greater than expected,with 14 hospitals with observing proportions significantly less than expected,and with 33 hospitals with appropriate proportions.We noted a negative correlation between different performance groups of HOT and median GDP per capita(P=0.04).Conclusions The use of HOT varied across China and was negatively correlated with the levels of provincial economic levels.A local HOT guideline is needed to address the wide variation in HOT use with respect to different regional economic levels in countries like China.

Risk of asthma in preterm infants with bronchopulmonary dysplasia: a systematic review and meta‑analysis

Background This study aimed to systematically review and meta-analyze the available literature on the association between preterm infant bronchopulmonary dysplasia(BPD)and pre-adulthood asthma.Methods Studies examining the association between BPD and asthma in children and adolescents were systematically reviewed,and a meta-analysis was conducted.We searched Scopus,Embase,Web of Science,PubMed,and Cochrane Library from the database inception to March 26,2022.The pooled odds ratio(OR)estimate was used in our meta-analysis to calculate the correlation between BPD and the probability of developing asthma before adulthood.Stata 12.0 was used to conduct the statistical analysis.Results The correlation between asthma and BPD in preterm newborns was examined in nine studies.We used a random effect model to pool the OR estimate.Our results indicated a marked increase in the risk of subsequent asthma in preterm infants with BPD[OR=1.73,95% confidence interval(CI)=1.43-2.09].Moreover,there was no obvious heterogeneity across the studies(P=0.617,I^(2)=0%).The pooled OR remained stable and ranged from 1.65(95%CI=1.35-2.01)to 1.78(95%CI=1.43-2.21).Regarding publication bias,the funnel plot for asthma risk did not reveal any noticeable asymmetry.We further performed Begg’s and Egger’s tests to quantitatively evaluate publication bias.There was no evidence of a publication bias for asthma risk(P>|Z|=0.602 for Begg’s test,and P>|t|=0.991 for Egger’s test).Conclusions Our findings indicate that preterm infants with BPD have a much higher risk of developing asthma in the future(OR=1.73,95%CI=1.43-2.09).Preterm infants with BPD may benefit from long-term follow-up.

Risk factors and machine learning prediction models for bronchopulmonary dysplasia severity in the Chinese population

Background Bronchopulmonary dysplasia(BPD)is a common chronic lung disease in extremely preterm neonates.The outcome and clinical burden vary dramatically according to severity.Although some prediction tools for BPD exist,they seldom pay attention to disease severity and are based on populations in developed countries.This study aimed to develop machine learning prediction models for BPD severity based on selected clinical factors in a Chinese population.Methods In this retrospective,single-center study,we included patients with a gestational age<32 weeks who were diagnosed with BPD in our neonatal intensive care unit from 2016 to 2020.We collected their clinical information during the maternal,birth and early postnatal periods.Risk factors were selected through univariable and ordinal logistic regression analyses.Prediction models based on logistic regression(LR),gradient boosting decision tree,XGBoost(XGB)and random forest(RF)models were implemented and assessed by the area under the receiver operating characteristic curve(AUC).Results We ultimately included 471 patients(279 mild,147 moderate,and 45 severe cases).On ordinal logistic regression,gestational diabetes mellitus,initial fraction of inspiration O_(2) value,invasive ventilation,acidosis,hypochloremia,C-reactive protein level,patent ductus arteriosus and Gram-negative respiratory culture were independent risk factors for BPD severity.All the XGB,LR and RF models(AUC=0.85,0.86 and 0.84,respectively)all had good performance.Conclusions We found risk factors for BPD severity in our population and developed machine learning models based on them.The models have good performance and can be used to aid in predicting BPD severity in the Chinese population.

Phase I trial of human umbilical cord-derived mesenchymal stem cells for treatment of severe bronchopulmonary dysplasia

Severe bronchopulmonary dysplasia(BPD)is a chronic lung disorder that primarily affects premature babies with extremely low birth weight and involves in multiple organ system;no effective pharmacotherapy for this disease exists,and mortality remains high.Based on the evidence from previous preclinical studies and phase I clinical trials,this study aims to test the safety of intravenous application of a single dose of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)in patients with severe BPD.The Mesenchymal Stem cells for Bronchopulmonary Dysplasia Treatment(MSBDT)trial is a single center,open-label,dose-escalation phase I clinical trial.Severe BPD patients were enrolled in Children Hospital of Chongqing Medical University,Chongqing,China.The first six patients were treated with low-dose hUC-MSCs(1×10^(6) cells/kg)and the next seven patients were treated with high-dose hUC-MSCs(5×10^(6) cells/kg).This study is registered with ClinicalTrials.gov,number NCT03558334.No prespecified infusion-associated adverse events,immediate complication,respiratory or cardiovascular compromise were observed during infusion and 24 h after infusion.No significant changes in safety laboratory values were observed.One death event occurred in the low-dose group on study day 10,and one death event occurred in the high-dose group on study day 24,while,after review in detail,the two cases are not believed to be infusion-associated events.In conclusion,intravenous application of a single dose of hUC-MSCs was tolerated in thirteen patients with severe BPD.

Bronchopulmonary dysplasia： pathogenesis, risk factors and early prevention strategies

The treatment of infants with established bronchopulmonary dysplasia （BPD） remains a common,frustrating and expensive problem in neonatology, pediatric PlUlmonology, pediatric critical care and general pediatrics.

Bosentan Is Associated with a Reduction in Right Ventricular Systolic Pressure N-Terminal Pro-Hormone B-Type Natriuretic Peptide Levels in Young Patients with Pulmonary Hypertension

Pulmonary hypertension is a rare and potentially fatal disease in children if left untreated. Emerging therapies, including Bosentan, a dual endothelin receptor antagonist, have shown significant benefits in the adult pulmonary hypertension population;however, few studies have assessed the efficacy and safety of endothelin receptor antagonists in infants and young children. Our study was a single-center retrospective analysis of patients less than two years of age with a confirmed diagnosis of pulmonary hypertension and initiated on Bosentan therapy between 2017 and 2020. Twelve cases met eligibility criteria. Demographic data, laboratory data, echocardiographic, and cardiac catheterization data were analyzed. With treatment, there was a statistically significant decrease in mean right ventricular systolic pressure estimated by the tricuspid regurgitation jet (79 ± 23 mmHg reduced to 52 ± 25 mmHg;p < 0.001) N-terminal pro-hormone B-type natriuretic peptide levels (21,071 reduced to 2,037;p < 0.001). Additionally, improvement and eventual normalization of right ventricular function and septal geometry was seen within the first four months of therapy. Patients who underwent cardiac catheterization after therapy initiation (n = 4) demonstrated hemodynamic improvements;however, only the decrease in diastolic pulmonary artery pressure was statistically significant (p = 0.018). No significant differences in hemoglobin, platelet count, or liver function tests were observed between groups. In conclusion, these data suggest that Bosentan may be an effective and relatively safe treatment option for children less than two years of age with pulmonary hypertension. Further long-term randomized control studies are necessary to validate the potential clinical benefit of utilizing this drug therapy in young children.

Bi-level Nasal Positive Airway Pressure(BiPAP)versus Nasal Continuous Positive Airway Pressure(CPAP)for Preterm Infants with Birth Weight Less Than 1500g and Respiratory Distress Syndrome Following INSURE Treatment:A Two-center Randomized Controlled Trial

The present study aimed to examine the effectiveness of bi-level positive airway pressure(BiPAP)versus continuous positive airway pressure(CPAP)in preterm infants with birth weight less than 1500 g and respiratory distress syndrome(RDS)following intubation-surfactant-extubation(INSURE)treatment.A two-center randomized control trial was performed.The primary outcome was the reintubation rate of infants within 72 h of age after INSURE.Secondary outcomes included bronchopulmonary dysplasia(BPD),necrotizing enterocolitis(NEC),retinopathy of prematurity(ROP)and incidences of adverse events.Lung function at one year of corrected age was also compared between the two groups.There were 140 cases in the CPAP group and 144 in the BiPAP group.After INSURE,the reintubation rates of infants within 72 h of age were 15%and 11.1%in the CPAP group and the BiPAP group,respectively(P>0.05).Neonates in the BiPAP group was on positive airway pressure(PAP)therapy three days less than in the CPAP group(12.6 d and 15.3 d,respectively,P<0.05),and on oxygen six days less than in the CPAP group(20.6 d and 26.9 d,respectively,P<0.05).Other outcomes such as BPD,NEC,ROP and feeding intolerance were not significantly different between the two groups(P>0.05).There was no difference in lung function at one year of age between the two groups(P>0.05).In conclusion,after INSURE,the reintubation rate of infants within 72 h of age was comparable between the BiPAP group and the CPAP group.BiPAP was superior to CPAP in terms of shorter durations(days)on PAP support and oxygen supplementation.There were no differences in the incidences of BPD and ROP,and lung function at one year of age between the two ventilation methods.

Intratracheal administration of umbilical cord-derived mesenchymal stem cells attenuates hyperoxia-induced multi-organ injury via heme oxygenase-1 and JAK/STAT pathways

BACKGROUND Bronchopulmonary dysplasia(BPD)is not merely a chronic lung disease,but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure.Despite advances in current management strategies,limited progress has been made in reducing the BPD-related systemic damage.Meanwhile,although the protective effects of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)or their exosomes on hyperoxia-induced lung injury have been explored by many researchers,the underlying mechanism has not been addressed in detail,and few studies have focused on the therapeutic effect on systemic multiple organ injury.AIM To investigate whether hUC-MSC intratracheal administration could attenuate hyperoxia-induced lung,heart,and kidney injuries and the underlying regulatory mechanisms.METHODS Neonatal rats were exposed to hyperoxia(80%O_(2)),treated with hUC-MSCs intratracheal(iT)or intraperitoneal(iP)on postnatal day 7,and harvested on postnatal day 21.The tissue sections of the lung,heart,and kidney were analyzed morphometrically.Protein contents of the bronchoalveolar lavage fluid(BALF),myeloper oxidase(MPO)expression,and malondialdehyde(MDA)levels were examined.Pulmonary inflammatory cytokines were measured via enzyme-linked immunosorbent assay.A comparative transcriptomic analysis of differentially expressed genes(DEGs)in lung tissue was conducted via RNA-sequencing.Subsequently,we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target mRNA and proteins related to inflammatory and oxidative responses.RESULTS iT hUC-MSCs administration improved pulmonary alveolarization and angiogenesis(P<0.01,P<0.01,P<0.001,and P<0.05 for mean linear intercept,septal counts,vascular medial thickness index,and microvessel density respectively).Meanwhile,treatment with hUC-MSCs iT ameliorated right ventricular hypertrophy(for Fulton’s index,P<0.01),and relieved reduced nephrogenic zone width(P<0.01)and glomerular diameter(P<0.001)in kidneys.Among the beneficial effects,a reduction of BALF protein,MPO,and MDA was observed in hUC-MSCs groups(P<0.01,P<0.001,and P<0.05 respectively).Increased pro-inflammatory cytokines tumor necrosis factor-alpha,interleukin(IL)-1β,and IL-6 expression observed in the hyperoxia group were significantly attenuated by hUC-MSCs administration(P<0.01,P<0.001,and P<0.05 respectively).In addition,we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs iT compared with rats reared in hyperoxia(P<0.05).Transcriptomic analysis showed that the DEGs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses,epithelial cell proliferation,and vasculature development.hUC-MSCs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group.hUC-MSCs increased heme oxygenase-1(HO-1),JAK2,and STAT3 expression,and their phosphorylation in the lung,heart,and kidney(P<0.05).Remarkably,no significant difference was observed between the iT and iP administration.CONCLUSION iT hUC-MSCs administration ameliorates hyperoxia-induced lung,heart,and kidney injuries by activating HO-1 expression and JAK/STAT signaling.The therapeutic benefits of local iT and iP administration are equivalent.

Emerging role of cellular senescence in normal lung development and perinatal lung injury

Cellular senescence is a status of irreversible growth arrest,which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external factors.Senescent cells are typically enlarged and flattened,and characterized by numerous molecular features.The latter consists of increased surfaceome,increased resid-ual lysosomal activity at pH 6.0(manifested by increased activity of senescence-associated beta-galactosidase[SA-𝛽-gal]),senescence-associated mitochondrial dysfunction,cytoplasmic chromatin fragment,nuclear lamin b1 exclusion,telomere-associated foci,and the senescence-associated secretory phenotype.These features vary depending on the stressor leading to senescence and the type of senescence.Cellular senescence plays pivotal roles in organismal aging and in the pathogenesis of aging-related diseases.Interestingly,senescence can also both promote and inhibit wound healing processes.We recently report that senescence as a programmed pro-cess contributes to normal lung development.Lung senescence is also observed in Down Syndrome,as well as in premature infants with bronchopulmonary dysplasia and in a hyperoxia-induced rodent model of this disease.Furthermore,this senescence results in neonatal lung injury.In this review,we briefly discuss the molecular features of senescence.We then focus on the emerging role of senescence in normal lung development and in the pathogenesis of bronchopulmonary dysplasia as well as putative signaling pathways driving senescence.Finally,we discuss potential therapeutic approaches targeting senescent cells to prevent perinatal lung diseases.

Oxygen administration in the care of neonates： a double-edged sword

Objective To evaluate the use of oxygen in neonates in the past, present and future Data sources The data are mainly from Pubmed with relevant published articles from the 1940s to the present with some information gathered from web searches.Study selection Studies evaluating the use of oxygen in premature and term infants through history with original milestone articles included.Results There are still many unknowns about the proper use of oxygen in preterm and term infants but many studies suggest that both liberal use （resulting in a blood oxygen saturation of greater than 94%） as well as restrictive use （resulting in a blood oxygen saturation of less than 80%-85%） are detrimental and have long term consequences on the infant.Conclusions Definitive studies evaluating the appropriate concentration and duration of supplemental oxygen are ongoing and will help in the management of term and preterm infants requiring oxygen.

Prematurity and the burden of influenza and respiratory syncytial virus disease

Background:Respiratory morbidity of former preterm infants and especially those with bronchopulmonary dysplasia(BPD)is high during infancy and early childhood.Data sources:We performed a review based on a literature search including EMBASE,MEDLINE,and CINAHL databases to identify all relevant papers published in the English and German literature on influenza and respiratory syncytial virus infection associated with preterm infant,prematurity,and BPD between 1980 and 2014.Results:Recurrent respiratory symptoms remain common at preschool age,school age and even into young adulthood.Acute viral respiratory tract infections due to different pathogens cause significant morbidity and necessitate rehospitalizations during the fi rst years of life.Infl uenza virus infection plays a minor role compared to respiratory syncytial virus(RSV)associated respiratory tract infection during infancy and early childhood.Nevertheless,particular morbidity to both viruses is high.Conclusions:The particular burden of both viral diseases in preterm infants is dominated by RSV and its associated rehospitalizations during the fi rst two years of life.Prophylactic measures include vaccination against influenza virus of family members and caregivers and active immunization starting at the age of 6 months,and monthly injections of palivizumab during the cold season to avoid severe RSV disease and its sequelae.