Lung (2008) 186:75–89
DOI 10.1007/s00408-007-9069-z
STATE OF THE ART REVIEW
Prevention and Treatment of Bronchopulmonary Dysplasia:
Contemporary Status and Future Outlook
Laura Cerny Æ John S. Torday Æ Virender K. Rehan
Received: 17 December 2007 / Accepted: 27 December 2007 / Published online: 30 January 2008
Ó Springer Science+Business Media, LLC 2008
Abstract Despite tremendous advances in neonatology,
bronchopulmonary dysplasia (BPD) remains a major cause
of morbidity and mortality among premature infants. Any
intervention that would reduce the risk of BPD or improve
its outcome is likely to have substantial clinical and
financial benefits. However, there is a clear lack of an
effective agent for the treatment and/or prevention of BPD.
This is due to an incomplete understanding of the molecular mechanisms involved in its pathogenesis. Taking a
basic biological approach, our laboratory has discovered
that disruption of normal alveolar homeostatic signaling is
centrally involved in this process. Using a number of in
vitro and in vivo models, our laboratory has demonstrated
that stabilization of the normal alveolar homeostatic signaling pathway(s) can prevent and/or rescue the molecular
injuries caused by the insults that lead to BPD. Here, we
review the existing approaches to prevent and treat BPD
L. Cerny
Harbor-UCLA-CHOC Neonatal Perinatal Fellowship Program,
Los Angeles Biomedical Research Institute at Harbor UCLA
Medical Center, Torrance, California 90502, USA
J. S. Torday
Departments of Pediatrics and Obstetrics and Gynecology, Los
Angeles Biomedical Research Institute at Harbor UCLA Medical
Center, Torrance, California 90502, USA
V. K. Rehan
Department of Pediatrics and Neonatal Intensive Care Unit, Los
Angeles Biomedical Research Institute at Harbor UCLA Medical
Center, Torrance, California 90502, USA
V. K. Rehan (&)
Department of Pediatrics, Los Angeles Biomedical Research
Institute at Harbor UCLA Medical Center, 1124 West Carson
Street, Torrance, CA 90502, USA
e-mail: vrehan@labiomed.org
and then, based on our insights into the pathogenesis of
BPD, we propose novel and innovative therapeutic options
that impact the disease on a cell/molecular level, unlike
most of the current treatments available for BPD.
Keywords Bronchopulmonary dysplasia
Chronic lung disease Hyperoxia Inhaled nitric oxide
Parathyroid hormone-related protein
Peroxisome proliferator-activated receptor c Prematurity
Surfactant Volutrauma
Abbreviations
ADRP
Adipocyte differentiation-related protein
ATII
Alveolar type II
BPD
Bronchopulmonary dysplasia
CC10
Clara cell 10-kDa protein
CLD
Chronic lung disease
FDA
Food and Drug Administration
GA
Gestational age
iNO
Inhaled nitric oxide
IVH
Intraventricular hemorrhage
NCPAP
Nasal continuous positive airway pressure
NEC
Necrotizing enterocolitis
PaCO2
Arterial partial pressure of carbon dioxide
PDA
Patent ductus arteriosus
PTHrP
Parathyroid hormone-related protein
PVH
Periventricular hemorrhage
PVL
Periventricular leukomalacia
PPARc
Peroxisome proliferator-activated receptor c
ROP
Retinopathy of prematurity
RDS
Respiratory distress syndrome
RGZ
Rosiglitazone
SNIPPV
Synchronized nasal intermittent positive
pressure ventilation
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SIMV
TA
VLBWI
Wingless/
int
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Synchronized intermittent mechanical
ventilation
Tracheal aspirate
Very-low-birth-weight Infant
Wnt
Introduction
Bronchopulmonary dysplasia (BPD) is a chronic pulmonary disorder that is the consequence of abnormally repaired
lung damage due to premature birth and lung immaturity.
The clinical definition of BPD established by the National
Institute of Child Health and Human Development Workshop on BPD in 2001 stratifies the definition based upon
gestational age (GA) at birth. Infants born at less than
32 weeks postmenstrual age (PMA) are classified as having
mild BPD if they require oxygen for the first 28 days, but
are in room air at 36 weeks PMA or time of discharge;
moderate BPD if they require oxygen for the first 28 days
and need less than 30% oxygen at 36 weeks PMA or time
of discharge; and severe BPD if they require oxygen for the
first 28 days and are still requiring 30% or more oxygen
and/or continuous positive airway pressure or mechanical
ventilation at 36 weeks PMA or discharge. For infants born
32 weeks or more PMA, the categories of mild, moderate,
and severe are defined the same; however, the time to
evaluate the oxygen status is 56 days postnatal age or
discharge, rather than 36 weeks. Of note, a physiologic test
such as pulse oximetry should be performed to truly assess
the need of oxygen because there is much variation in
oxygen treatment practices. Furthermore, for a child to be
classified as having BPD, he or she should display persistence of common clinical features of respiratory distress
syndrome [1].
Despite tremendous advances in neonatal care in general, and neonatal respiratory care in particular, BPD still
remains a major cause of morbidity and mortality among
premature infants [2]. Although these medical advances
may have decreased the severity of BPD, its incidence has
not decreased, and may in fact have actually increased [1,
3]. The incidence of BPD increases with decreasing birth
weight and currently affects approximately 30% of infants
with birth weights less than 1000 g [2]. Affected infants
have both short- and long-term clinical issues, including,
but not limited to, a complicated initial neonatal intensive
care course, poor growth, neurodevelopmental delays, and
repeated hospitalizations during the first few years of life
[4–6]. Therefore, any intervention that would reduce the
risk of BPD or improve its outcome is likely to have
substantial clinical and financial benefits. Despite this,
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there is a clear lack of an effective agent for the treatment
and/or prevention of BPD.
‘‘Old’’ versus ‘‘New’’ BPD
In the 1960s, when Northway described BPD, he described
it as a chronic lung disease (CLD) of relatively larger
preterm infants who required ventilation with high pressures and oxygen for prolonged periods of time [7]. It was
characterized by four well-defined clinical, radiologic, and
histopathologic findings. The hallmarks of the now socalled ‘‘old BPD’’ were severe large airway injury, interstitial and alveolar edema, and extensive small airway
disease with alternating areas of overinflation and fibrosis.
With the introduction of antenatal steroids, routine surfactant replacement for respiratory distress syndrome
(RDS), and modern respiratory care, in contrast, the ‘‘new’’
BPD occurs primarily in extremely premature infants,
occurs after only modest ventilatory and oxygen needs, and
is not accompanied by the classic clinical and radiologic
stages of the ‘‘old’’ BPD. The most dramatic histopathologic finding is ‘‘arrested alveolarization’’ with minimal
large or small airway disease, and relatively less inflammation and fibrosis [2, 8] (Table 1).
Why Prevention and Treatment Have Not Worked
Thus Far
The primary prevention of BPD through elimination of the
quintessential risk factor, prematurity, has not yet been
achieved and is unlikely to be achievable in the near future
because of the lack of understanding of the pathophysiology of preterm labor. Up until now, the available
preventive/treatment strategies for BPD have also suffered
the same limitations, i.e., lack of understanding of the
Table 1 Comparsion of ‘‘old’’ versus ‘‘new’’ bronchopulmonary
dysplasia
Old BPD
New BPD
Larger preterm infants
Extremely premature infants
High ventilation and oxygen needs Modest ventilation and oxygen
needs
Severe large airway injury
Interstitial and alveolar edema
Minimal large airway disease
Arrested alveolarization
Extensive small airway disease
with alternating areas of
overinflation and fibrosis
Minimal small airway disease
with less inflammation and
fibrosis
Pulmonary artery muscularization Fewer and abnormal pulmonary
arteries
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molecular processes involved in both normal and abnormal
lung development. The preventive interventions such as
antenatal and postnatal steroids, ‘‘kinder and gentler’’
ventilation, early closure of patent ductus arteriosus (PDA),
treatment of prenatal and postnatal infections, fluid
restriction, various nutrient supplements (vitamin A, inositol, polyunsaturated fatty acids), and, most recently, nitric
oxide administration are either not effective or are associated with unacceptable side effects [9–12]. Most of the
these interventions are of an empiric nature, failing to
target the underlying molecular processes that lead to BPD,
which may precisely be the reason that none of these
interventions have been effective in preventing BPD.
Therefore, the available preventive strategies for BPD are
not effective, not safe, and not based on a thorough
understanding of the pathogenesis of BPD. With recent
advances in our understanding of the cell/molecular processes involved in both normal and abnormal lung
development, in particular the mechanism of alveolar
development and its failure in BPD, there is now new hope
for not only preventing and treating BPD, but also possibly
reversing established disease [13].
The intent of this article is to review some of the
existing approaches to prevent and manage BPD, which
target the symptoms (Table 2) and then describe a state-ofthe-art approach to the prevention and treatment of BPD
that impacts the disease on a cell/molecular level, unlike
most of the treatments we currently have.
Table 2 Current treatments for bronchopulmonary dysplasia
Therapy
Strategy/mechanism of action
Benefit/comment
Ventilation
Avoid ventilation when possible with the use of NCPAP
or SNIPPV
Minimizes volu/barotrauma caused by ventilation
Minimize ventilator exposure time.
Accept permissive hypercapnia
Oxygen
Accept oxygen saturations between 88 and 92%
Prevents oxygen toxicity
Surfactant
Provide exogenous pulmonary surfactant to the deficient
neonate to decrease alveolar surface tension and
improve lung compliance
Possible reduction in BPD or death at 28 days
Inhaled nitric oxide
Decreases V/Q mismatch, reduces inflammation, and
restores normal growth patterns in premature lung
No overall reduction in BPD but a trend toward
reduction in BPD in select populations
Caffeine
Decreases apnea by acting as a central respiratory
stimulant, by decreasing the threshold to CO2, and by
decreasing diaphragmatic fatigue
Decreases duration of PPV and possibly frequency of
BPD. However, neurodevelopmental studies to
ensure safety are awaited
Induces lung maturation
Reduces the incidence and severity of RDS and
neonatal death but not the incidence of BPD
Systemic
Anti-inflammatory
Significant reduction in the incidence of BPD but have
negative neurodelevopmental consequences
Inhaled
Steroids
Antenatal
Postnatal
Local anti-inflammatory with minimal systemic effects
Ineffective in reducing incidence of BPD
Antibiotics
Treatment of pathogens causing
infection/inflammation
Treatment of Ureaplasma has not shown a decrease in
BPD
Diuretics
Reduce pulmonary edema
Improved lung function in short-term but no decrease
in the incidence of BPD
Bronchodilators
Dilate airways by relaxation of bronchial smooth
muscle to improve compliance/tidal volume and
reduce airway resistance
Provide adequate calories for somatic and pulmonary
growth and injury/repair
Insufficient data to evaluate safety and efficacy for
prevention or treatment of BPD
Allows providing adequate calories for improved
growth in the face of fluid restriction
Vitamin A
Important for growth, immunity, and integrity of
epithelial cells
Decreases incidence of BPD but safety not fully
established
Inositol
Essential nutrient for cell signaling, cell membrane
maintenance, and maturation of surfactant
Protect against inflammation and oxygen toxicity,
both known contributors to BPD
A trend toward reduction in the risk of death or BPD
but needs more studies
Have not proven successful in reducing the incidence
of BPD
Nutrition/fluid restriction
Antioxidants and
anti-inflammatory agents
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Existing Approaches to Prevent and/or Treat BPD
Kinder and Gentler Ventilatory Management
Volutrauma/barotrauma from mechanical ventilation is one
of the key risk factors for the development of BPD. A
potential approach to prevent BPD, therefore, is to avoid
mechanical ventilation, for example, by using noninvasive
ventilatory support modalities such as nasal continuous
positive airway pressure (NCPAP) and synchronized nasal
intermittent positive pressure ventilation (SNIPPV). Support for early NCPAP and avoidance of mechanical
ventilation was first provided by Avery et al. [14] in 1985
in a study in which it was shown that the incidence of BPD
at Columbia-Presbyterian Medical Center (Columbia) in
New York was significantly less than the other study
centers. The strategy at Columbia encourages early use of
NCPAP. A follow-up study by Van Marter et al. [15] in
2000 compared the experience at Columbia-New York to
Harvard-Boston and again found a lower incidence of BPD
at Columbia, which was attributed to lower rates of initiation of mechanical ventilation. Though the incidence of
BPD using the Columbia approach is lower, the question as
to its severity needs to be addressed, as those patients who
are not intubated do not see the potential benefits of surfactant. The success of early NCPAP improves with
gestational age and experience of the user, implying that it
may be a feasible option in a subset of patients in experienced centers [16]. Although minimizing the use of
mechanical ventilation by using early NCPAP has shown
trends toward decreased incidence of BPD, further randomized controlled trials are needed to confirm these
results [17, 18].
As described above, early/prophylactic NCPAP is a
promising tool for reduction in ventilator use and incidence
of BPD. NCPAP also has been evaluated in the postextubation setting to prevent reintubation. A meta-analysis of
randomized trials has shown that extubation to NCPAP
versus headbox oxygen significantly reduced the incidence
of apnea and oxygen requirements [19]. In addition to
continuous positive pressure ventilation, other modes of
nasal ventilation are being used. One mode that has been
studied is SNIPPV, which provides breaths in addition to
the continuous pressure. A meta-analysis of SNIPPV versus NCPAP after extubation showed a significant benefit
for the preterm infants extubated to SNIPPV in terms of
prevention of failed extubation and a trend toward
decreased CLD in the SNIPPV group [20]. Another recent
study suggested that infants on SNIPPV versus NCPAP
after extubation had a significantly lower need for supplemental oxygen and a lower incidence of BPD. This
study, however, was not randomized [21], and further
studies are needed to confirm the benefits of SNIPPV.
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For those infants who are supported on mechanical
ventilation, the ideal ventilation strategy is still not clear.
The general strategy is to minimize pulmonary damage by
minimizing time on the ventilator, reducing peak inspiratory pressure, restricting tidal volume to 3–6 cc/kg, and
using short inspiratory times of 0.24–0.4 s [22, 23]. The
concept of permissive hypercapnia has allowed us to
rethink our target PaCO2 levels and subsequently rationalize lower ventilator settings. Studies have shown that
aiming for PaCO2 goals of 45–55 mmHg versus 35–
45 mmHg resulted in shorter duration of ventilation. A
multicenter trial conducted by the National Institute of
Child Health and Human Development Neonatal Research
Network showed that permissive hypercapnia resulted in a
trend toward a decrease in the incidence of BPD. There
were no trends toward worse short-term neurodevelopmental outcomes in the higher PaCO2 cohort and a metaanalysis revealed IVH actually decreased in the permissive
hypercapnia group versus control. Findings suggesting
decrease in the incidence of IVH are important, as some of
the initial concerns of accepting higher PaCO2 levels
included potential disruption of cerebral autoregulation of
blood flow. Permissive hypercapnia may have other benefits in addition to decreased ventilator requirements,
including more efficient PaCO2 elimination and a shift of
the oxygen-dissociation curve to the right, allowing
improved oxygen delivery to the tissues [24]. It should be
noted, however, that a recent study found that infants
randomized to target PaCO2 range of 55–65 mmHg versus
35–45 mmHg for the first 7 days of life were found to have
trends toward higher incidence of BPD or death and significantly increased combined outcome of mental
impairment at 18–22 months or death. The study was
stopped before completion [25]. Although the concepts of
permissive hypercapnia and minimizing the damage
inflicted by mechanical ventilation remain promising, we
must use caution in the application of permissive hypercapnia until more data are available.
Use of high-frequency oscillatory ventilation (HFOV)
has been evaluated as both a mode of ventilation for prophylaxis against BPD and as a rescue mode for infants in
severe respiratory failure. A meta-analysis of 11 trials
comparing early use of HFOV to conventional ventilation
showed a modest reduction in BPD but no statistically
significant effect on mortality, short-term neurologic outcomes, ICH, or PVL [26]. However, many other recent
studies have provided conflicting data [27–29]. These
conflicting data are likely to be due to differences in the
study populations among various studies. HFOV has also
been used as a rescue mode for infants in severe respiratory
failure, but the evidence that this approach can reduce BPD
or improve long-term outcomes in preterm infants is not
yet available [18, 26].
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Other ventilatory modes employed to reduce BPD
include patient-triggered ventilation and volume-targeted
ventilation. Patient-triggered ventilation modes such as
assist control and synchronized intermittent mechanical
ventilation (SIMV) were introduced with the hope that
such ventilation modes would decrease the incidence of
BPD. However, a meta-analysis of randomized trials
evaluating patient-triggered modes does not show a significant decrease in the incidence of BPD. Use of patienttriggered modes, however, was shown to shorten the
duration of ventilation if started in the recovery phase but
not early in the acute phase of illness [26]. Another strategy
being evaluated is volume-targeted versus pressure-control
ventilation to determine if one is superior. A meta-analysis
of four randomized trials comparing volume-targeted with
pressure-limited ventilation showed that the use of volumetargeted ventilation significantly decreases the duration of
mechanical ventilation as well as the rate of pneumothorax,
but did not show a significant decrease in death. There was,
however, a reduction in the incidence of BPD among the
surviving infants. Further studies are needed to confirm
these results and explore other modes that ventilators are
now capable of delivering [26, 30].
Oxygen Supplementation
Oxygen toxicity plays a major role in the pathogenesis of
lung injury and BPD as well as other systemic diseases
such as retinopathy of prematurity (ROP), necrotizing
enterocolitis (NEC), and intraventricular/periventricular
(IVH/PVH) hemorrhage, necessitating the need to establish
a balance between appropriate oxygen delivery and toxicity. Although studies have shown that hyperoxia can have
major effects on lung tissue, including, but not limited to,
increased proliferation of alveolar type II (ATII) cells and
fibroblasts, alterations in the surfactant system, increases in
inflammatory cells and cytokines, increased collagen
deposition, and decreased alveolarization and microvascular density, there is also concern that hypoxia can lead to
decreased growth and poor neurodevelopmental outcomes.
The lack of sound data has contributed, therefore, to the
wide variation in practice between care providers in terms
of the accepted oxygen saturation range. Recent data support, however, that aiming for saturation targets in the
range of 85–93%, rather than [92%, decreases the incidence of ROP, oxygen use at 36 weeks, and use of
postnatal steroids without increasing rates of NEC, IVH/
PVH, periventricular leukomalacia (PVL), or having a
detrimental effect on developmental outcomes [31]. Furthermore, a recent study showed that targeting a high
oxygen saturation goal of 95–98% in infants born at less
than 30 weeks of GA and who were oxygen-dependent at
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32 weeks had no significant benefit on growth or development [32]. Although determining appropriate saturation
ranges is important, another issue that is now apparent is
our inability to maintain infants within set target ranges,
regardless of what saturations are set. Some studies have
revealed that infants are within set ranges as little as 50%
of the time. An important goal for the neonatal community
to achieve, therefore, is to avoid frequent oxygen fluctuations to both hypoxic and hyperoxic ranges [33].
Medications
Pulmonary surfactant
The use of pulmonary surfactant has been instrumental in
changing the face of the ‘‘old’’ BPD. The currently available surfactants are either animal-derived (natural) or
synthetic. The original synthetic surfactants contained
phospholipids and lacked the surfactant proteins present in
natural surfactants. The current evidence suggests that the
use of natural surfactant versus synthetic surfactant leads to
greater improvement in initial ventilator requirements,
lower incidence of pneumothorax, and a trend toward
increased survival [34]. However, in some studies the use
of natural surfactant had a slightly higher incidence of
IVH, but a similar incidence of grades 3 and 4 IVH. Other
concerns about the use of animal-derived products include
transmission of infectious agents, immune reactions, and
the presence of other impurities. These concerns, however,
have not been realized [34, 35].
As a result of concerns about animal-derived products,
there have been attempts to make an improved synthetic
surfactant. Lucinactant is a new synthetic surfactant (also
known as Surfaxin) that contains sinapultide, a peptide that
mimicks human SP-B. Compared with porcine-derived
poractant alfa (Curosurf), Surfaxin showed similar efficacy
and safety for treatment of RDS [36]. Additional studies
showed that Surfaxin was more effective than colfosceril
palmitate (synthetic surfactant) for prevention of RDS, it
reduced the incidence of BPD compared with colfosceril,
and it decreased the RDS-related mortality rates compared
with beractant (bovine-derived). The side-effect profile for
Surfaxin was as good as or better than colfosceril palmitate
and beractant for the secondary outcomes of air leaks, IVH,
PVL, ROP, pulmonary hemorrhage, PDA, NEC, and apnea
[37]. Furthermore, a 1-year follow-up comparing infants
who received lucinactant versus other surfactants in two
trials revealed that the infants who received lucinactant had
similar neurologic outcomes compared with infants who
received colfosceril palmitate, beractant, and poractant [38].
These initial trials of Surfaxin have yielded promising results
and strongly suggest that this new surfactant functions better
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clinically than previous synthetic surfactants. Unfortunately,
questions about quality control during its production have
hampered trials to further prove its superior efficacy and
safety. Furthermore, a meta-analysis of two studies comparing protein-containing synthetic surfactants versus
animal-derived surfactants for prevention and treatment of
RDS showed that there were no statistically significant differences between the groups for mortality at 36 weeks, CLD,
or the combined outcome of death or CLD [39].
In terms of the timing of surfactant administration and
its efficacy, a meta-analysis of four randomized controlled
studies evaluating early (within 2 h of life) versus late
surfactant administration favored the use of early administration by showing reductions in the risk of
pneumothorax, pulmonary interstitial emphysema, neonatal
mortality, and CLD or death at 36 weeks. The use of early
surfactant treatment also showed a trend toward reduction
in the risk for BPD or death at 28 days [40]. It should be
noted, however, that when evaluating the overall use of
surfactant, there has not been a significant reduction in the
incidence of BPD [38].
Inhaled nitric oxide (iNO)
The properties of iNO, including its ability to decrease
ventilation/perfusion mismatch, reduction of inflammation,
and restoration of more normal patterns of growth in the
premature lung, make it a candidate for the treatment of
BPD. However, the available data on iNO for prevention or
treatment of BPD is inconsistent [10, 41–44]. For example,
a multicenter randomized trial by Kinsella et al. [41] in
2006 showed that in infants less than 34 weeks GA with
respiratory failure requiring mechanical ventilation, there
was no significant decrease in BPD with the use of lowdose iNO. In the subpopulation of infants weighing 1000–
1250 g, however, they did find a reduction in BPD. Ballard
et al. [10] in 2006 found that infants less than 1250 g who
received iNO had shorter hospital stays and shorter durations of oxygen use, but no decrease in BPD incidence.
Taken together, the available studies are suggesting that
iNO may have its place in the treatment of BPD, especially
for particular subsets of infants such as those who are more
than 1000 g and are older than 7 days. Again, however,
further studies are needed to support this conclusion and to
determine first safety and then optimal dose, timing, and
duration of iNO use in preterm infants [42, 43].
Caffeine
Caffeine has been shown to decrease the frequency of
apnea of prematurity and mechanical ventilation during the
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first week of life. A large randomized international study
by Schmidt et al. [45] showed that in infants who received
caffeine, positive pressure support was discontinued
1 week earlier than in the group of infants assigned to
placebo. Furthermore, caffeine significantly reduced the
frequency of BPD, defined as a need for supplemental
oxygen at the age of 36 weeks PMA. However, the primary
outcome of this study, i.e., evaluation of the neurologic
outcome of this cohort at 18–21 months, is still pending.
Results of long-term follow-up will be important in confirming the safety of caffeine. Potential risks of caffeine
use include poor weight gain secondary to increased oxygen consumption and the fact that methyxanthines inhibit
adenosine receptors, since adenosine has a neuroprotective
role in the brain against hypoxia and ischemia [45].
Corticosteroids
Antenatal
Knowing that inflammation plays an important role in the
pathogenesis of BPD, agents that control inflammation are
a logical choice for treatment and/or prevention of BPD.
Corticosteroids have strong anti-inflammatory properties
and therefore have been extensively studied as agents to
prevent and treat BPD. Many studies have shown that
antenatal corticosteroids have benefits for the infant,
including reduction in fetal or neonatal death, RDS, and
IVH. In a large review of six studies including 818 infants,
however, there was no statistically significant difference in
BPD between those infants exposed to antenatal steroids
and control [46, 47].
Systemic Steroids
Initial data on the use of ‘‘early’’ systemic steroids were
promising for the prevention of BPD. A meta-analysis of
21 randomized controlled trials comparing systemic steroids given at less than 96 h of life versus control showed
significant decreases in the incidence of BPD at both 28
and 36 weeks and in death or BPD, ROP, and PDA. The
incidences of mortality, IVH, PVL, NEC, and pulmonary
hemorrhage were not significantly different between the
two groups. The concerns, however, came with the evaluation of late neurodevelopmental outcomes. Infants
receiving ‘‘early’’ systemic steroids were found to have a
higher incidence of cerebral palsy, developmental delay,
and abnormal neurologic examinations. The rate of combined death or major neurosensory disability in these
studies, however, was not significantly increased in the
steroid-exposed group [48]. Until we have further long-
Lung (2008) 186:75–89
term follow-up on patients treated with systemic steroids,
the neonatal community needs to avoid the use of ‘‘early’’
systemic steroids as much as possible. Another potential
use of early systemic corticosteroids is for the treatment of
adrenal insufficiency in premature infants. However, a
study by Watterberg et al. [49] revealed that the use of
low-dose hydrocortisone therapy did not improve survival
without BPD. In this study, there were also significant
concerns about the increase in gastrointestinal perforation
in the treatment group. Furthermore, the combination of
indomethacin and hydrocortisone appeared to have an
additive risk of perforation.
Attempts at finding the optimal timing for administration of systemic steroids that may provide pulmonary
benefit without neurologic sequelae has led to the examination of ‘‘moderately early’’ (7–14 days) and ‘‘late’’
systemic (beyond 7 days) steroid use [50, 51]. Although
infants receiving ‘‘moderately early’’ or ‘‘late’’ systemic
steroids compared to controls show early extubation and
decreased BPD at 28 days and 36 weeks, decreased combined outcome of death or BPD, and decreased number of
children discharged home on oxygen, these regimens are
associated with significant side effects, including hypertension, hyperglycemia, hypertrophic cardiomyopathy, and
infection. Furthermore, the limited available long-term
neurologic follow-up, again, puts the use of these regimens
into question [49, 50].
Inhaled Steroids
Due to the concerns of side effects of systemic steroids,
inhaled steroids have been studied as a possible way to
deliver local benefit with less systemic side effects. If given
during the first 2 weeks of life to ventilated infants with
birth weights less than 1500 g, inhaled corticosteroids do
not reduce the incidence of BPD [52]. There is, however,
some evidence to suggest that inhaled steroids reduce the
use of systemic postnatal steroid use, but this has not been
a consistent finding [52]. Studies comparing inhaled versus
systemic corticosteroid use for both treatment and prevention of BPD in very-low-birth-weight infants have also
been performed [53, 54]. Based on the available data,
neither inhaled nor systemic steroids can currently be
recommended for the treatment or prevention of BPD.
Antibiotics for Infection/Chorioamnionitis
Premature infants are commonly delivered in the setting of
maternal chorioamnionitis. Infants born to mothers with
chorioamnionitis tend to initially have accelerated lung
maturation with less RDS, but are then at higher risk for
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developing BPD [55]. Although we know that inflammation is a key element in the development of BPD, how
postnatal inflammation affects development of the lung that
has been exposed to chronic infection in utero is not
known. For now, our goal should be to decrease proinflammatory exposures of the preterm lung both in utero and
in the newborn period [56].
A logical approach to decreasing inflammation is to treat
infection, which is a common source of inflammation in the
neonatal population. One of the common pathogens that
colonize the respiratory tract of preterm infants is Ureaplasma urealyticum. Colonization with Ureaplasma is
thought to be a risk factor for the development of BPD
[57]. One study evaluating lung specimens revealed that
Ureaplasma-infected specimens were associated with more
myofibroblast proliferation and interstitial fibrosis than
lung specimens affected by other pathogens [58]. A few
studies have been performed to see if in infants less than
30 weeks GA requiring ventilatory support, treatment of
Ureaplasma would decrease the incidence of BPD. One
study looked at prophylactic treatment with erythromycin
in culture-unknown patients, while another study looked at
erythromycin treatment in culture-positive infants. Neither
study showed a decrease in BPD or death following
treatment with erythromycin [59]. A promising pilot study
by Ballard et al. [60] in 2007 showed that in infants with
birth weight of less than 1000 g who had prophylactic
treatment with azithromycin versus placebo had less postnatal steroid use and significantly shorter mechanical
ventilation. Again, further larger prospective randomized
controlled studies are needed to evaluate the effect of
treating Ureaplasma infection on the incidence of BPD.
Diuretics
Infants with BPD have a tendency to retain fluid and
develop pulmonary edema. To balance the fluid status of
these infants with adequate calorie delivery, diuretics are
often incorporated in the management plan. Review of the
literature shows that aerosolized diuretics may temporarily
improve pulmonary mechanics, but not enough data are
available on long-term outcomes to show benefit [61].
Evaluation of the use of systemic diuretics that act on the
distal tubule show that in infants older than 3 weeks with
BPD there is improved lung compliance, but there is no
evidence to support decreased need for ventilatory support
or improved long-term outcomes [62]. A review of the use
of loop diuretics shows that in infants less than 3 weeks of
age furosemide has inconsistent effects, and in infants older
than 3 weeks of age furosemide improves oxygenation and
lung compliance. However, no data are available to show a
decrease in BPD with the use of furosemide [63].
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Bronchodilators
Bronchodilators are used to dilate small airways by relaxing bronchial smooth muscle. Bronchodilators are
potentially useful in the prevention or treatment of BPD, as
many studies of pulmonary mechanics have shown shortterm improvements in compliance and tidal volume and
decreased airway resistance when bronchodilators are used
in infants with CLD. However, in the only randomized
controlled trial on use of bronchodilators for prevention or
treatment of CLD, with mortality or CLD as the primary
outcome, prophylactic use of salbutamol did not show
significant differences in mortality, CLD, or duration of
ventilation or oxygen requirement when compared to
controls. Currently, there are insufficient data to evaluate
the efficacy and safety of bronchodilators for prevention or
treatment of BPD, and therefore their use to prevent BPD is
not recommended [64].
Nutrition/Fluid Management
Maximizing caloric intake helps injury repair. The optimal
approach to feeding premature infants is not yet known and
we have no available studies evaluating the benefits of
increased ([135 kcal/kg/day) energy intake versus standard energy intake [65]. However, it is known that
decreased protein and calorie intake can significantly
decrease alveolar number [66]. Fluid management is
another important aspect of BPD care. Fluid restriction,
without compromise of calories, can improve lung function
and decrease oxygen requirements and may decrease the
risk of BPD [67]. Diuretics are often used to assist in
achieving adequate kilocalories for growth without volume
overload.
Vitamin A
Vitamin A plays an important role in vision, immunity, and
growth, and in the integrity of epithelial cells such as in the
respiratory tract. Preterm infants have low serum vitamin A
levels and studies suggest that infants with low levels of
vitamin A are at increased risk for BPD. A multicenter,
blinded, randomized trial in infants with a mean birth
weight of 770 g showed that 5000 IU of vitamin A
administered intramuscularly three times per week for four
weeks decreased death or CLD significantly in the treatment group (relative risk [RR] = 0.89). The study showed
that one additional infant survived without CLD for every
14–15 infants treated and that the control and treatment
groups had similar numbers of infants with potential signs
of vitamin A toxicity [68]. Analysis of the vitamin A
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cohort from this study at 18–24 months revealed that the
vitamin A group had similar mortality and neurodevelopmental outcomes as the control group [9]. Furthermore, a
meta-analysis of seven trials showed a reduction in death or
oxygen requirement at 1 month of age (RR = 0.93) and a
decrease in oxygen requirement at 36 weeks PMA
(RR = 0.87) in infants with a birth weight of less than
1000 g receiving vitamin A supplementation [9]. Potential
risks of vitamin A include toxicity leading to increased
intracranial pressure, mucous membrane lesions, and
emesis. Furthermore, vitamin A is administered intramuscularly, which induces pain, local inflammation, and risk of
bleeding [68, 69].
Inositol
Inositol is an essential nutrient that plays important biological roles, including cell signaling, cytoskeleton
assembly, cell membrane maintenance, fat breakdown, and
maturation of pulmonary surfactant. Inositol is present in
human milk. It has been shown that infants with BPD have
lower serum levels of inositol. Prior to the availability of
surfactant for routine use, supplemental inositol was evaluated as a potential treatment for RDS and BPD [70].
Review of the literature suggests that there is a reduction in
the risk of death or BPD in two trials (RR = 0.56) with
inositol supplementation, but a multicenter, randomized,
controlled trial of surfactant-treated infants is needed to
confirm the benefits [71]. Risks of inositol supplementation
were not identified, presumably because it is a naturally
occurring compound.
Antioxidants/Proteinase Inhibitors/Anti-inflammatory
Proteins
Given the deficiency of antioxidant defenses in the premature infant and oxidant exposure as an important
predisposing factor for BPD, it is logical to expect that
administration of antioxidants, both antenatally and postnatally, might reduce BPD. These potential therapies
include using antioxidant vitamins, superoxide dismutase,
alpha-1 proteinase inhibitor, and Clara cell protein. There
is very limited information on antenatal antioxidant supplementation and BPD. Even after years of work by Davis
et al. [72], this mode of treatment has not yet proven to be
effective. However, maternal supplementation with antioxidant vitamins C and E has been shown to reduce the
occurrence of pre-eclampsia and, therefore, should reduce
the rate of preterm delivery and thus should indirectly
reduce the incidence of BPD [73, 74]. However, at present,
the impact of antenatal antioxidant supplementation in
Lung (2008) 186:75–89
reducing BPD is not completely known. Use of postnatally
administered antioxidants such as superoxide dismutase
has also been disappointing. Superoxide dismutase is an
enzyme produced in the human body that participates in
protection against oxygen free radicals. Studies of exogenous superoxide dismutase suggest that it is safe; however,
there is no clear benefit for preventing BPD [75]. Alpha-1
proteinase plays a protective role against tissue damage.
Attempts to treat with alpha-1 proteinase showed a trend
toward decreased oxygen dependency at 28 days postnatal
age, but it did not reduce the risk of BPD [76, 77]. Clara
cell 10-kDa protein (CC10), a naturally occurring antiinflammatory protein in the respiratory tract, was found to
be deficient in ventilated premature infants who develop
BPD. If given endotracheally, it has been shown to result in
decreased inflammatory markers in tracheal aspirate fluid.
However, further studies are needed to evaluate recombinant CC10’s role in preventing BPD [78]. On the whole,
exogenous antioxidants, proteinase inhibitors, and antiinflammatory proteins have not proven successful in
reducing the incidence of BPD.
Novel Insights into the Molecular Basis of BPD
The initiation and continued use of mechanical ventilation
in infants with birth weights of less than 1250 g is the
strongest risk factor for the development of BPD. The
surfactant-deficient alveoli of such premature infants
undergo breath-by-breath collapse (derecruitment) and rerecruitment, resulting in atelectrauma, which sets in motion
the molecular cascade resulting in the structural and morphologic changes characteristic of BPD. Experimental
studies in preterm animals have clearly demonstrated that
even a few large tidal volume breaths can result in acute
lung injury that initiates the cascade of molecular events
leading to BPD [79]. Given the central role of alveolar
stretch in initiating the molecular injury leading to BPD, it
is logical to pursue a stretch-sensitive gene(s) that may be
expressed in the pulmonary alveolus and that is (are)
essential for its structure and function. Parathyroid hormone-related protein (PTHrP) is one such gene. It is
expressed in the developing endoderm and its receptor is
present on the adepithelial mesoderm, and, most importantly, PTHrP knockout causes a stage-specific inhibition of
fetal mouse lung development [80]. The lungs of these mice
fail to transition from the pseudoglandular to the canalicular
stage of lung development, i.e., failure of alveolarization, a
hallmark of the ‘‘new’’ BPD. Based on cell/molecular
mechanisms driven by PTHrP that are essential for normal
physiologic lung development, we have taken a basic biological approach to elucidate the pathophysiology and
molecular mechanism involved in the pathogenesis of BPD.
83
Physiologic Role of PTHrP in Alveolar Homeostasis
Under the influence of sonic hedgehog, the developing
endoderm expresses PTHrP and its receptor on the
adjoining mesenchyme. PTHrP binding to its receptor on
the mesenchyme activates the protein kinase A pathway,
which actively downregulates the default Wingless/int
(Wnt) pathway and upregulates the adipogenic pathway
through a key nuclear transcription factor, peroxisome
proliferator activated receptor c (PPARc), and its downstream regulatory genes adipocyte differentiation related
protein (ADRP) and leptin (Fig. 1) [81]. ADRP is necessary for the transit of neutral lipid from the lipofibroblast to
the alveolar type II (ATII) cell for surfactant phospholipid
synthesis. Lipofibroblasts, in turn, secrete leptin, which acts
on its receptor on ATII cells, stimulating both surfactant
phospholipid and protein synthesis. Since PTHrP stimulates leptin production by lung fibroblasts, it provides a
complete growth factor-mediated paracrine loop for the
synthesis of pulmonary surfactant [82]. Overall, PTHrP
signaling, by inhibiting Wingless/int signaling, inhibits the
default myogenic phenotype and, by stimulating the
PPARc signaling, induces the lipogenic phenotype, which
is necessary for maintaining alveolar homeostasis through
its paracrine effects on interstitial fibroblasts and ATII cells
[13]. Specifically, the interstitial lipofibroblast phenotype
provides protection against oxygen free radicals (i.e., protection against oxotrauma), trafficks neutral lipid substrate
Fig. 1 Parathyroid hormone-related protein (PTHrP), secreted by the
alveolar type II cell, binds to its receptor on the adjoining alveolar
interstitial fibroblast, activating the protein kinase A pathway, which
actively downregulates the default Wingless/int (Wnt) pathway and
upregulates the adipogenic pathway through the key nuclear transcription factor peroxisome proliferator activated receptor c (PPARc)
and its downstream regulatory genes adipocyte differentiation related
protein (ADRP) and leptin. Lipofibroblasts in turn secrete leptin,
which acts on its receptor on alveolar type II cell, stimulating
surfactant synthesis
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84
to ATII cells for surfactant phospholipid synthesis (i.e.,
protection against atelectrauma), and causes ATII cell
proliferation (i.e., protection against any insult causing
epithelial injury), thereby promoting alveolar growth,
development, and injury repair [13, 83]. Physiologically,
this would stabilize the alveolus, thus preventing its collapse, maintaining adequate gas exchange, and reducing
the energy expenditure by decreasing the work of breathing. On the other hand, although myofibroblasts may also
be important for normal lung development, these cells are
the hallmark of all CLDs in both the neonate and the adult
[84]. In the developing lung, myofibroblasts are fewer in
number and localize to the periphery of the alveolar septa,
where they very likely participate in the formation of new
septa [85]. However, in CLDs, myofibroblasts not only
increase in number but are also abnormally located in the
center of the alveolar septum in great abundance. In summary, PTHrP signaling is critical in maintaining alveolar
homeostasis. Under the influence of cyclic stretch, PTHrP
is secreted by the ATII cell, which acts on its receptor on
the adjacent lipofibroblast, which in turn secretes leptin
that facilitates surfactant synthesis by the ATII cells,
underlining the importance of PTHrP signaling in maintaining alveolar homeostasis. If normal PTHrP signaling is
interrupted, e.g., by conditions such as prematurity, volutrauma, exposure to hyperoxia or inflammatory cytokines,
all conditions that are known to be associated with BPD,
normal alveolar homeostasis is altered and interstitial
fibroblasts undergo molecular and phenotypic changes
consistent with the development of BPD. Using a wide
variety of pathophysiologic insults associated with BPD,
i.e., barotrauma, oxotrauma, and infection, we have found
that there are type II cell and/or fibroblast cell/molecular
effects generated by these insults that can lead to the BPD
phenotype. Furthermore, at least in animal models using
PTHrP and PPARc agonists, we have effectively abrogated
specific alveolar molecular changes following barotrauma,
oxotrauma, and infection that are known to lead to BPD.
Complementing these studies in animal models, as elaborated upon next, we have also examined the significance of
PTHrP signaling in human BPD.
PTHrP Signaling in Human BPD
We hypothesized that PTHrP levels in the tracheal aspirates (TA) of ventilated very-low-birth-weight infants
(VLBWI) would correlate with the development of BPD.
We examined whether TA PTHrP content during the first
week of life correlated with the later development of BPD.
Forty VLBWIs [birth weight = 943 ± 302 g (mean ±
SD); gestational age = 27 ± 2 weeks; 21 males and 19
females] who were ventilated for RDS were studied. The
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Lung (2008) 186:75–89
TAs were collected once daily until the infants were extubated and the samples were assayed for PTHrP. The
levels of TA PTHrP correlated with the later development
of BPD. PTHrP in the TA during the first week of life was
significantly lower in those infants who developed BPD
(12/40) than among those who did not (28/40). The PTHrP
levels also correlated with the duration of mechanical
ventilation needed in these infants. PTHrP B 1.32 pg/mg
protein predicted the subsequent development of BPD
maximally [84.6% correct classifications (true positives + true negatives)], with a sensitivity of 76.9% and
specificity of 88.5%. Using a TA PTHrP level of 1.32 pg/
mg protein as the cutoff, we constructed Kaplan-Meier
curves to compare the duration of ventilation needed
between the two groups, i.e., less than or equal to and
greater than 1.32 pg/mg protein TA PTHrP level. Infants
with TA PTHrP levels greater than 1.32 pg/mg protein
were off ventilatory support significantly earlier. To
determine how PTHrP levels compared with the other
known predictors of BPD, such as birth weight (\1000 g),
GA (\ 28 weeks), and gender (male), we performed multivariate logistic regression analysis for these four variables
in predicting the development of BPD. Of these variables,
PTHrP B 1.32 pg/mg protein was the strongest predictor
of BPD and remained so after adjusting for the other three
variables, i.e., birth weight less than 1000 g, GA less than
28 weeks, and male gender. From these data we concluded
that lower TA PTHrP content during the first week of life
in ventilated VLBWI inversely correlates with prolonged
ventilation and the subsequent development of BPD.
Scientific Rationale for Proposing PTHrP/PPARc
Agonists and Other Novel Interventions for the
Prevention of BPD
It is clear from what is briefly outlined above that we have
systematically demonstrated the central role of PTHrPdriven epithelial-mesenchymal signaling in maintaining
alveolar homeostasis. The lipofibroblast expresses PPARc,
ADRP, and leptin in response to PTHrP signaling from the
ATII cell, resulting in direct protection of the mesoderm
against oxidant injury, and protection against atelectasis by
augmenting surfactant phospholipid and protein synthesis.
Disruption of PTHrP signaling between ATII cells and
fibroblasts downregulates the adipogenic signaling pathway and upregulates the myogenic signaling pathway,
causing myofibroblast transdifferentiation [13, 86–91].
Unlike lipofibroblasts, myofibroblasts cannot promote ATII
cell growth and differentiation [13], leading to the failed
alveolarization characteristic of BPD. A variety of factors
associated with failed alveolarization, i.e., barotrauma,
oxotrauma, and infection, all cause disruption of PTHrP/
Lung (2008) 186:75–89
PPARc signaling and myofibroblast transdifferentiation
in vitro [13, 86–88, 91] and in vivo [89, 90]. More
importantly, we have shown that PTHrP/PPARc signaling
pathway agonists such rosiglitazone (RGZ) can effectively
prevent or rescue myofibroblast transdifferentiation,
therefore, preventing the inhibition of alveolarization in the
developing lung. Therefore, it makes a compelling case for
using PTHrP/PPARc agonists to prevent BPD. However, as
yet there are no human data to show that normalization of
PTHrP levels is effective in preventing or treating BPD.
Impaired Vascularization in BPD
Abnormal vascular growth and the decreased alveolarization are the central hallmarks of the ‘‘new’’ BPD. However,
the mechanism(s) that interferes with vascular growth is
poorly understood. Of the many angiogenic factors, vascular endothelial growth factor (VEGF) has been shown to
play a central role in pulmonary vascular development. It is
a potent stimulant of angiogenesis, promotes vascular
remodeling, and enhances endothelial survival. Furthermore, it has been shown that inhibition of vascular growth
in and of itself directly impairs alveolarization. Recent
studies have convincingly demonstrated reduced VEGF
signaling in the lungs of infants with fatal BPD, suggesting
that by upregulating VEGF signaling, it might be possible
to maintain normal alveolarization in the face of insults
that lead to BPD [92, 93]. Therefore, it is not surprising
that novel approaches that protect the immature endothelium and enhance vascular growth are being actively
pursued [94, 95]. It is important to note that PTHrP, in
addition to its role in pulmonary surfactant homeostasis,
also modulates alveolar capillary perfusion [96] and helps
in ventilation/perfusion matching, suggesting that PTHrP
signaling as discussed above is not only critical for ATII
cell/fibroblast interactions, but also for alveolar/endothelial
crosstalk.
Stem Cell Research
As the hallmark of the ‘‘new’’ BPD is arrest of alveolarization and abnormal vascular growth, the potential for
stem cells to supplement natural repair and regeneration of
lung tissue is of potential importance. Adult bone marrow
(BM)-derived cells have been shown to have the capability
of differentiating into nonhematopoietic lineages. However, due to the complexity of the lung, the use of BM cells
for lung repair has been slower than for their use in other
tissues [97]. Hennrick et al. [98] in 2007 show that tracheal
aspirate fluid from premature infants on mechanical ventilators contains mesenchymal stem cells with
85
differentiation potential into mesenchymal cells of different lineages. The role of these cells is yet to be fully
determined. However, better understanding of the cells
involved in the pathogenesis of BPD will lend itself to
potential repair/replacement with stem cell technology. In
particular, knowledge of the intrinsic molecular mechanisms that allow for recruitment of stem cells for lung
repair would allow engineering and targeting of such cells
for treating BPD.
Although the novel molecular insights into the pathogenesis of BPD reviewed above provide a rational
framework to design innovative therapeutic molecular
interventions against BPD, the safety of these interventions
remains to be proven. In addition to the documentation of
the efficacy, the absence of any major side effects will be
of paramount significance in the development and clinical
application of these proposed interventions. This is particularly true since the PTHrP/PPARc and VEGF signaling
pathways are not lung-specific and are known to be
expressed in almost all organ systems in the body. Therefore, until lung-specific targeting of these approaches can
be ensured, the clinical application of the concepts outlined
above would be challenging. This is further highlighted by
the recent concerns about a significant increase in the risk
of heart attack and a nonsignificant increase in the risk of
cardiovascular death in patients with type 2 diabetes
receiving PPARc agonist RGZ as compared to controls.
Use of PPARc agonists will need to undergo further scrutiny before they could be used for reducing BPD [99, 100].
Conclusions
Despite all the advances in neonatal care, BPD remains a
major cause of morbidity and mortality among premature
infants. As one can gather from this review, there is no
single approach or agent that has been clearly shown to
prevent or treat human BPD. There have been very few
well-designed studies that have tested specific interventions to treat BPD as their endpoint. This is partly because
most often the pulmonary changes in BPD improve with
time due to the normal pulmonary repair process, making it
hard to separate the effect of treatment from the normal
repair process. Nevertheless, the affected infant remains at
risk for repeated hospitalizations and growth failure, particularly during the first year of life, and ultimately
neurodevelopmental delay, mandating long-term follow-up
and close vigilance on the part of everyone involved in the
child’s care.
Although once the condition has developed there is no
specific intervention to treat it, the following approach at
least minimizes the chances of developing severe BPD: (1)
Aim to prolong fetal gestation for as long as safely
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Lung (2008) 186:75–89
possible. (2) When indicated, ensure administration of
antenatal steroids. (3) If possible, avoid intubation altogether, but if intubation and ventilation for respiratory
distress are necessary, administer pulmonary surfactant as
early as possible. (4) Ventilate at the lowest acceptable
ventilatory settings. (5) Accept lower blood oxygen saturations as well as higher PaCO2 values. (6) Intramuscular
administration of vitamin A during the first month of life
might reduce BPD. In addition, refinement of existing
therapeutic approaches such as aerosolized delivery of the
surfactant Surfaxin (AerosurfTM, Disocovery Laboratories)
might confer additional benefit in further reducing the
possibility of BPD. Furthermore, use of agents with known
benefit in other pulmonary diseases, such as iNO, may find
a place in the treatment of BPD. Currently, however, there
is not adequate evidence to suggest that routine iNO
administration in extremely preterm infants with respiratory failure prevents BPD. Novel therapeutic approaches
such as stem cell infusion, PTHrP and VEGF supplementations, and administration of PPARc agonists that are
based on our understanding of the molecular mechanisms
involved in the pathogenesis of BPD hold promise for the
future. However, it is critically important to further judiciously study these physiologically and developmentally
relevant interventions with the intent of effectively and
safely treating the developing neonate. Finally, another
research focus should be to identify specific and sensitive
biomarkers that could be followed, preferentially noninvasively, to predict the development of BPD and also to
follow its clinical progression/regression.
Acknowledgments This work was supported by grants from the
National Institutes of Health (HL55268 and HL 75405), the American
Heart Association (0265127Y), the Tobacco-Related Disease
Research Program (14RT-0073 and 15IT-0250), and Philip Morris
USA, Inc. and Philip Morris International (11108–02).
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