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Pediatrics. 2011 July; 128(1): 111–126.
PMCID: PMC3124103

Targeting Inflammation to Prevent Bronchopulmonary Dysplasia: Can New Insights Be Translated Into Therapies?

Clyde J. Wright, MDcorresponding authora,b and Haresh Kirpalani, BM, MSca,b,c


Bronchopulmonary dysplasia (BPD) frequently complicates preterm birth and leads to significant long-term morbidity. Unfortunately, few therapies are known to effectively prevent or treat BPD. Ongoing research has been focusing on potential therapies to limit inflammation in the preterm lung. In this review we highlight recent bench and clinical research aimed at understanding the role of inflammation in the pathogenesis of BPD. We also critically assess currently used therapies and promising developments in the field.

Keywords: infant, newborn, bronchopulmonary dysplasia, inflammation, NF-κB, randomized controlled trials, postnatal steroid therapy, mechanical ventilation

Preterm birth affects 12.5% of pregnancies in the United States, and this rate continues to increase.1 The common corollary, bronchopulmonary dysplasia (BPD), affects up to 43% of infants born at <1500 g.2 BPD has long-lasting effects including poor neurodevelopmental outcomes and long-term pulmonary dysfunction.3,4 Unfortunately, few interventions currently used to prevent or treat BPD do so with certain benefit that outweighs harm. Only caffeine has a narrow confidence interval (CI) around estimates of efficacy, whereas those for postnatal steroids and vitamin A are wide.5 Because inflammation is central to the pathogenesis of BPD, it is disappointing that this understanding has not translated into useful therapies. Here we review recent concepts on inflammation that might help identify potential new therapeutic targets and highlight specific mediators with human correlates in the pathogenesis of BPD. The transcription factor nuclear factor κB (NF-κB) is a central cellular mediator of inflammation and is linked to the pathogenesis of many pulmonary diseases including acute respiratory distress syndrome, asthma, and chronic obstructive pulmonary disease.6 Here we discuss its potential pathogenic role in BPD. Finally, we critically evaluate whether common clinical interventions, including mechanical ventilation, administration of glucocorticoids, and emerging therapies, affect the impact of inflammation on the preterm lung. Despite an enormous body of bench work that has identified key molecular components of the inflammatory cascade, we conclude that much of this work has not yet been translated into evidence-based therapies.5,7


General and Methodologic Considerations

In 1975, Philip8 proposed that the etiology of BPD was multifactorial, largely composed of external forces: the duration of exposure to oxygen and pressure. As inflammation entered this paradigm, it included external sources (chorioamnionitis, postnatal infections), iatrogenic sources (ventilation, oxygen), and the internal host response.915 In 1999, Jobe16 amended Philip's model to incorporate multiple dimensions of inflammation and created a unified model of “new BPD.” However, even as this paradigm was confirmed by experimental data, few innovative therapies have proven efficacious. Is it useful to ask “why not?”

Several methodologic issues complicate moving potential therapies from bench to bedside for the treatment of BPD. One issue is the obvious difficulty of extrapolating animal data to human preterm infants. This issue is especially evident when the animal studies use 1 insult (eg, hyperoxia, lipopolysaccharide [LPS]) of limited duration, which is an infrequent occurrence in human newborns. However, single-hit models do carry explanatory power and generate hypotheses relevant to human disease (Table 1). However, the molecular redundancy within the complex inflammatory process complicates the translation of experimental interventions into treatments. The multiple stimuli and pathways that lead to NF-κB activation illustrate this complexity (Fig 1). Finally, human studies remain of small size. For example, of the nearly 30 studies that have attempted to predict BPD from proinflammatory biomarkers in tracheal aspirate, blood, and urine samples,1719 only 2 were of “reasonable size” to address population risks.20,21 Ambavalan et al20 examined 1067 preterm infants in a prospective cohort study, of which 606 infants developed BPD. An early (at <3 days of life) increase in serum levels of interleukin 8 (IL-8) and IL-10 or early decreases in levels of RANTES (regulated on activation normal t-cell expressed and secreted) protein and (at days of life 14–21) increases in the level of IL-6 predicted BPD (Table 2). Bose et al21 studied 1506 infants but excluded 38% of the original cohort secondary to death or lack of follow-up.21 They found that the protective effect of an elevated RANTES level (at <7 days of life) was lost after adjusting for mechanical ventilation. These 2 large studies need replication to better characterize timing and the importance of such markers.

Inflammatory Mediators With Animal and Human Data That Suggest a Role in the Pathogenesis of BPD
The transcription factor NF-κB regulates the cellular response to inflammatory and oxidant stress, as well as stretch. Normally, NF-κB remains sequestered in the cytoplasm bound to members of a family of inhibitory proteins: IκB. ...
Estimates of Risk Conferred by Selected Predisposing Factors for BPD

NF-κB: A Potential Link Between Oxidant and Inflammatory Stress and BPD

The transcription factor NF-κB regulates the cellular response to inflammatory and oxidant stress.22 Activation of this ubiquitous transcription factor potentially determines the net cellular response to inflammatory and oxidant insult in the lung. In the “oxygen radical disease” model, Saugstad2325 proposed an intracellular abundance of reactive oxygen species contributed to the pathogenesis of BPD. Inflammatory and oxidant insults stimulate NF-κB via discrete signaling pathways, which fine-tune the cellular response.22 In a quiescent cell, NF-κB remains sequestered in the cytoplasm bound to a member of the IκB family of inhibitory proteins (α, β, ε).26 After phosphorylation and degradation of the inhibitory proteins, NF-κB translocates to the nucleus. The dimeric NF-κB complex is composed of different combinations of 5 subunits: p50, p52, p65, c-Rel, and RelB. Once in the nucleus, specific subunit dimer combinations bind to unique DNA oligonucleotide sequences.27 Adding further control, some dimeric complexes contain transactivation domains (p65–p50 heterodimers) that increase gene transcription, whereas others (p50–p50 homodimers) repress gene transcription.28 Many proinflammatory mediators associated with BPD are direct targets of NF-κB (Fig 1). After activation, NF-κB increases expression of its inhibitory protein IκBα, which shuttles NF-κB dimers out of the nucleus and results in a tightly regulated negative feedback loop.29 Finally, each of the 3 inhibitory proteins (IκBα, IκBβ, and IκBε) have unique characteristics, and their presence determines a complex oscillatory pattern of NF-κB–regulated gene expression.30 Together, this complexity enables NF-κB to tightly control the transcription of genes.

NF-κB displays maturational differences in response to oxidant and inflammatory stress. For example, neonatal lymphocytes show increased NF-κB activation in response to various stimuli when compared with their adult counterparts.31,32 Similarly, fetal lung fibroblasts, in contrast to adult cells, demonstrate hyperoxia-induced NF-κB activation.33 In vivo, hyperoxia-induced NF-κB activation is enhanced in alveolar epithelium and endothelium of neonatal mice but not in adults.34 Both inflammatory and oxidant stress-induced activation of NF-κB impairs branching morphogenesis in the developing lung,35,36 which suggests that NF-κB not only controls the expression of proinflammatory genes but also controls the expression of growth factors and proapoptotic and antiapoptotic proteins.37 Therefore, there may be unintended consequences of modulating NF-κB activation in the developing lung.

Some human data link NF-κB to BPD. It is unclear yet whether the presence of activated NF-κB indicates its pathologic role or merely represents a response to injury. Nevertheless, if tracheal aspirates from preterm infants contain leukocytes demonstrating NF-κB activation, there is an increased risk of developing BPD38 and an association with severity of RDS,39 duration of mechanical ventilation, Ureaplasma urealyticum colonization, and exposure to chorioamnionitis.40 Agents that inhibit NF-κB activation have shown promise in clinical trials aimed at preventing BPD. These agents include dexamethasone, azithromycin, nitric oxide (NO), and pentoxifylline.4144

Prenatal and Fetal Modulators of Inflammation

Genetics of the Host Responses to Inflammation

The genetic predisposition for BPD was recently reviewed comprehensively.12,4547 Parker et al48 first proposed a genetic susceptibility to BPD when they found that the BPD status of 1 twin predicted BPD in the second twin. Subsequent studies of 450 and 318 preterm twins characterized a risk for BPD from both genetic and environmental factors.49,50 Beyond these twin-birth association studies, specific nucleotide polymorphisms (SNPs) have been investigated. However, the excitement that this has generated is tempered by the methodologic constraints on the validity of some studies, which sometimes include less-than-stringent levels of statistical significance, given the issue of multiple testing.5153 Thirty-three studies have linked BPD to specific SNPs.12,5372 These studies enrolled between 33 and 1209 patients. Many of these studies focused on SNPs in proinflammatory and anti-inflammatory mediators including tumor necrosis factor α (TNFα), IL-4, IL-10, IL-12, monocyte chemoattractant protein 1 (MCP-1), surfactant protein A (SPA), surfactant protein D (SPD), transforming growth factor β (TGFβ), mannose-binding lectin, matrix metalloproteinase 16 (MMP-16), and interferon γ (IFNγ). Note that although small studies have suggested a link between TNF-308 SNPs and the risk of developing BPD, a recent meta-analysis that included a total of 804 infants failed to show statistical significance for this relationship (Table 2).66 Although small studies are hypothesis-generating, only larger studies can address the methodologic and statistical criteria outlined by Attia et al5153 to provide robust validation of previous findings.

Ureaplasma Infection and Chorioamnionitis: Causal Agents or Prevalent Bystanders?

The old neonatal obsession with the potential role of U urealyticum was reviewed recently73 but with new twists. Although U urealyticum colonization in preterm sheep does not result in BPD, in nonhuman primate models it does.7478 One meta-analysis of 23 studies that included 751 infants revealed a significant association between U urealyticum colonization and BPD at 36 weeks (Table 2).79 However, the authors urged caution, because the included studies demonstrated large heterogeneity, and the greatest association was present in the smallest studies. Results of more recent research have been conflicting; some studies have shown an association of U urealyticum colonization with BPD,80,81 whereas others have shown no association.82,83 Because U urealyticum causes intra-amniotic bacterial infection, its role in BPD may have been exaggerated.

Similar considerations apply to chorioamnionitis. Although clinical chorioamnionitis (defined as maternal fever and uterine-abdominal wall tenderness) occurs in 40% of preterm pregnancies at <28 weeks,84 histologic chorioamnionitis occurs in up to 80% of these pregnancies.85 In 1996, Watterberg et al86 proposed a causal link between histologic chorioamnionitis and BPD. However, receipt of antenatal steroids was an exclusion criterion in that study. Studies performed since the widespread administration of antenatal steroids to pregnant mothers threatening preterm birth have shown either a protective effect or no association between chorioamnionitis and BPD.87100 In a large population-based study of 798 premature infants with a 90% rate of exposure to antenatal steroids, histologic chorioamnionitis protected against BPD.101 Moreover, evidence of a fetal response to inflammation, evidenced by umbilical vasculitis, conferred more protection than chorioamnionitis alone.99 Future studies should not only discern the presence of chorioamnionitis but also the fetal response to it.

Because NF-κB has a central role in regulating the cellular response to inflammation, does it play a role in the fetal response to chorioamnionitis? Animal models of the fetal inflammatory response syndrome (FIRS) suggest that it does. Exposure to intra-amniotic LPS increases NF-κB activation in bronchoalveolar lavage–derived neutrophils and monocytes of lambs.102 In a murine model of LPS chorioamnionitis, NF-κB activation led to an enhanced type II cell maturation.103 Furthermore, human preterm amnion cells show a more pronounced NF-κB response to LPS compared with term controls.104 Similarly, NF-κB activation is seen in fetal capillaries of human infants with funisitis and chorioamnionitis.105 These findings suggest that NF-κB may mediate inflammation in the fetal lung.

Postnatal Modulators

Bacterial Sepsis in the Neonate

The term systemic inflammatory response syndrome (SIRS) has been adapted to children and newborns.106 However, it may not be sensitive and, thus, may miss bacterial infections107; here we discuss data only in which positive growth identifies an organism. Stoll et al108 demonstrated that rates of BPD increased from 35% to 62% in a cohort of 5447 very low birth weight infants from the Neonatal Research Network after early-onset sepsis (odds ratio [OR]: 2.4 [95% CI: 1.2–4.7]). This relationship was confirmed recently in a population study from Israel of 15 839 infants (OR: 1.74 [95% CI: 1.24–2.43]).109 It is interesting to note that the protective effect of chorioamnionitis and funisitis on the development of BPD was lost if the infant experienced early-onset sepsis (OR: 1.98 [95% CI: 1.15–3.39]).101 In fact, Lahra et al101 found that the infants at highest risk for BPD were born to mothers without histologic chorioamnionitis but who had experienced sepsis (OR: 2.71 [95% CI: 1.64–4.51]). Late-onset sepsis also increases the risk of BPD (relative risk [RR]: 2.32 [95% CI: 1.95–2.77]).110,111 These data suggest that irrespective of the timing, inflammatory exposure from sepsis plays an important role in the development of BPD.

Oxygen Toxicity

Hyperoxia is a powerful proinflammatory stimulus, and its role in the pathogenesis of BPD was reviewed recently.112,113 Although a full discussion of hyperoxia-induced pulmonary inflammation is beyond the scope of this review, recent clinical studies are relevant. Even short-term exposure to hyperoxia affects the developing lung. When infants born at 24 to 28 weeks' gestation were randomly assigned to resuscitation in the delivery room with either 90% or 30% oxygen, the incidence of BPD at 36 weeks' gestation was reduced from 31.7% to 15.4% (RR: 0.51 [95% CI: 0.21–1.21]).114 Infants exposed to 90% oxygen had significantly elevated serum TNFα and IL-8 levels. In addition, a recent meta-analysis revealed that limiting oxygen exposure in the NICU by adopting lower pulse-oximetry goals could reduce the incidence of BPD in premature infants from 40.8% to 29.7% (OR: 0.73 [95% CI: 0.63–0.86]).115 This meta-analysis was validated by the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) which showed that infants who were randomly assigned to lower pulse-oximetry goals less frequently developed BPD (RR: 0.82 [95% CI: 0.72–0.93]) and retinopathy of prematurity (RR: 0.52 [95% CI: 0.37–0.73]).116 However, concerns about lowering oxygen-saturation ranges have arisen. Specifically, infants enrolled in the SUPPORT-NICHD trial and randomly assigned to lower pulse-oximetry goals had a higher mortality rate by discharge (number needed to harm: 27) (RR: 1.27 [95% CI: 1.01–1.60]).116 However, this was only 1 of 4 separate ways of assessing mortality (at 7 days, 14 days, 36 weeks' postmenstrual age, or by discharge) that was statistically significant. Results from 3 similar large, randomized controlled trials (RCTs) (Canadian Oxygenation Trial [COT] and Benefits of Oxygen Saturation Targeting II [BOOST II], and BOOST-UK) are pending.117,118 We advise that neonatologists retain equipoise while these trials answer whether adopting lower pulse-oximetry goals will improve outcomes at 18 to 22 months, which is the a priori primary outcome of all 4 of these trials.

Molecular Mechanisms Signaling Stretch: Understanding Barotrauma/Volutrauma in Animal Models

Excessive lung stretching results in barotrauma/volutrauma and is a powerful proinflammatory force.119 Multiple signaling pathways, including NF-κB, translate stretch into a proinflammatory signal,120,125 and the degree of stretch determines unique cytokine-expression profiles. Preterm lambs subjected to large-tidal-volume ventilation show upregulation of multiple proinflammatory mediators including IL-1β, IL-6, IL-8, and Toll-like receptors 2 (TLR-2) and 4 (TLR-4).126 In addition, systemic inflammation occurs, indicated by a hepatic acute-phase response.122 There are strong developmental differences in the pulmonary cytokine response to excessive stretch.127,128 For example, acute exposure to high-tidal-volume ventilation and hyperoxia induces a pulmonary cytokine response (IL-1β, IL-6, and TNFα) in adult mice, which is attenuated in neonates. Even then, chronic exposure to hyperoxia and high-tidal-volume ventilation will induce pulmonary cytokine release (TNFα and IL-6) in the newborn lung.128

Animal data suggest that the inflammatory response to stretch can be prevented. Lung injury induced in mice exposed to hyperoxia and high-tidal-volume ventilation is reversed by NF-κB inhibition.129 Dexamethasone inhibits NF-κB activation and prevents lung cytokine expression in mice exposed to high-tidal-volume ventilation.130 It is significant that IL-6 elevation in ventilated preterm lambs is attenuated by gentle ventilation (lower tidal volumes).131 The mode of ventilation also plays a role, as indicated by the fact that intubated piglets had markedly differing cytokine responses compared with animals ventilated with high-frequency nasal ventilation.132 These data suggest that modification of current practices could decrease inflammation and injury in the preterm lung.


Therapies that may decrease inflammation in the preterm lung are vitiated by uncertainty (wide CIs around estimates of efficacy or harm) and fraught with potential undesired serious adverse effects (eg, cerebral palsy after postnatal steroids). Because the search for efficacious anti-inflammatory agents continues, we highlight emerging therapies for preventing or treating BPD.

Interruption of Key Components of the Inflammatory Cascade

The commonest paradigm for inflammation is not BPD but, rather, severe sepsis.133 Superficially, it might be logical to ask whether cytokine cascades integral to inflammation could be blocked by antibody therapy. Several large adult trials have investigated this avenue for treating severe sepsis. By 2000, 60 trials that used various monoclonal antibodies directed at TNFα had recruited 4197 patients and showed a cumulative reduction in 28-day mortality rates (OR: 0.87 [95% CI: 0.76–0.98]).133 This modest benefit has led to consideration of polyclonal TNFα antibodies.134 Other trials have evaluated the efficacy of IL-1 receptor antagonist and platelet-activating factor receptor antagonist with similar cumulative ORs.135 Such modest reductions in mortality have not yet passed into clinical practice because of continued uncertainty.

These limited benefits to date may reflect the redundancy of the inflammatory system, which has led to attempts to broaden the inflammatory target. Because of its pivotal role in microthrombi formation in sepsis, protein C has been the focus of much attention. However, despite initial excitement (PROWESS [Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis]),136 the promise of recombinant activated protein C has not been borne out in adults. The meta-analysis of 4911 participants with severe sepsis revealed no reduction in 28-day mortality rates (RR: 0.92 [95% CI: 0.72–1.18]).137 There have been no trials limited to newborns, and this group may be at increased risk for bleeding complications.138,139 Similar to neonatologists who lack useful treatments for BPD, adult intensivists are revisiting the use of low-dose corticosteroids for the treatment of sepsis.140

The Anti-inflammatory Component of Stem Cell Therapy for Preventing BPD

Research using stem cells to prevent or treat developing BPD has burgeoned over the past decade.141144 There are several different stem cells (embryonic stem cells, bone marrow–derived stem cells, and tissue progenitor cells), but most work in neonatal lung injury has focused on bone marrow–derived mesenchymal stem cells (MSCs). Controversy remains as to whether these cells can actually engraft in the lung and differentiate into lung epithelial cells.145 If they do, these cells may protect and repair the damaged lung by several mechanisms: physical repair by adopting a native cell phenotype or repair of existing cells by exerting immunomodulatory, anti-inflammatory, and antiapoptotic effects. Some of the protective effect of MSC administration are conferred by paracrine mediators, termed the “MSC secretome.”143 Results of preclinical studies indicate a role of MSCs in the treatment of acute lung injury in adults146; however, their role in the treatment of BPD remains to be defined.

In newborn rodents, systemic administration of stem cells obtained from either bone marrow or cord blood attenuates hyperoxia-induced lung inflammation.147150 However, administration of conditioned medium from mesenchymal cells can provide similar levels of protection.149 Furthermore, newborn rats treated with cord blood MSCs display attenuated pulmonary myeloperoxidase, IL-6, TNFα, and transforming growth factor β expression.147 More data are needed to determine if anti-inflammatory effects help explain the protection seen with stem cell administration.

Gentle Ventilation: Limiting the Damage We Cause

Inflammation is a major component of ventilator-induced lung injury in adults151 and newborn infants.152,153 Three ventilatory strategies impact inflammatory changes in the lung: noninvasive approaches; low-tidal-volume ventilation; and the use of positive end-expiratory pressure (PEEP).

The “gentle-ventilation” approach is increasingly taken with the preterm infant to avoid intubation with noninvasive ventilator support. It is true that individual trials of aggressive early continuous positive airway pressure (CPAP) therapy versus intubated ventilation in the delivery room have not resulted in a reduced rate of BPD.154156 Nonetheless, pooling data on combined mortality and BPD at 36 weeks' corrected age has suggested a benefit (Table 3). Other strategies of gentle ventilation include intubation to deliver surfactant and early extubation.157,158 Nasal intermittent mandatory ventilation (NIMV) holds promise,159 but larger trial results are pending.160

Efficacy of Continuous Positive Airway Pressure for Prevention of BPD or Death

An extension of gentle ventilation is a low-tidal-volume strategy. An adult RCT that demonstrated that low-tidal-volume ventilation improved mortality rates in adults with acute respiratory distress syndrome161 sparked much work in newborns. Mechanistically, only sparse RCT data have shown effects of differing modes of ventilation on inflammatory mediators. Lista et al162 randomly assigned preterm infants to either high-frequency oscillatory ventilation or low-tidal-volume guarantee and found reduced inflammatory markers in tracheal aspirates in those who were assigned to low-tidal-volume guarantee. A Cochrane analysis confirmed a statistically significant reduction of death and/or BPD (number needed to treat: 8) (RR: 0.73 [95% CI: 0.57–0.93]) with targeted low-tidal-volume ventilation.163 Together with animal studies, these data suggest that using gentle ventilation may result in decreased pulmonary inflammation in preterm neonates who need respiratory support.

For adult disease, Gattinoni et al164 urged PEEP to recruit lung volume. Muscedere et al165 showed that in an in vitro model, setting PEEP above the lower inflection point preserved the lung's mechanical properties and attenuated proinflammatory cytokine expression.166 Using appropriate lung-opening pressure with an adequate lower inflection point in newborn piglets exposed to mechanical ventilation reduces the influx of activated leukocytes into the lungs.167 However, finding the appropriate opening pressures in adult humans is tricky168 and is impractical in neonates because it requires paralysis. This may explain why use of an “appropriate PEEP” was never implemented clinically or tested in trials despite observed benefits in infants.169 Studies that define empirical levels of PEEP that should be set in newborns have been sparse.170,171 However, several adult trials of high-PEEP versus low-PEEP strategies have been completed.172 In general, an empirical oxygen grid against varying PEEP levels was used to set PEEP, rather than pulmonary function tests. An individual patient meta-analysis revealed an overall reduction of the end point of days in hospital and days on respiratory support,173 which suggests that simply identifying and using ideal PEEP may reduce inflammatory changes in the preterm lung.


Macrolides have both antimicrobial and anti-inflammatory properties.174 Azithromycin decreased IL-6 expression and improved lung morphology and mortality rates in neonatal rats exposed to hyperoxia.175 Furthermore, azithromycin inhibited inflammatory stress–induced NF-κB activation in tracheal aspirate cells taken from premature infants.43 A pilot study that evaluated the safety and effectiveness of azithromycin in extremely low birth weight infants showed that the treatment group received fewer days of mechanical ventilation, but the study was underpowered to find a difference in the rate of BPD.176 A phase 2 study is currently underway to determine the effectiveness of this therapy in decreasing the incidence of BPD.177

NO and Its Role as an Anti-inflammatory Agent

Data from several large RCTs performed to determine if NO can prevent BPD in preterm infants are still being combined into a meta-analysis from individual patient data.178 However, the National Institutes of Health Consensus for Inhaled Nitric Oxide Therapy for Premature Infants mandates new trials before it can be considered a standard of care.179 Here we briefly discuss the anti-inflammatory properties of NO.180,181 Many of its anti-inflammatory properties are mediated through the inhibition of canonical, inflammatory stress–induced, and atypical, oxidant stress–induced NF-κB activation.44,182193 This is seen in healthy adult human subjects who have a higher endogenous NO production and associated NF-κB inhibition when compared with asthmatic subjects and those with pulmonary hypertension.194 To date, no data exist to answer whether NO affects NF-κB signaling in the preterm lung.


The role of antioxidants in preventing BPD was reviewed recently.195 The largest RCT evaluated intratracheal copper zinc superoxide dismutase to prevent BPD in infants who weighed <1200 g.196 This treatment did not alter the incidence of BPD, but treated infants had significantly better pulmonary outcomes at 1 year of age. Some have voiced a concern about the potential untoward effect of scavenging reactive oxygen species given their role in intracellular signaling in the developing lung, brain, and retina.197 The role of antioxidants for the prevention of BPD remains unclear.


Neonatologists and corticosteroids have had a long and unstable relationship.198201 Systemic glucocorticoids decrease inflammation and increase both surfactant synthesis and lung epithelial differentiation in the developing lung.202,203 Irrespective of the precise mechanism, corticosteroids seem to have some benefit in treating ventilator-dependent infants at high risk for BPD. Efficacy of postnatal dexamethasone for treating ventilator dependency in BPD was first shown in 1983.204 As postnatal corticosteroid use became routine, infants were treated prophylactically with longer courses and higher doses. This treatment practice dominated the 1990s. When Yeh et al205 showed an increased risk of cerebral palsy in infants exposed to corticosteroids early, practices abruptly changed. A meta-analysis of controlled trials revealed a relationship between early dexamethasone exposure and cerebral palsy.206 A major outcry ensued against steroids that limited their use, even for late disease.207,208 Unfortunately, no distinction was made between the early, indiscriminate use of steroids and late, targeted use of this therapy. The influential statements of the American Academy of Pediatrics made it virtually impermissible to use steroids,209 although there were occasional voices urging caution over the interpretation of the data.210,211 This climate sabotaged an RCT that was designed to address the impact of postnatal corticosteroids on the primary outcome of neurodevelopmental outcome, which was stopped early because of a lack of equipoise.212 Consequently, clinicians are left with broad confidence estimates for all efficacy or harm outcomes (Table 4).

Efficacy of Selected Treatments for the Prevention of BPD

The limited number of useful therapies available to prevent BPD, along with a decrease in steroid use, seemed to result in a rising incidence of BPD.212214 The recent meta-regression that demonstrated that corticosteroids will decrease the risk of poor neurodevelopmental outcome if an infant's baseline risk of developing BPD is >55%, along with recent updates of the Cochrane reviews, have affected our thinking.215217 They argue that the widespread use of steroids to prevent BPD is contraindicated but that therapy for ventilator dependency or early BPD is warranted.218 Thus, determining an infant's risk of developing BPD becomes even more clinically important. Simple lung mechanics are unlikely to be helpful.219 Although exhaled NO has been proposed as a marker of inflammation, whether it is a better predictor of BPD over simple clinical predictors (eg, birth weight) remains unclear.220 However, end-tidal carbon monoxide on day-of-life 14 does predict BPD well (OR: 15.17 [95% CI: 2.02–113.8]).221 Confirmation of this and other new predictive tools are needed.

Hence, the dexamethasone pendulum is beginning to swing back, as a recent statement from the American Academy of Pediatrics confirmed.222 Concerns about dexamethasone have led some investigators to evaluate the use of hydrocortisone for preventing BPD.223 A systematic review of available RCTs revealed no effect of hydrocortisone on preventing BPD.201 However, most trials have used very low doses of hydrocortisone, especially when compared with the doses of dexamethasone used to prevent BPD. Others have advocated even lower doses of dexamethasone.224 It remains eminently arguable that given the limited treatment options for the prevention of BPD, and its serious consequences,225,226 the use of glucocorticoids is appropriate for specific patients at high risk of developing BPD.203,227


The role of inflammation in the pathogenesis of BPD is firmly established. Unfortunately, clinicians have few therapeutic interventions for limiting inflammation and preventing BPD. Because the etiology of BPD is multifactorial, anti-inflammatory therapies may represent only part of the solution. Only by combining bench translational studies and rigorous trials will practice at the bedside result in limiting lung injury in the preterm infant.

Drs Wright and Kirpalani contributed substantially to the conception and design of the article, were involved in the drafting and revising of the article, and have given final approval of the version to be published.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Funded by the National Institutes of Health (NIH).


bronchopulmonary dysplasia
confidence interval
nuclear factor κB
nitric oxide
single-nucleotide polymorphism
tumor necrosis factor
odds ratio
relative risk
randomized controlled trial
mesenchymal stem cell
positive end-expiratory pressure


1. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84 [PubMed]
2. Stoll BJ, Hansen NI, Bell EF, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010;126(3):443–456 [PMC free article] [PubMed]
3. Greenough A. Long-term pulmonary outcome in the preterm infant. Neonatology. 2008;93(4):324–327 [PubMed]
4. Anderson PJ, Doyle LW. Neurodevelopmental outcome of bronchopulmonary dysplasia. Semin Perinatol. 2006;30(4):227–232 [PubMed]
5. Schmidt B, Roberts R, Millar D, Kirpalani H. Evidence-based neonatal drug therapy for prevention of bronchopulmonary dysplasia in very-low-birth-weight infants. Neonatology. 2008;93(4):284–287 [PubMed]
6. Wright J, Christman J. The role of nuclear factor κ B in the pathogenesis of pulmonary diseases: implications for therapy. Am J Respir Med. 2003;2(3):211–219 [PubMed]
7. Fok TF. Adjunctive pharmacotherapy in neonates with respiratory failure. Semin Fetal Neonatal Med. 2009;14(1):49–55 [PubMed]
8. Philip AG. Oxygen plus pressure plus time: the etiology of bronchopulmonary dysplasia. Pediatrics. 1975;55(1):44–50 [PubMed]
9. Speer CP. New insights into the pathogenesis of pulmonary inflammation in preterm infants. Biol Neonate. 2001;79(3–4):205–209 [PubMed]
10. Speer CP. Pulmonary inflammation and bronchopulmonary dysplasia. J Perinatol. 2006;26(suppl 1):S57–S62; discussion S63–S54 [PubMed]
11. Speer CP. Inflammation and bronchopulmonary dysplasia: a continuing story. Semin Fetal Neonatal Med. 2006;11(5):354–362 [PubMed]
12. Bhandari V, Gruen JR. The genetics of bronchopulmonary dysplasia. Semin Perinatol. 2006;30(4):185–191 [PubMed]
13. Ryan RM, Ahmed Q, Lakshminrusimha S. Inflammatory mediators in the immunobiology of bronchopulmonary dysplasia. Clin Rev Allergy Immunol. 2008;34(2):174–190 [PubMed]
14. Speer CP. Chorioamnionitis, postnatal factors and proinflammatory response in the pathogenetic sequence of bronchopulmonary dysplasia. Neonatology. 2009;95(4):353–361 [PubMed]
15. Hayes D, Jr, Feola DJ, Murphy BS, Shook LA, Ballard HO. Pathogenesis of bronchopulmonary dysplasia. Respiration. 2010;79(5):425–436 [PubMed]
16. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res. 1999;46(6):641–643 [PubMed]
17. Bose CL, Dammann CE, Laughon MM. Bronchopulmonary dysplasia and inflammatory biomarkers in the premature neonate. Arch Dis Child Fetal Neonatal Ed. 2008;93(6):F455–F461 [PubMed]
18. Bhandari A, Bhandari V. Pitfalls, problems, and progress in bronchopulmonary dysplasia. Pediatrics. 2009;123(6):1562–1573 [PubMed]
19. Paananen R, Husa AK, Vuolteenaho R, Herva R, Kaukola T, Hallman M. Blood cytokines during the perinatal period in very preterm infants: relationship of inflammatory response and bronchopulmonary dysplasia. J Pediatr. 2009;154(1):39–43.e33 [PubMed]
20. Ambalavanan N, Carlo WA, D'Angio CT, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Cytokines associated with bronchopulmonary dysplasia or death in extremely low birth weight infants. Pediatrics. 2009;123(4):1132–1141 [PMC free article] [PubMed]
21. Bose C, Laughon M, Allred EN, et al. ; Elgan Study Investigators Blood protein concentrations in the first two postnatal weeks that predict bronchopulmonary dysplasia among infants born before the 28th week of gestation. Pediatr Res. 2011;69(4):347–353 [PMC free article] [PubMed]
22. Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function. Nat Rev Mol Cell Biol. 2007;8(1):49–62 [PubMed]
23. Saugstad OD. Update on oxygen radical disease in neonatology. Curr Opin Obstet Gynecol. 2001;13(2):147–153 [PubMed]
24. Saugstad OD. Oxidative stress in the newborn: a 30-year perspective. Biol Neonate. 2005;88(3):228–236 [PubMed]
25. Saugstad OD. Hypoxanthine as an indicator of hypoxia: its role in health and disease through free radical production. Pediatr Res. 1988;23(2):143–150 [PubMed]
26. Hayden MS, Ghosh S. Shared principles in NF-κB signaling. Cell. 2008;132(3):344–362 [PubMed]
27. Hoffmann A, Natoli G, Ghosh G. Transcriptional regulation via the NF-κB signaling module. Oncogene. 2006;25(51):6706–6716 [PubMed]
28. Chen LF, Greene WC. Shaping the nuclear action of NF-κB. Nat Rev Mol Cell Biol. 2004;5(5):392–401 [PubMed]
29. Renner F, Schmitz ML. Autoregulatory feedback loops terminating the NF-κB response. Trends Biochem Sci. 2009;34(3):128–135 [PubMed]
30. Hoffmann A, Levchenko A, Scott ML, Baltimore D. The IκB-NF-κB signaling module: temporal control and selective gene activation. Science. 2002;298(5596):1241–1245 [PubMed]
31. Kilpinen S, Henttinen T, Lahdenpohja N, Hulkkonen J, Hurme M. Signals leading to the activation of NF-κ B transcription factor are stronger in neonatal than adult T lymphocytes. Scand J Immunol. 1996;44(1):85–88 [PubMed]
32. Vancurova I, Bellani P, Davidson D. Activation of nuclear factor-κB and its suppression by dexamethasone in polymorphonuclear leukocytes: newborn versus adult. Pediatr Res. 2001;49(2):257–262 [PubMed]
33. Wright CJ, Zhuang T, La P, Yang G, Dennery PA. Hyperoxia-induced NF-κB activation occurs via a maturationally sensitive atypical pathway. Am J Physiol Lung Cell Mol Physiol. 2009;296(3):L296–L306 [PubMed]
34. Yang G, Abate A, George AG, Weng YH, Dennery PA. Maturational differences in lung NF-κB activation and their role in tolerance to hyperoxia. J Clin Invest. 2004;114(5):669–678 [PMC free article] [PubMed]
35. Dieperink HI, Blackwell TS, Prince LS. Hyperoxia and apoptosis in developing mouse lung mesenchyme. Pediatr Res. 2006;59(2):185–190 [PubMed]
36. Benjamin JT, Carver BJ, Plosa EJ, et al. NF-κB activation limits airway branching through inhibition of Sp1-mediated fibroblast growth factor-10 expression. J Immunol. 2010;185(8):4896–4903 [PubMed]
37. Karin M, Lin A. NF-κB at the crossroads of life and death. Nat Immunol. 2002;3(3):221–227 [PubMed]
38. Bourbia A, Cruz MA, Rozycki HJ. NF-κB in tracheal lavage fluid from intubated premature infants: association with inflammation, oxygen, and outcome. Arch Dis Child Fetal Neonatal Ed. 2006;91(1):F36–F39 [PMC free article] [PubMed]
39. Cao L, Liu C, Cai B, et al. Nuclear factor-κ B expression in alveolar macrophages of mechanically ventilated neonates with respiratory distress syndrome. Biol Neonate. 2004;86(2):116–123 [PubMed]
40. Cheah FC, Winterbourn CC, Darlow BA, Mocatta TJ, Vissers MC. Nuclear factor κB activation in pulmonary leukocytes from infants with hyaline membrane disease: associations with chorioamnionitis and Ureaplasma urealyticum colonization. Pediatr Res. 2005;57(5 pt 1):616–623 [PubMed]
41. Haddad JJ, Land SC, Tarnow-Mordi WO, Zembala M, Kowalczyk D, Lauterbach R. Immunopharmacological potential of selective phosphodiesterase inhibition. II. Evidence for the involvement of an inhibitory-κB/nuclear factor-κB-sensitive pathway in alveolar epithelial cells. J Pharmacol Exp Ther. 2002;300(2):567–576 [PubMed]
42. Aghai Z, Kumar S, Farhath S, et al. Dexamethasone suppresses expression of nuclear factor-κB in the cells of tracheobronchial lavage fluid in premature neonates with respiratory distress. Pediatr Res. 2006;59(6):811–815 [PubMed]
43. Aghai ZH, Kode A, Saslow JG, et al. Azithromycin suppresses activation of nuclear factor-κ B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants. Pediatr Res. 2007;62(4):483–488 [PubMed]
44. Wright CJ, Agboke F, Chen F, La P, Yang G, Dennery PA. Nitric oxide inhibits hyperoxia-induced NF-κB activation in neonatal pulmonary microvascular endothelial cells. Pediatr Res. 2010;68(6):484–489 [PMC free article] [PubMed]
45. Bokodi G, Treszl A, Kovacs L, Tulassay T, Vasarhelyi B. Dysplasia: a review. Pediatr Pulmonol. 2007;42(10):952–961 [PubMed]
46. Lavoie PM, Dube MP. Genetics of bronchopulmonary dysplasia in the age of genomics. Curr Opin Pediatr. 2010;22(2):134–138 [PubMed]
47. Parton LA, Strassberg SS, Qian D, Galvin-Parton PA, Cristea IA. The genetic basis for bronchopulmonary dysplasia. Front Biosci. 2006;11:1854–1860 [PubMed]
48. Parker RA, Lindstrom DP, Cotton RB. Evidence from twin study implies possible genetic susceptibility to bronchopulmonary dysplasia. Semin Perinatol. 1996;20(3):206–209 [PubMed]
49. Bhandari V, Bizzarro MJ, Shetty A, et al. ; Neonatal Genetics Study Group Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics. 2006;117(6):1901–1906 [PubMed]
50. Lavoie PM, Pham C, Jang KL. Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the national institutes of health. Pediatrics. 2008;122(3):479–485 [PubMed]
51. Attia J, Ioannidis JP, Thakkinstian A, et al. How to use an article about genetic association. A: Background concepts. JAMA. 2009;301(1):74–81 [PubMed]
52. Attia J, Ioannidis JP, Thakkinstian A, et al. How to use an article about genetic association: B. Are the results of the study valid? JAMA. 2009;301(2):191–197 [PubMed]
53. Attia J, Ioannidis JP, Thakkinstian A, et al. How to use an article about genetic association: C. What are the results and will they help me in caring for my patients? JAMA. 2009;301(3):304–308 [PubMed]
54. Derzbach L, Bokodi G, Treszl A, Vasarhelyi B, Nobilis A, Rigo J., Jr Selectin polymorphisms and perinatal morbidity in low-birthweight infants. Acta Paediatr. 2006;95(10):1213–1217 [PubMed]
55. Härtel C, König I, Köster S, et al. Genetic polymorphisms of hemostasis genes and primary outcome of very low birth weight infants. Pediatrics. 2006;118(2):683–689 [PubMed]
56. Pavlovic J, Papagaroufalis C, Xanthou M, et al. Genetic variants of surfactant proteins A, B, C, and D in bronchopulmonary dysplasia. Dis Markers. 2006;22(5–6):277–291 [PMC free article] [PubMed]
57. Bokodi G, Derzbach L, Banyasz I, Tulassay T, Vasarhelyi B. Association of interferon gamma T+874A and interleukin 12 p40 promoter CTCTAA/GC polymorphism with the need for respiratory support and perinatal complications in low birthweight neonates. Arch Dis Child Fetal Neonatal Ed. 2007;92(1):F25–F29 [PMC free article] [PubMed]
58. Capoluongo E, Vento G, Rocchetti S, et al. Mannose-binding lectin polymorphisms and pulmonary outcome in premature neonates: a pilot study. Intensive Care Med. 2007;33(10):1787–1794 [PubMed]
59. Concolino P, Capoluongo E, Santonocito C, et al. Genetic analysis of the dystroglycan gene in bronchopulmonary dysplasia affected premature newborns. Clin Chim Acta. 2007;378(1–2):164–167 [PubMed]
60. Hilgendorff A, Heidinger K, Pfeiffer A, et al. Association of polymorphisms in the mannose-binding lectin gene and pulmonary morbidity in preterm infants. Genes Immun. 2007;8(8):671–677 [PubMed]
61. Strassberg SS, Cristea IA, Qian D, Parton LA. Single nucleotide polymorphisms of tumor necrosis factor-alpha and the susceptibility to bronchopulmonary dysplasia. Pediatr Pulmonol. 2007;42(1):29–36 [PubMed]
62. Bertalan R, Patocs A, Vasarhelyi B, et al. Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene. J Steroid Biochem Mol Biol. 2008;111(1–2):91–94 [PubMed]
63. Hadchouel A, Decobert F, Franco-Montoya ML, et al. Matrix metalloproteinase gene polymorphisms and bronchopulmonary dysplasia: identification of MMP16 as a new player in lung development. PLoS One. 2008;3(9):e3188. [PMC free article] [PubMed]
64. Karjalainen MK, Haataja R, Hallman M. Haplotype analysis of ABCA3: association with respiratory distress in very premature infants. Ann Med. 2008;40(1):56–65 [PubMed]
65. Kwinta P, Bik-Multanowski M, Mitkowska Z, Tomasik T, Legutko M, Pietrzyk JJ. Genetic risk factors of bronchopulmonary dysplasia. Pediatr Res. 2008;64(6):682–688 [PubMed]
66. Chauhan M, Bombell S, McGuire W. Tumour necrosis factor (−308A) polymorphism in very preterm infants with bronchopulmonary dysplasia: a meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):F257–F259 [PubMed]
67. Hilgendorff A, Heidinger K, Bohnert A, et al. Association of polymorphisms in the human surfactant protein-D (SFTPD) gene and postnatal pulmonary adaptation in the preterm infant. Acta Paediatr. 2009;98(1):112–117 [PubMed]
68. Ataç FB, Ince DA, Verdi H, et al. Lack of association between FXIII-Val34Leu, FVII-323 del/ins, and transforming growth factor beta1 (915G/T) gene polymorphisms and bronchopulmonary dysplasia: a single-center study. DNA Cell Biol. 2010;29(1):13–18 [PubMed]
69. Ince DA, Atac FB, Ozkiraz S, et al. The role of plasminogen activator inhibitor-1 and angiotensin-converting enzyme gene polymorphisms in bronchopulmonary dysplasia. Genet Test Mol Biomarkers. 2010;14(5):643–647 [PMC free article] [PubMed]
70. Koroglu OA, Onay H, Erdemir G, et al. Mannose-binding lectin gene polymorphism and early neonatal outcome in preterm infants. Neonatology. 2010;98(4):305–312 [PubMed]
71. Mailaparambil B, Krueger M, Heizmann U, Schlegel K, Heinze J, Heinzmann A. Genetic and epidemiological risk factors in the development of bronchopulmonary dysplasia. Dis Markers. 2010;29(1):1–9 [PMC free article] [PubMed]
72. Spiegler J, Gilhaus A, Konig IR, et al. Polymorphisms in the renin-angiotensin system and outcome of very-low-birthweight infants. Neonatology. 2010;97(1):10–14 [PubMed]
73. Viscardi RM. Ureaplasma species: role in diseases of prematurity. Clin Perinatol. 2010;37(2):393–409 [PMC free article] [PubMed]
74. Yoder BA, Coalson JJ, Winter VT, Siler-Khodr T, Duffy LB, Cassell GH. Effects of antenatal colonization with Ureaplasma urealyticum on pulmonary disease in the immature baboon. Pediatr Res. 2003;54(6):797–807 [PubMed]
75. Viscardi RM, Atamas SP, Luzina IG, et al. Antenatal Ureaplasma urealyticum respiratory tract infection stimulates proinflammatory, profibrotic responses in the preterm baboon lung. Pediatr Res. 2006;60(2):141–146 [PubMed]
76. Polglase GR, Hillman NH, Pillow JJ, et al. Ventilation-mediated injury after preterm delivery of Ureaplasma parvum colonized fetal lambs. Pediatr Res. 2010;67(6):630–635 [PubMed]
77. Polglase GR, Dalton RG, Nitsos I, et al. Pulmonary vascular and alveolar development in preterm lambs chronically colonized with Ureaplasma parvum. Am J Physiol Lung Cell Mol Physiol. 2010;299(2):L232–L241 [PubMed]
78. Novy MJ, Duffy L, Axthelm MK, et al. Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques. Reprod Sci. 2009;16(1):56–70 [PubMed]
79. Schelonka RL, Katz B, Waites KB, Benjamin DK., Jr Critical appraisal of the role of Ureaplasma in the development of bronchopulmonary dysplasia with metaanalytic techniques. Pediatr Infect Dis J. 2005;24(12):1033–1039 [PubMed]
80. Payne MS, Goss KC, Connett GJ, et al. Molecular microbiological characterization of preterm neonates at risk of bronchopulmonary dysplasia. Pediatr Res. 2010;67(4):412–418 [PubMed]
81. Colaizy TT, Morris CD, Lapidus J, Sklar RS, Pillers DA. Detection of ureaplasma DNA in endotracheal samples is associated with bronchopulmonary dysplasia after adjustment for multiple risk factors. Pediatr Res. 2007;61(5 pt 1):578–583 [PubMed]
82. Aaltonen R, Vahlberg T, Lehtonen L, Alanen A. Ureaplasma urealyticum: no independent role in the pathogenesis of bronchopulmonary dysplasia. Acta Obstet Gynecol Scand. 2006;85(11):1354–1359 [PubMed]
83. Goldenberg RL, Andrews WW, Goepfert AR, et al. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol. 2008;198(1):41–e45 [PMC free article] [PubMed]
84. Newton ER. Preterm labor, preterm premature rupture of membranes, and chorioamnionitis. Clin Perinatol. 2005;32(3):571–600 [PubMed]
85. Salafia CM, Vogel CA, Vintzileos AM, Bantham KF, Pezzullo J, Silberman L. Placental pathologic findings in preterm birth. Am J Obstet Gynecol. 1991;165(4 pt 1):934–938 [PubMed]
86. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics. 1996;97(2):210–215 [PubMed]
87. Elimian A, Verma U, Beneck D, Cipriano R, Visintainer P, Tejani N. Histologic chorioamnionitis, antenatal steroids, and perinatal outcomes. Obstet Gynecol. 2000;96(3):333–336 [PubMed]
88. Redline RW, Wilson-Costello D, Hack M. Placental and other perinatal risk factors for chronic lung disease in very low birth weight infants. Pediatr Res. 2002;52(5):713–719 [PubMed]
89. Kent A, Dahlstrom JE. Chorioamnionitis/funisitis and the development of bronchopulmonary dysplasia. J Paediatr Child Health. 2004;40(7):356–359 [PubMed]
90. Dempsey E, Chen MF, Kokottis T, Vallerand D, Usher R. Outcome of neonates less than 30 weeks gestation with histologic chorioamnionitis. Am J Perinatol. 2005;22(3):155–159 [PubMed]
91. Andrews WW, Goldenberg RL, Faye-Petersen O, Cliver S, Goepfert AR, Hauth JC. The Alabama Preterm Birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am J Obstet Gynecol. 2006;195(3):803–808 [PubMed]
92. Goldenberg RL, Andrews WW, Faye-Petersen OM, Cliver SP, Goepfert AR, Hauth JC. The Alabama preterm birth study: corticosteroids and neonatal outcomes in 23- to 32-week newborns with various markers of intrauterine infection. Am J Obstet Gynecol. 2006;195(4):1020–1024 [PubMed]
93. Richardson BS, Wakim E, daSilva O, Walton J. Preterm histologic chorioamnionitis: impact on cord gas and pH values and neonatal outcome. Am J Obstet Gynecol. 2006;195(5):1357–1365 [PubMed]
94. Kewitz G, Wudel S, Hopp H, Hopfenmuller W, Vogel M, Roots I. Below median birth weight in appropriate-for-gestational-age preterm infants as a risk factor for bronchopulmonary dysplasia. J Perinat Med. 2008;36(4):359–364 [PubMed]
95. Been JV, Zimmermann LJ. Histological chorioamnionitis and respiratory outcome in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(3):F218–F225 [PubMed]
96. Been JV, Rours IG, Kornelisse RF, et al. Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants. Am J Obstet Gynecol. 2009;201(6):587.e1–587.e8 [PubMed]
97. Kaukola T, Tuimala J, Herva R, Kingsmore S, Hallman M. Cord immunoproteins as predictors of respiratory outcome in preterm infants. Am J Obstet Gynecol. 2009;200(1):100.e1–100.e8 [PubMed]
98. Laughon M, Allred EN, Bose C, et al. ; ELGAN Study Investigators Patterns of respiratory disease during the first 2 postnatal weeks in extremely premature infants. Pediatrics. 2009;123(4):1124–1131 [PMC free article] [PubMed]
99. Prendergast M, May C, Broughton S, et al. Chorioamnionitis, lung function and bronchopulmonary dysplasia in prematurely born infants. Arch Dis Child Fetal Neonatal Ed. 2010; In press [PubMed]
100. Lee HJ, Kim EK, Kim HS, Choi CW, Kim BI, Choi JH. Chorioamnionitis, respiratory distress syndrome and bronchopulmonary dysplasia in extremely low birth weight infants. J Perinatol. 2011;31(3):166–170 [PubMed]
101. Lahra MM, Beeby PJ, Jeffery HE. Intrauterine inflammation, neonatal sepsis, and chronic lung disease: a 13-year hospital cohort study. Pediatrics. 2009;123(5):1314–1319 [PubMed]
102. Cheah FC, Pillow JJ, Kramer BW, et al. Airway inflammatory cell responses to intra-amniotic lipopolysaccharide in a sheep model of chorioamnionitis. Am J Physiol Lung Cell Mol Physiol. 2009;296(3):L384–L393 [PubMed]
103. Prince LS, Okoh VO, Moninger TO, Matalon S. Lipopolysaccharide increases alveolar type II cell number in fetal mouse lungs through Toll-like receptor 4 and NF-κB. Am J Physiol Lung Cell Mol Physiol. 2004;287(5):L999–L1006 [PubMed]
104. Jung HS, Yoon BH, Jun JK, Kim M, Kim YA, Kim CJ. Differential activation of mitogen activated protein kinases and nuclear factor-κB in lipopolysaccharide-treated term and preterm amnion cells. Virchows Arch. 2005;447(1):45–52 [PubMed]
105. Kramer BW, Kaemmerer U, Kapp M, et al. Decreased expression of angiogenic factors in placentas with chorioamnionitis after preterm birth. Pediatr Res. 2005;58(3):607–612 [PubMed]
106. Goldstein B, Giroir B, Randolph A. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6(1):2–8 [PubMed]
107. Hofer N, Muller W, Resch B. Systemic inflammatory response syndrome (SIRS) definition and correlation with early-onset bacterial infection of the newborn. Arch Dis Child Fetal Neonatal Ed. 2010;95(2):F151. [PubMed]
108. Stoll BJ, Hansen N, Fanaroff AA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. N Engl J Med. 2002;347(4):240–247 [PubMed]
109. Klinger G, Levy I, Sirota L, Boyko V, Lerner-Geva L, Reichman B.; Israel Neonatal Network Outcome of early-onset sepsis in a national cohort of very low birth weight infants. Pediatrics. 2010;125(4). Available at: [PubMed]
110. Fanaroff AA, Korones SB, Wright LL, et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network. Pediatr Infect Dis J. 1998;17(7):593–598 [PubMed]
111. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110(2 pt 1):285–291 [PubMed]
112. Bhandari V. Hyperoxia-derived lung damage in preterm infants. Semin Fetal Neonatal Med. 2010;15(4):223–229 [PMC free article] [PubMed]
113. Didrik Saugstad O. Oxygen and oxidative stress in bronchopulmonary dysplasia. J Perinat Med. 2010;38(6):571–577 [PubMed]
114. Vento M, Moro M, Escrig R, et al. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease. Pediatrics. 2009;124(3). Available at: [PubMed]
115. Saugstad OD, Aune D. In search of the optimal oxygen saturation for extremely low birth weight infants: a systematic review and meta-analysis. Neonatology. 2010;100(1):1–8 [PubMed]
116. Carlo WA, Finer NN, Walsh MC, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362(21):1959–1969 [PMC free article] [PubMed]
117. BOOSTII: Benefits of Oxygen Saturation Targeting. Available at: Accessed February 22, 2011
118. Canadian Oxygen Trial (COT). Available at: Accessed February 22, 2011
119. Tschumperlin DJ, Boudreault F, Liu F. Recent advances and new opportunities in lung mechanobiology. J Biomech. 2010;43(1):99–107 [PMC free article] [PubMed]
120. Sanchez-Esteban J, Wang Y, Gruppuso PA, Rubin LP. Mechanical stretch induces fetal type II cell differentiation via an epidermal growth factor receptor-extracellular-regulated protein kinase signaling pathway. Am J Respir Cell Mol Biol. 2004;30(1):76–83 [PubMed]
121. Kumar A, Lnu S, Malya R, et al. Mechanical stretch activates nuclear factor-κB, activator protein-1, and mitogen-activated protein kinases in lung parenchyma: implications in asthma. FASEB J. 2003;17(13):1800–1811 [PubMed]
122. Wang Y, Maciejewski BS, Lee N, et al. Strain-induced fetal type II epithelial cell differentiation is mediated via cAMP-PKA-dependent signaling pathway. Am J Physiol Lung Cell Mol Physiol. 2006;291(4):L820–L827 [PubMed]
123. Copland IB, Reynaud D, Pace-Asciak C, Post M. Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2006;291(3):L487–L495 [PubMed]
124. Copland IB, Post M. Stretch-activated signaling pathways responsible for early response gene expression in fetal lung epithelial cells. J Cell Physiol. 2007;210(1):133–143 [PubMed]
125. Wang Y, Maciejewski BS, Drouillard D, et al. A role for caveolin-1 in mechanotransduction of fetal type II epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2010;298(6):L775–L783 [PubMed]
126. Hillman NH, Moss TJ, Kallapur SG, et al. Brief, large tidal volume ventilation initiates lung injury and a systemic response in fetal sheep. Am J Respir Crit Care Med. 2007;176(6):575–581 [PMC free article] [PubMed]
127. Kornecki A, Tsuchida S, Ondiveeran HK, et al. Lung development and susceptibility to ventilator-induced lung injury. Am J Respir Crit Care Med. 2005;171(7):743–752 [PubMed]
128. Copland IB, Martinez F, Kavanagh BP, et al. High tidal volume ventilation causes different inflammatory responses in newborn versus adult lung. Am J Respir Crit Care Med. 2004;169(6):739–748 [PubMed]
129. Liu YY, Liao SK, Huang CC, Tsai YH, Quinn DA, Li LF. Role for nuclear factor-κB in augmented lung injury because of interaction between hyperoxia and high stretch ventilation. Transl Res. 2009;154(5):228–240 [PubMed]
130. Held HD, Boettcher S, Hamann L, Uhlig S. Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-κB and is blocked by steroids. Am J Respir Crit Care Med. 2001;163(3 pt 1):711–716 [PubMed]
131. Wallace MJ, Probyn ME, Zahra VA, et al. Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs. Respir Res. 2009;10:19. [PMC free article] [PubMed]
132. Reyburn B, Li M, Metcalfe DB, et al. Nasal ventilation alters mesenchymal cell turnover and improves alveolarization in preterm lambs. Am J Respir Crit Care Med. 2008;178(4):407–418 [PMC free article] [PubMed]
133. Marshall JC. Clinical trials of mediator-directed therapy in sepsis: what have we learned? Intensive Care Med. 2000;26(suppl 1):S75–S83 [PubMed]
134. Rice TW, Wheeler AP, Morris PE, et al. Safety and efficacy of affinity-purified, anti-tumor necrosis factor-alpha, ovine Fab for injection (CytoFab) in severe sepsis. Crit Care Med. 2006;34(9):2271–2281 [PubMed]
135. Eichacker PQ, Parent C, Kalil A, et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med. 2002;166(9):1197–1205 [PubMed]
136. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699–709 [PubMed]
137. Marti-Carvajal A, Salanti G, Cardona AF. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev. 2008;(1):CD004388. [PubMed]
138. Kylat RI, Ohlsson A. Recombinant human activated protein C for severe sepsis in neonates. Cochrane Database Syst Rev. 2006;(2):CD005385. [PubMed]
139. Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007;369(9564):836–843 [PubMed]
140. Minneci PC, Deans KJ, Eichacker PQ, Natanson C. The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis. Clin Microbiol Infect. 2009;15(4):308–318 [PMC free article] [PubMed]
141. Lee JW, Gupta N, Serikov V, Matthay MA. Potential application of mesenchymal stem cells in acute lung injury. Expert Opin Biol Ther. 2009;9(10):1259–1270 [PMC free article] [PubMed]
142. van Haaften T, Thebaud B. Adult bone marrow-derived stem cells for the lung: implications for pediatric lung diseases. Pediatr Res. 2006;59(4 pt 2):94R–99R [PubMed]
143. Abman SH, Matthay MA. Mesenchymal stem cells for the prevention of bronchopulmonary dysplasia: delivering the secretome. Am J Respir Crit Care Med. 2009;180(11):1039–1041 [PubMed]
144. Pierro M, Thebaud B. Mesenchymal stem cells in chronic lung disease: culprit or savior? Am J Physiol Lung Cell Mol Physiol. 2010;298(6):L732–L734 [PubMed]
145. Kassmer SH, Krause DS. Detection of bone marrow-derived lung epithelial cells. Exp Hematol. 2010;38(7):564–573 [PMC free article] [PubMed]
146. Matthay MA, Thompson BT, Read EJ, et al. Therapeutic potential of mesenchymal stem cells for severe acute lung injury. Chest. 2010;138(4):965–972 [PubMed]
147. Chang YS, Oh W, Choi SJ, et al. Human umbilical cord blood-derived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats. Cell Transplant. 2009;18(8):869–886 [PubMed]
148. van Haaften T, Byrne R, Bonnet S, et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med. 2009;180(11):1131–1142 [PMC free article] [PubMed]
149. Aslam M, Baveja R, Liang OD, et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med. 2009;180(11):1122–1130 [PMC free article] [PubMed]
150. Balasubramaniam V, Ryan SL, Seedorf GJ, et al. Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice. Am J Physiol Lung Cell Mol Physiol. 2010;298(3):L315–L323 [PubMed]
151. Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med. 2006;32(1):24–33 [PubMed]
152. Attar MA, Donn SM. Mechanisms of ventilator-induced lung injury in premature infants. Semin Neonatol. 2002;7(5):353–360 [PubMed]
153. Sweet DG, Carnielli V, Greisen G, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants: 2010 update. Neonatology. 2010;97(4):402–417 [PubMed]
154. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008;358(7):700–708 [PubMed]
155. Finer NN, Carlo WA, Walsh MC, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010;362(21):1970–1979 [PMC free article] [PubMed]
156. Dunn M, Kaempf J, de Klerk A, et al. Delivery room management of preterm infants at risk for respiratory distress syndrome (RDS). EPAS2010;1670.2
157. Stevens TP, Harrington EW, Blennow M, Soll RF. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev. 2007;(4):CD003063. [PubMed]
158. Rojas MA, Lozano JM, Rojas MX, et al. ; Colombian Neonatal Research Network Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics. 2009;123(1):137–142 [PubMed]
159. Lemyre B, Davis PG, de Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity. Cochrane Database Syst Rev. 2002;(1):CD002272. [PubMed]
160. Nasal Intermittent Positive Pressure Ventilation in Premature Infants (NIPPV). Available at: Accessed March 2, 2011
161. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301–1308 [PubMed]
162. Lista G, Castoldi F, Bianchi S, Battaglioli M, Cavigioli F, Bosoni MA. Volume guarantee versus high-frequency ventilation: lung inflammation in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2008;93(4):F252–F256 [PubMed]
163. Wheeler K, Klingenberg C, McCallion N, Morley CJ, Davis PG. Volume-targeted versus pressure-limited ventilation in the neonate. Cochrane Database Syst Rev. 2010;(11):CD003666. [PubMed]
164. Gattinoni L, Pelosi P, Crotti S, Valenza F. Effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome. Am J Respir Crit Care Med. 1995;151(6):1807–1814 [PubMed]
165. Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med. 1994;149(5):1327–1334 [PubMed]
166. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest. 1997;99(5):944–952 [PMC free article] [PubMed]
167. Monkman SL, Andersen CC, Nahmias C, et al. Positive end-expiratory pressure above lower inflection point minimizes influx of activated neutrophils into lung. Crit Care Med. 2004;32(12):2471–2475 [PubMed]
168. Mehta S, Stewart TE, MacDonald R, et al. Temporal change, reproducibility, and interobserver variability in pressure-volume curves in adults with acute lung injury and acute respiratory distress syndrome. Crit Care Med. 2003;31(8):2118–2125 [PubMed]
169. Mathe JC, Clement A, Chevalier JY, Gaultier C, Costil J. Use of total inspiratory pressure-volume curves for determination of appropriate positive end-expiratory pressure in newborns with hyaline membrane disease. Intensive Care Med. 1987;13(5):332–336 [PubMed]
170. Castoldi F, Daniele I, Fontana P, Cavigioli F, Lupo E, Lista G. Lung recruitment maneuver during volume guarantee ventilation of preterm infants with acute respiratory distress syndrome. Am J Perinatol. 2011; In press [PubMed]
171. De Jaegere A, van Veenendaal MB, Michiels A, van Kaam AH. Lung recruitment using oxygenation during open lung high-frequency ventilation in preterm infants. Am J Respir Crit Care Med. 2006;174(6):639–645 [PubMed]
172. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006;354(17):1775–1786 [PubMed]
173. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303(9):865–873 [PubMed]
174. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med. 2004;117(suppl 9A):5S–11S [PubMed]
175. Ballard HO, Bernard P, Qualls J, Everson W, Shook LA. Azithromycin protects against hyperoxic lung injury in neonatal rats. J Investig Med. 2007;55(6):299–305 [PubMed]
176. Ballard HO, Anstead MI, Shook LA. Azithromycin in the extremely low birth weight infant for the prevention of bronchopulmonary dysplasia: a pilot study. Respir Res. 2007;8:41. [PMC free article] [PubMed]
177. Trial II of Lung Protection With Azithromycin in the Preterm Infant. Available at: Accessed May 19, 2011
178. Askie LM, Ballard RA, Cutter G, et al. Inhaled Nitric Oxide in preterm infants: a systematic review and individual patient data meta-analysis. BMC Pediatr. 2010;10:15. [PMC free article] [PubMed]
179. Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference Statement: inhaled nitric-oxide therapy for premature infants. Pediatrics. 2011;127(2):363–369 [PubMed]
180. Arul N, Konduri GG. Inhaled nitric oxide for preterm neonates. Clin Perinatol. 2009;36(1):43–61 [PubMed]
181. Cirino G, Distrutti E, Wallace JL. Nitric oxide and inflammation. Inflamm Allergy Drug Targets. 2006;5(2):115–119 [PubMed]
182. Reynaert N, Ckless K, Korn S, et al. Nitric oxide represses inhibitory κB kinase through S-nitrosylation. Proc Natl Acad Sci U S A. 2004;101(24):8945–8950 [PubMed]
183. Matthews J, Botting C, Panico M, Morris H, Hay R. Inhibition of NF-κB DNA binding by nitric oxide. Nucleic Acids Res. 1996;24(12):2236–2242 [PMC free article] [PubMed]
184. Kelleher ZT, Matsumoto A, Stamler JS, Marshall HE. NOS2 regulation of NF-κB by S-nitrosylation of p65. J Biol Chem. 2007;282(42):30667–30672 [PubMed]
185. Marshall H, Stamler J. Inhibition of NF-κ B by S-nitrosylation. Biochemistry. 2001;40(6):1688–1693 [PubMed]
186. Ckless K, van der Vliet A, Janssen-Heininger Y. Oxidative-nitrosative stress and post-translational protein modifications: implications to lung structure-function relations—arginase modulates NF-κB activity via a nitric oxide-dependent mechanism. Am J Respir Cell Mol Biol. 2007;36(6):645–653 [PMC free article] [PubMed]
187. Janssen-Heininger Y, Poynter M, Baeuerle P. Recent advances towards understanding redox mechanisms in the activation of nuclear factor κB. Free Radic Biol Med. 2000;28(9):1317–1327 [PubMed]
188. Spiecker M, Peng H, Liao J. Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IκBalpha. J Biol Chem. 1997;272(49):30969–30974 [PubMed]
189. Levrand S, Pesse B, Feihl F, et al. Peroxynitrite is a potent inhibitor of NF-{κ}B activation triggered by inflammatory stimuli in cardiac and endothelial cell lines. J Biol Chem. 2005;280(41):34878–34887 [PMC free article] [PubMed]
190. Yakovlev V, Barani I, Rabender C, et al. Tyrosine nitration of IκBalpha: a novel mechanism for NF-κB activation. Biochemistry. 2007;46(42):11671–11683 [PMC free article] [PubMed]
191. Peng HB, Libby P, Liao JK. Induction and stabilization of I κ B alpha by nitric oxide mediates inhibition of NF-κ B. J Biol Chem. 1995;270(23):14214–14219 [PubMed]
192. Franek W, Chowdary Y, Lin X, et al. Suppression of nuclear factor-κ B activity by nitric oxide and hyperoxia in oxygen-resistant cells. J Biol Chem. 2002;277(45):42694–42700 [PubMed]
193. Howlett CE, Hutchison JS, Veinot JP, Chiu A, Merchant P, Fliss H. Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs. Am J Physiol. 1999;277(3 pt 1):L596–L605 [PubMed]
194. Raychaudhuri B, Dweik R, Connors MJ, et al. Nitric oxide blocks nuclear factor-κB activation in alveolar macrophages. Am J Respir Cell Mol Biol. 1999;21(3):311–316 [PubMed]
195. Davis JM, Auten RL. Maturation of the antioxidant system and the effects on preterm birth. Semin Fetal Neonatal Med. 2010;15(4):191–195 [PubMed]
196. Davis JM, Parad RB, Michele T, Allred E, Price A, Rosenfeld W.; North American Recombinant Human CuZnSOD Study Group Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics. 2003;111(3):469–476 [PubMed]
197. Jankov RP, Negus A, Tanswell AK. Antioxidants as therapy in the newborn: some words of caution. Pediatr Res. 2001;50(6):681–687 [PubMed]
198. Jobe AH. Postnatal corticosteroids for bronchopulmonary dysplasia. Clin Perinatol. 2009;36(1):177–188 [PMC free article] [PubMed]
199. Doyle LW, Ehrenkranz RA, Halliday HL. Dexamethasone treatment after the first week of life for bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology. 2010;98(4):289–296 [PubMed]
200. Doyle LW, Ehrenkranz RA, Halliday HL. Dexamethasone treatment in the first week of life for preventing bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology. 2010;98(3):217–224 [PubMed]
201. Doyle LW, Ehrenkranz RA, Halliday HL. Postnatal hydrocortisone for preventing or treating bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology. 2010;98(2):111–117 [PubMed]
202. Bancalari E. Corticosteroids and neonatal chronic lung disease. Eur J Pediatr. 1998;157(suppl 1):S31–S37 [PubMed]
203. Laughon MM, Smith PB, Bose C. Prevention of bronchopulmonary dysplasia. Semin Fetal Neonatal Med. 2009;14(6):374–382 [PMC free article] [PubMed]
204. Mammel MC, Green TP, Johnson DE, Thompson TR. Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia. Lancet. 1983;1(8338):1356–1358 [PubMed]
205. Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics. 1998;101(5). Available at: [PubMed]
206. Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr. 2001;1:1. [PMC free article] [PubMed]
207. Barrington KJ. Postnatal steroids and neurodevelopmental outcomes: a problem in the making. Pediatrics. 2001;107(6):1425–1426 [PubMed]
208. Jobe AH. Glucocorticoids in perinatal medicine: misguided rockets? J Pediatr. 2000;137(1):1–3 [PubMed]
209. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics. 2002;109(2):330–338 [PubMed]
210. Taylor C, Shah PS, Dunn MS. Meta-analysis of postnatal steroid use challenged. Pediatrics. 2002;109(4):716–717; author reply 716–717 [PubMed]
211. Jacobs HC, Chapman RL, Gross I. Premature conclusions on postnatal steroid effects. Pediatrics. 2002;110(1 pt 1):200–201; author reply 200–201 [PubMed]
212. Shinwell ES, Lerner-Geva L, Lusky A, Reichman B. Less postnatal steroids, more bronchopulmonary dysplasia: a population-based study in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2007;92(1):F30–F33 [PMC free article] [PubMed]
213. Yoder BA, Harrison M, Clark RH. Time-related changes in steroid use and bronchopulmonary dysplasia in preterm infants. Pediatrics. 2009;124(2):673–679 [PubMed]
214. Kobaly K, Schluchter M, Minich N, et al. Outcomes of extremely low birth weight (<1 kg) and extremely low gestational age (<28 weeks) infants with bronchopulmonary dysplasia: effects of practice changes in 2000 to 2003. Pediatrics. 2008;121(1):73–81 [PubMed]
215. Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2010;(1):CD001146. [PubMed]
216. Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics. 2005;115(3):655–661 [PubMed]
217. Halliday HL, Ehrenkranz RA, Doyle LW. Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2009;(1):CD001145. [PubMed]
218. Halliday HL. Postnatal steroids: the way forward. Arch Dis Child Fetal Neonatal Ed. 2011;96(3):F158–F159 [PubMed]
219. Kirpalani H, Schmidt B, Gaston S, Santos R, Wilkie R. Birthweight, early passive respiratory system mechanics, and ventilator requirements as predictors of outcome in premature infants with respiratory failure. Pediatr Pulmonol. 1991;10(3):195–198 [PubMed]
220. May C, Williams O, Milner AD, et al. Relation of exhaled nitric oxide levels to development of bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed. 2009;94(3):F205–F209 [PubMed]
221. May C, Patel S, Kennedy C, et al. Prediction of bronchopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed. 2011; In press [PubMed]
222. Watterberg KL.; American Academy of Pediatrics, Committee on Fetus and Newborn Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics. 2010;126(4):800–808 [PubMed]
223. Rademaker KJ, de Vries LS, Uiterwaal CS, Groenendaal F, Grobbee DE, van Bel F. Postnatal hydrocortisone treatment for chronic lung disease in the preterm newborn and long-term neurodevelopmental follow-up. Arch Dis Child Fetal Neonatal Ed. 2008;93(1):F58–F63 [PubMed]
224. Yates HL, Newell SJ. Minidex: very low dose dexamethasone (0.05 mg/kg per day) in chronic lung disease. Arch Dis Child Fetal Neonatal Ed. 2011;96(3):F190–F194 [PubMed]
225. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003;289(9):1124–1129 [PubMed]
226. Walsh MC, Morris BH, Wrage LA, et al. Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes. J Pediatr. 2005;146(6):798–804 [PubMed]
227. Eichenwald EC, Stark AR. Are postnatal steroids ever justified to treat severe bronchopulmonary dysplasia? Arch Dis Child Fetal Neonatal Ed. 2007;92(5):F334–F337 [PMC free article] [PubMed]
228. Kunsch C, Rosen CA. NF-κ B subunit-specific regulation of the interleukin-8 promoter. Mol Cell Biol. 1993;13(10):6137–6146 [PMC free article] [PubMed]
229. Auten RL, Jr, Mason SN, Tanaka DT, Welty-Wolf K, Whorton MH. Anti-neutrophil chemokine preserves alveolar development in hyperoxia-exposed newborn rats. Am J Physiol Lung Cell Mol Physiol. 2001;281(2):L336–L344 [PubMed]
230. De Dooy J, Ieven M, Stevens W, De Clerck L, Mahieu L. High levels of CXCL8 in tracheal aspirate samples taken at birth are associated with adverse respiratory outcome only in preterm infants younger than 28 weeks gestation. Pediatr Pulmonol. 2007;42(3):193–203 [PubMed]
231. Baier RJ, Loggins J, Kruger TE. Monocyte chemoattractant protein-1 and interleukin-8 are increased in bronchopulmonary dysplasia: relation to isolation of Ureaplasma urealyticum. J Investig Med. 2001;49(4):362–369 [PubMed]
232. Hiscott J, Marois J, Garoufalis J, et al. Characterization of a functional NF-κ B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol Cell Biol. 1993;13(10):6231–6240 [PMC free article] [PubMed]
233. Johnson BH, Yi M, Masood A, et al. A critical role for the IL-1 receptor in lung injury induced in neonatal rats by 60% O2. Pediatr Res. 2009;66(3):260–265 [PubMed]
234. Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-κ B transcription factor. Mol Cell Biol. 1990;10(5):2327–2334 [PMC free article] [PubMed]
235. Choo-Wing R, Nedrelow JH, Homer RJ, Elias JA, Bhandari V. Developmental differences in the responses of IL-6 and IL-13 transgenic mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol. 2007;293(1):L142–L150 [PubMed]
236. Choi CW, Kim BI, Kim HS, Park JD, Choi JH, Son DW. Increase of interleukin-6 in tracheal aspirate at birth: a predictor of subsequent bronchopulmonary dysplasia in preterm infants. Acta Paediatr. 2006;95(1):38–43 [PubMed]
237. von Bismarck P, Claass A, Schickor C, Krause MF, Rose-John S. Altered pulmonary interleukin-6 signaling in preterm infants developing bronchopulmonary dysplasia. Exp Lung Res. 2008;34(10):694–706 [PubMed]
238. Chetty A, Cao GJ, Severgnini M, Simon A, Warburton R, Nielsen HC. Role of matrix metalloprotease-9 in hyperoxic injury in developing lung. Am J Physiol Lung Cell Mol Physiol. 2008;295(4):L584–L592 [PubMed]
239. Ekekezie II, Thibeault DW, Simon SD, Norberg M, Merrill JD, Ballard RA, et al. Low levels of tissue inhibitors of metalloproteinases with a high matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio are present in tracheal aspirate fluids of infants who develop chronic lung disease. Pediatrics. 2004;113(6):1709–1714 [PubMed]
240. Teferedegne B, Green MR, Guo Z, Boss JM. Mechanism of action of a distal NF-κB-dependent enhancer. Mol Cell Biol. 2006;26(15):5759–5770 [PMC free article] [PubMed]
241. Vozzelli MA, Mason SN, Whorton MH, Auten RL., Jr Antimacrophage chemokine treatment prevents neutrophil and macrophage influx in hyperoxia-exposed newborn rat lung. Am J Physiol Lung Cell Mol Physiol. 2004;286(3):L488–L493 [PubMed]
242. Baier RJ, Majid A, Parupia H, Loggins J, Kruger TE. CC chemokine concentrations increase in respiratory distress syndrome and correlate with development of bronchopulmonary dysplasia. Pediatr Pulmonol. 2004;37(2):137–148 [PubMed]
243. Johnston CJ, Mango GW, Finkelstein JN, Stripp BR. Altered pulmonary response to hyperoxia in Clara cell secretory protein deficient mice. Am J Respir Cell Mol Biol. 1997;17(2):147–155 [PubMed]
244. Ramsay PL, DeMayo FJ, Hegemier SE, Wearden ME, Smith CV, Welty SE. Clara cell secretory protein oxidation and expression in premature infants who develop bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;164(1):155–161 [PubMed]
245. Levine CR, Gewolb IH, Allen K, et al. The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res. 2005;58(1):15–21 [PubMed]
246. Kevill KA, Bhandari V, Kettunen M, et al. A role for macrophage migration inhibitory factor in the neonatal respiratory distress syndrome. J Immunol. 2008;180(1):601–608 [PubMed]
247. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354(20):2112–2121 [PubMed]
248. Tyson JE, Wright LL, Oh W, et al. Vitamin A supplementation for extremely low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1999;340(25):1962–1968 [PubMed]

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