Treatment Of Bronchopulmonary Dysplasia Research Articles

Quercetin attenuates the hyperoxic lung injury in neonatal mice: Implications for Bronchopulmonary dysplasia (BPD)

Quercetin (QU) is one of the most common flavonoids that are present in a wide variety of fruits, vegetables, and beverages. This compound possesses potent anti-inflammatory and anti-oxidant properties. Supplemental oxygen is routinely administered to premature infants with pulmonary insufficiency. However, hyperoxia is one of the major risk factors for the development of bronchopulmonary dysplasia (BPD), which is also termed chronic lung disease in premature infants. Currently, no preventive approaches have been reported against BPD. The treatment of BPD is notably limited to oxygen administration, ventilatory support, and steroids. Since QU has been shown to be effective in reducing inflammation and oxidative stress in various disease models, we hypothesized that the postnatal QU treatment of newborn mice will protect against hyperoxic lung injury by the upregulation of the phase I (CYP1A/B) and/or phase II, NADPH quinone reductase enzymes. Newborn C57BL/6J mice within 24 h of birth with the nursing dams were exposed to either 21% O2 (air) and/or 85% O2 (hyperoxia) for 7 days. The mice were treated, intraperitoneally (i.p.) once every other day with quercetin, at a concentration of 20 mg/kg, or saline alone from postnatal day (PND) 2–6. The mice were sacrificed on day 7, and lung and liver tissues were collected. The expression levels of CYP1A1, CYP1B1, NQO1 proteins and mRNA as well as the levels of MDA-protein adducts were analyzed in lung and liver tissues. The findings indicated that QU attenuated hyperoxia-mediated lung injury by reducing inflammation and improving alveolarization with decreased number of neutrophil and macrophage infiltration. The attenuation of this lung injury correlated with the upregulation of CYP1A1/CYP1B1/NQO1 mRNA, proteins and the down regulation of NF-kB levels and MDA-protein adducts in lung and liver tissues. The present study demonstrated the potential therapeutic value of quercetin in the prevention and/or treatment of BPD.

Recent Advances in Bronchopulmonary Dysplasia: Pathophysiology, Prevention, and Treatment.

Bronchopulmonary dysplasia (BPD) is potentially one of the most devastating conditions in premature infants with longstanding consequences involving multiple organ systems including adverse effects on pulmonary function and neurodevelopmental outcome. Here we review recent studies in the field to summarize the progress made in understanding in the pathophysiology, prognosis, prevention, and treatment of BPD in the last decade. The work reviewed includes the progress in understanding its pathobiology, genomic studies, ventilatory strategies, outcomes, and therapeutic interventions. We expect that this review will help guide clinicians to treat premature infants at risk for BPD better and lead researchers to initiate further studies in the field.

Recent advances in postnatal glucocorticoid therapies for prevention and treatment of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a common chronic lung injury in preterm infants.glucocorticoid(GC) is one of the most controversial therapies for prevention and treatment of BPD.Current evidence shows that systemic or partial, inhaled or intratracheal instilled GC can reduce the incidence of BPD.Systemic GC may lead to short or long-term adverse outcomes among the patients, especially early (within 1 week) postnatal GC therapy in preterm infants increased risk of adverse neurodevelopmental outcomes.Systemic low-dose and short course of GC can be considered by clinicians with caution to use for the infant who is ventilator-dependent and at risk of severe BPD at postnatal 1-2 weeks.Further randomized controlled research is needed to evaluate the effect and long-term outcomes of inhaled or intratracheal instilled GC therapies in infants at risk for BPD. Key words: Glucocorticoid; Bronchopulmonary dysplasia; Prevention; Treatment

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia

BackgroundThe long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain.MethodsWe randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months.ResultsAdequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04).ConclusionsAmong surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190.)

Are inhaled steroids safe and effective for prevention or treatment of bronchopulmonary dysplasia?

Are inhaled steroids safe and effective for prevention or treatment of bronchopulmonary dysplasia?

Race Effects of Inhaled Nitric Oxide in Preterm Infants: An Individual Participant Data Meta-Analysis

To assess whether inhaled nitric oxide (iNO) improves survival without bronchopulmonary dysplasia (BPD) for preterm African American infants. An individual participant data meta-analysis was conducted, including 3 randomized, placebo-controlled trials that enrolled infants born at <34 weeks of gestation receiving respiratory support, had at least 15% (or a minimum of 10 infants in each trial arm) of African American race, and used a starting iNO of >5 parts per million with the intention to treat for 7 days minimum. The primary outcome was a composite of death or BPD. Secondary outcomes included death before discharge, postnatal steroid use, gross pulmonary air leak, pulmonary hemorrhage, measures of respiratory support, and duration of hospital stay. Compared with other races, African American infants had a significant reduction in the composite outcome of death or BPD with iNO treatment: 49% treated vs 63% controls (relative risk, 0.77; 95% CI, 0.65-0.91; P = .003; interaction P = .016). There were no differences between racial groups for death. There was also a significant difference between races (interaction P = .023) of iNO treatment for BPD in survivors, with the greatest effect in African American infants (P = .005). There was no difference between racial groups in the use of postnatal steroids, pulmonary air leak, pulmonary hemorrhage, or other measures of respiratory support. iNO therapy should be considered for preterm African American infants at high risk for BPD. iNO to prevent BPD in African Americans may represent an example of a racially customized therapy for infants.

Mesenchymal stem cells for the prevention and treatment of bronchopulmonary dysplasia in preterm infants.

Bronchopulmonary dysplasia (BPD) remains a major complication of prematurity and currently lacks efficient treatments. Mesenchymal stem/stromal cells (MSCs) have been extensively explored as a potential therapy in several preclinical and clinical settings. Human and animal MSCs have been shown to prevent and treat lung injury in various preclinical models of lung diseases, including experimental BPD. To determine if MSCs, administered intravenously or endotracheally, are safe and effective in preventing or treating BPD, or both, in preterm infants. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 10), MEDLINE via PubMed (1966 to 6 November 2016), Embase (1980 to 6 November 2016), and CINAHL (1982 to 6 November 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs. We considered RCTs and quasi-RCTs investigating prevention or treatment of BPD, or both, in preterm infants. Two review authors independently assessed trial quality according to prespecified criteria. We found no RCTs or quasi-RCTs addressing the use of MSCs for prevention or treatment of BPD in premature infants. Two RCTs are currently registered and ongoing. There is insufficient evidence to determine the safety and efficacy of MSCs in the treatment or prevention of BPD in premature infants. The results of the ongoing trials addressing this issue are expected in the near future.

Mesenchymal stem cells in the pathogenesis and treatment of bronchopulmonary dysplasia: a clinical review.

Advances in neonatal medicine have led to increased survival of infants born at the limits of viability, resulting in an increased incidence of bronchopulmonary dysplasia (BPD). BPD is a chronic lung disease of premature infants characterized by the arrest of alveolarization, fibroblast activation, and inflammation. BPD leads to significant morbidity and mortality in the neonatal period and is one of the leading causes of chronic lung disease in children. The past decade has brought a surge of trials investigating cellular therapies for the treatment of pulmonary diseases. Mesenchymal stem cells (MSCs) are of particular interest because of their ease of isolation, low immunogenicity, and anti-inflammatory and reparative properties. Clinical trials of MSCs have demonstrated short-term safety and tolerability; however, studies have also shown populations of MSCs with adverse pro-inflammatory and myofibroblastic characteristics. Cell-based therapies may represent the next breakthrough therapy for the treatment of BPD, however, there remain barriers to implementation as well as gaps in knowledge of the role of endogenous MSCs in the pathogenesis of BPD. Concurrent high-quality basic science, translational, and clinical studies investigating the fundamental pathophysiology underlying BPD, therapeutic mechanisms of exogenous MSCs, and logistics of translating cellular therapies will be important areas of future research.

Mesenchymal Stromal Cell Therapy in Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis of Preclinical Studies.

Extreme prematurity is the leading cause of death among children under 5 years of age. Currently, there is no treatment for bronchopulmonary dysplasia (BPD), the most common complication of extreme prematurity. Experimental studies in animal models of BPD suggest that mesenchymal stromal cells (MSCs) are lung protective. To date, no systematic review and meta‐analysis has evaluated the preclinical evidence of this promising therapy. Our protocol was registered with Collaborative Approach to Meta‐Analysis and Review of Animal Data from Experimental Studies prior to searching MEDLINE (1946 to June 1, 2015), Embase (1947 to 2015 Week 22), Pubmed, Web of Science, and conference proceedings (1990 to present) for controlled comparative studies of neonatal animal models that received MSCs or cell free MSC‐derived conditioned media (MSC‐CM). Lung alveolarization was the primary outcome. We used random effects models for data analysis and followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses reporting guidelines. We screened 990 citations; 25 met inclusion criteria. All used hyperoxia‐exposed neonatal rodents to model BPD. MSCs significantly improved alveolarization (Standardized mean difference of −1.330, 95% confidence interval [CI −1.724, −0.94, I2 69%]), irrespective of timing of treatment, source, dose, or route of administration. MSCs also significantly ameliorated pulmonary hypertension, lung inflammation, fibrosis, angiogenesis, and apoptosis. Similarly, MSC‐CM significantly improved alveolarization, angiogenesis, and pulmonary artery remodeling. MSCs, tested exclusively in hyperoxic rodent models of BPD, show significant therapeutic benefit. Unclear risk of bias and incomplete reporting in the primary studies highlights nonadherence to reporting standards. Overall, safety and efficacy in other species/large animal models may provide useful information for guiding the design of clinical trials. Stem Cells Translational Medicine 2017;6:2079–2093

Postnatal Corticosteroids to Treat or Prevent Bronchopulmonary Dysplasia in Preterm Infants

Background: The lungs of particularly newborn are fragile and can be easily damaged. With injury, scarring may follow which is translated into difficult breathing and increased oxygen needs, a condition called bronchopulmonary dysplasia (BPD) or Chronic Lung Disease (CLD). Since inflammation plays an important role in the pathogenesis of CLD, corticosteroids, especially dexamethasone, have been extensively used to avert or treat CLD. Thus, several studies suggest that systemic corticosteroids decrease the duration of ventilator dependence. Aim of the Study: investigate the beneficial and harmful effects of the use of steroid in the prevention and treatment of BPD. Methods: A systematic review and meta-analysis of observational studies and randomized controlled trials was conducted. A review of the scientific literature. Pubmed, Embase and Central were searched to identify randomized controlled trials that investigated postnatal corticosteroids treatment for BPD were the primary endpoints. Identification of papers and data extraction were performed by two independent researchers. We searched for relevant trials in the Cochrane Library, MEDLINE (from 1955), Embase (from 1970), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to September 2017.Results: The search yielded seven RCTs which enrolled a total of 1862 participants eligible for inclusion in the present review. There were significant beneficial outcomes such as lower rates of failure to extubate and decreased risks of chronic lung disease at both 28 days (RR 0.84, 95% CI 0.83 to 0.87) and 36 weeks' postmenstrual age (RR 0.77, 95% CI 0.72 to 0.84), death or chronic lung disease at 28 days (RR 0.9, 95% CI 0.85 to 0.96) and 36 weeks' postmenstrual age (RR 0.91, 95% CI 0.87 to 0.96). Nevertheless, there were no significant differences in the rates of neonatal mortality (RR= 1.06, 95% CI 0.93, 1.26), periventricular leukomalacia (RR 1.16, 95% CI 0.9 to 1.46), necrotizing enterocolitis or pulmonary haemorrhage (RR 1.21, 95% CI 0.83 to 1.62). In contrast, gastrointestinal bleeding (RR 2.13, 95% CI 1.41 to 2.84) and intestinal perforation (RR 1.77, 95% CI 1.46 to 2.1) were imperative adverse effects. Moreover, many adverse neurological effects were found at follow-up examinations, including developmental delay (RR 1.72, 95% CI 1.4 to 2.05) and cerebral palsy (RR 1.56, 95% CI 1.03 to 2.1). Additionally, the rates of the combined outcomes of death or cerebral palsy (1.92, 95% CI 1.18 to 2.67), or of death or major neurosensory disability (RR 1.25, 95% CI 0.98 to 1.53), were not significantly increased. In subgroup analyses by type of corticosteroid, most of the advantageous and disadvantageous effects were related chiefly to dexamethasone whilst hydrocortisone had slight effect on any of the outcomes except for an increase in intestinal perforation and a borderline reduction in patent ductus arteriosus. The overall risk for bias was low as all were RCTs using robust methods. Conclusion: despite the fact that early corticosteroid treatment can have beneficial outcome for BPD management through facilitation of extubation and decreasing the risk of chronic lung disease and patent ductus arteriosus, it ,on the other hand, results in short-term adverse effects including gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Clinicians should carefully assess the risks of a short course of glucocorticoid therapy to mitigate BPD for premature neonates such that an individualized decision should be made in conjunction with the infant's parents.

Impact of Diuretic Therapy in the Treatment of Bronchopulmonary Dysplasia and Acute Kidney Injury in the Neonatal Population.

Diuretics are among the most frequently prescribed medications in the neonatal intensive care unit (NICU), despite minimal data regarding the safety and efficacy of their use in the neonatal population. Off-label diuretic therapy is used in preterm and full-term infants to both optimize kidney function and improve respiratory status. This article examines the literature specific to the impact of diuretic therapy in the NICU and compares the benefits versus risks of utilization as they pertain to the prevention and treatment of renal and pulmonary dysfunction in this population. A comprehensive literature search of online databases was performed, utilizing: CINAHL via EBSCO, PubMed, and ProQuest. Full-text, peer-reviewed, clinical trials, and review articles published in the English language between 2005 and 2015 were searched. Diuretics rank as the seventh most frequently prescribed medication in the NICU. More than 8% of all NICU patients and 37% of infants born at less than 32 gestational weeks and weighing less than 1500 g are exposed to diuretics. Benefits include lung fluid resorption acceleration, improved urine output, fluid retention counteraction, and augmentation of physiologic weight loss. Diuretics are currently utilized in the NICU at an alarming rate, without adequate clinical trials regarding their safety and efficacy of use. Updated studies are needed regarding short- and long-term outcomes of diuretic use, as well as overall general outcome data regarding the impact and evaluation of diuretic usage in the NICU population.

Stromal derived factor-1 mediates the lung regenerative effects of mesenchymal stem cells in a rodent model of bronchopulmonary dysplasia

BackgroundMesenchymal stem cells (MSCs) attenuate lung injury in experimental models of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1), a chemokine secreted by MSCs, modulates angiogenesis and stem cell recruitment. Here we tested the hypothesis that SDF-1 mediates MSC protective effects in experimental BPD by modulating angiogenesis.MethodsSDF-1 was knocked down in MSCs using lentiviral vectors carrying anti-SDF-1 short hairpin RNA (MSC-SDF KD). Non-silencing short hairpin RNA was used as control (MSC-NS control). Newborn rats exposed to normoxia or hyperoxia (FiO2 = 0.85) for 3 weeks, were randomly assigned to receive a single intra-tracheal injection (IT) of MSC-NS control or MSC-SDF KD (1 × 106 cells/50 μl) or placebo on postnatal day 7. The degree of alveolarization, lung angiogenesis, inflammation, and pulmonary hypertension (PH) were assessed at postnatal day 21.ResultsAdministration of IT MSC-NS control improved lung alveolarization, angiogenesis and inflammation, and attenuated PH in newborn rats with hyperoxia-induced lung injury (HILI). In contrast, knockdown of SDF-1 in MSCs significantly reduced their beneficial effects on alveolarization, angiogenesis, inflammation and PH.ConclusionsThe therapeutic benefits of MSCs in neonatal HILI are in part mediated by SDF-1, through anti-inflammatory and angiogenesis promoting mechanisms. Therapies directly targeting this chemokine may provide a novel strategy for the treatment of BPD.

Newborn Mice Lacking the Gene for Cyp1a1 Are More Susceptible to Oxygen-Mediated Lung Injury, and Are Rescued by Postnatal β-Naphthoflavone Administration: Implications for Bronchopulmonary Dysplasia in Premature Infants.

Prolonged hyperoxia contributes to bronchopulmonary dysplasia (BPD) in preterm infants. β-Naphthoflavone (BNF) is a potent inducer of cytochrome P450 (CYP)1A enzymes, which have been implicated in hyperoxic injuries in adult mice. In this investigation, we tested the hypothesis that newborn mice lacking the Cyp1a1 gene would be more susceptible to hyperoxic lung injury than wild-type (WT) mice and that postnatal BNF treatment would rescue this phenotype by mechanisms involving CYP1A and/or NAD(P)H quinone oxidoreductase (NQO1) enzymes. Newborn WT or Cyp1a1-null mice were treated with BNF (10 mg/kg) or the vehicle corn oil (CO) i.p., from postnatal day (PND) 2 to 14 once every other day, while being maintained in room air or hyperoxia (85% O2) for 14 days. Both genotypes showed lung injury, inflammation, and alveolar simplification in hyperoxia, with Cyp1a1-null mice displaying increased susceptibility compared to WT mice. BNF treatment resulted in significant attenuation of lung injury and inflammation, with improved alveolarization in both WT and Cyp1a1-null mice. BNF exposed normoxic or hyperoxic WT mice showed increased expression of hepatic CYP1A1/1A2, pulmonary CYP1A1, and NQO1 expression at both mRNA and protein levels, compared with vehicle controls. However, BNF caused greater induction of hepatic CYP1A2 and pulmonary NQO1 enzymes in the Cyp1a1-null mice, suggesting that BNF protects against hyperoxic lung injury in WT and Cyp1a1-null mice through the induction of CYP1A and NQO1 enzymes. Further studies on the protective role of flavonoids against hyperoxic lung injury in newborns could lead to novel strategies for the prevention and/or treatment of BPD.

Prevention and treatment of bronchopulmonary dysplasia in preterm infants

With the development of perinatal medicine, the survival rate of preterm infants has risen these years, and the incidence of bronchopulmonary dysplasia(BPD)has also increased as a result.BPD is a chronic lung disease which is caused by multiple factors, It has complicated etiology and pathogenesis, high mortality early after birth, and high incidence of later adverse outcomes in respiratory and nervous systems, which seriously affect the survival rate and quality of life in preterm infants.This article will summarize the current situation in prevention and treatment of BPD. Key words: Bronchopulmonary dysplasia; Preterm infants

Inhaled dry salt micro particles in the treatment of bronchopulmonary dysplasia: a five case series report

Background. Despite current medical ad-vances, to this day there is no single medi-cal intervention to effectively prevent or treat bronchopulmonary dysplasia (BPD) in both preterm and term infants. Along with protective ventilation strategies, vari-ous drugs are being used or are being re-searched at this very moment, with the sole purpose of improving the general outcome for these patients. Inhaled dry salt micro particles therapy is now one of them. Materials and methods. This report pre-sents five patients, diagnosed with severe BPD. All of them received, complemen-tary to classical BPD management and respiratory support, continuous inhaled dry salt micro particles, via SaltMed car-tridges, for a period of 12 to 30 days. After only 24 hours of administration, we were able to observe a significant improvement in respiratory function and dynamics. It was possible to use a lower fraction of in-spired oxygen (FiO2), mean airway pres-sure (MAP) and peak inspiratory pressure (PIP) in all mechanically ventilated pa-tients. Higher tidal volumes were recorded and we observed improvement in oxygen-ation indexes.Conclusion. Continuously inhaled dry salt micro particles, administered complemen-tary to classic BPD management, could improve respiratory and overall morbid-ity and mortality in infants with any form of BPD. Further study of these possible effects is needed, as there is no data pub-lished on this matter so far.

Association between Birth Weight and Bronchopulmonary Dysplasia in &lt;32 Weeks of Singleton Infants

Objective: Intrauterine growth retardation of lung has been suggested as being one of the risk factors in the development of bronchopulmonary dysplasia (BPD). The aim of this study was to clarify birth weight percentile among Korean infants using the contemporary Korean reference curve for birth weight by gestational age published in 2014, and on the basis of that clarification, identify the association between birth weight percentile and BPD development. Methods: All newborn infants born at <32 weeks of gestation admitted to the neonatal intensive care unit of CHA Bundang Medical Center from January 2010 through December 2015 were reviewed. Infants were divided into BPD group and non-BPD group. BPD was defined as a need of oxygen or positive airway pressure at 36 weeks postmenstrual age. All prenatal and neonatal data were collected via retrospective chart review and analyzed by multivariate logistic regression analysis. Results: During the study period, 198 singleton infants were born at <32 weeks` gestation. Among these, 179 infants were included, 54 infants in BPD group and 125 infants in non-BPD group. Accor-ding to logistic regression analysis, lower gestational age, lower birth weight percentile, occurrence of late onset sepsis showed increased risk of BPD (odds ratio [OR] 0.77, P=0.027; OR 0.98, P=0.021; OR 7.98, P<0.0001). Conclusion: In this single center study, lower birth weight percentile in preterm infants seems to increase the risk of BPD. In these infants, anticipate the high risk of BPD and cautious treatment strategies are needed.

Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis.

Bronchopulmonary dysplasia (BPD) in preterm infants remains a major health burden despite many therapeutic interventions. Inhaled corticosteroids (IC) may be a safe and effective therapy. To assess the safety and efficacy of IC for prevention or treatment of BPD or death in preterm infants. PubMed, the Cochrane Library, Embase, and CINAHL from their inception until November 2015 together with other relevant sources. Randomized controlled trials of ICs versus placebo for either prevention or treatment of BPD. This meta-analysis used a random-effects model with assessment of quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Thirty-eight trials were identified, and 16 met inclusion criteria. ICs were associated with a significant reduction in death or BPD at 36 weeks' postmenstrual age (risk ratio [RR] = 0.86, 95% confidence interval [CI] 0.75 to 0.99, I2 = 0%, P = .03; 6 trials, n = 1285). BPD was significantly reduced (RR = 0.77, 95% CI 0.65 to 0.91, I2 = 0%, 7 trials, n = 1168), although there was no effect on death (RR = 0.97, 95% CI 0.42 to 2.2, I2 = 50%, 7 trials, n = 1270). No difference was found for death or BPD at 28 days' postnatal age. The use of systemic steroids was significantly reduced in treated infants (13 trials, n = 1537, RR = 0.87, 95% CI 0.76 to 0.98 I2 = 3%,). No significant differences were found in neonatal morbidities and other adverse events. Long-term follow-up data are awaited from a recent large randomized controlled trial. Very preterm infants appear to benefit from ICs with reduced risk for BPD and no effect on death, other morbidities, or adverse events. Data on long-term respiratory, growth, and developmental outcomes are eagerly awaited.

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice.

Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor+/-, limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomal-associated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.

Cell-based therapies for neonatal lung disease.

Preterm birth occurs in approximately 11% of all births worldwide. Advances in perinatal care have enabled the survival of preterm infants born as early as 23-24weeks of gestation. However, many are affected by bronchopulmonary dysplasia (BPD)-a common respiratory complication of preterm birth, which has life-long consequences for lung health. Currently, there is no specific treatment for BPD. Recent advances in stem cell research have opened new therapeutic avenues for prevention/repair of lung damage. This review summarizes recent pre-clinical data and early clinical translation of cell-based therapies for BPD.

The Improvement of Respiratory Performance After Phototherapy-Induced EPC Mobilization in Preterm Infants With RDS.

Many infants who develop bronchopulmonary dysplasia (BPD) are born with serious respiratory distress syndrome (RDS), which is associated with impaired vascular and alveolar growth. RDS is a breathing disorder that mostly affects preterm infants and occurs in infants whose lungs have not yet been fully developed. The use of surfactant in RDS treatment does not necessarily prevent BPD. Endothelial progenitor cells (EPCs) may contribute to lung angiogenesis for the prevention and treatment of BPD. The aim of this study was to evaluate the therapeutic efficacy of phototherapy for EPC release in preterm infants born with RDS. Seventy-five RDS preterm infants were divided into two groups: RDS with phototherapy and RDS without phototherapy. Respiratory indices were recorded for each patient. Circulating EPCs were isolated before and after phototherapy and colony forming efficiency, chemotactic, tubulogenic, proliferative, and functional properties of these cells were analyzed. Our results showed that phototherapy increased the release of EPCs into the circulation in RDS preterm infants, with augmentation of cell proliferation, tubulogenic, chemotactic, and proliferative properties of EPCs. Phototherapy-induced EPC release was associated with improved lung function as was recorded by significantly decrease in continuous positive airway pressure (CPAP) days, CPAP plus ventilator days, and PCO2 along with a significant increase in PO2 and PaO2 /FiO2 , resulting in markedly decreased rate of BPD occurrence in preterm infants with RDS. Overall, phototherapy is touted as a promising modality for the amelioration of respiratory performance and prohibition of BPD occurrence in RDS preterm infants. J. Cell. Biochem. 118: 594-604, 2017. © 2016 Wiley Periodicals, Inc.