REVIEW
published: 22 May 2017
doi: 10.3389/fmed.2017.00061
The Future of Bronchopulmonary
Dysplasia: Emerging
Pathophysiological Concepts and
Potential New Avenues of Treatment
Jennifer J. P. Collins 1*, Dick Tibboel 1, Ismé M. de Kleer 2, Irwin K. M. Reiss 3
and Robbert J. Rottier 1
1
Department of Pediatric Surgery, Sophia Children’s Hospital, Erasmus University Medical Centre, Rotterdam, Netherlands,
Division of Pediatric Pulmonology, Department of Pediatrics, Sophia Children’s Hospital, Erasmus University Medical
Centre, Rotterdam, Netherlands, 3 Division of Neonatology, Department of Pediatrics, Sophia Children’s Hospital, Erasmus
University Medical Centre, Rotterdam, Netherlands
2
Reviewed by:
Cristina Maria Alvira,
Stanford University, USA
Rory Edward Morty,
University of Giessen, Germany
Yearly more than 15 million babies are born premature (<37 weeks gestational age),
accounting for more than 1 in 10 births worldwide. Lung injury caused by maternal
chorioamnionitis or preeclampsia, postnatal ventilation, hyperoxia, or inflammation
can lead to the development of bronchopulmonary dysplasia (BPD), one of the most
common adverse outcomes in these preterm neonates. BPD patients have an arrest
in alveolar and microvascular development and more frequently develop asthma and
early-onset emphysema as they age. Understanding how the alveoli develop, and repair,
and regenerate after injury is critical for the development of therapies, as unfortunately
there is still no cure for BPD. In this review, we aim to provide an overview of emerging
new concepts in the understanding of perinatal lung development and injury from a
molecular and cellular point of view and how this is paving the way for new therapeutic
options to prevent or treat BPD, as well as a reflection on current treatment procedures.
*Correspondence:
Jennifer J. P. Collins
j.dewolf-collins@erasmusmc.nl
Keywords: bronchopulmonary dysplasia, chronic lung disease of prematurity, respiratory distress syndrome,
preterm birth, lung development, chronic lung disease
Edited by:
Anne Hilgendorff,
Ludwig-Maximilians-Universität
München, Germany
Specialty section:
This article was submitted to
Pulmonary Medicine,
a section of the journal
Frontiers in Medicine
Received: 30 January 2017
Accepted: 02 May 2017
Published: 22 May 2017
Citation:
Collins JJP, Tibboel D, de Kleer IM,
Reiss IKM and Rottier RJ (2017) The
Future of Bronchopulmonary
Dysplasia: Emerging
Pathophysiological Concepts and
Potential New Avenues of Treatment.
Front. Med. 4:61.
doi: 10.3389/fmed.2017.00061
Frontiers in Medicine | www.frontiersin.org
INTRODUCTION
Yearly over 15 million babies are born premature (<37 weeks gestational age), accounting for more
than 1 in 10 births worldwide, of which approximately 2.4 million babies are born before 32 weeks
of postmenstrual age (PMA) (1). Bronchopulmonary dysplasia (BPD) is the most common adverse
outcome in very preterm neonates with an incidence of 5–68%, depending on the cohort and definition used, which increases significantly with declining gestational age (2, 3). BPD develops as a
result of lung injury caused by maternal pre-eclampsia, chorioamnionitis, postnatal ventilation,
hyperoxia, and/or inflammation, leading to an arrest in alveolar and microvascular development
and pulmonary hypertension, although the relative contribution of the different pathogenic factors
for the individual patient is hard to identify (4). Originally, BPD (“old” BPD) was defined based on
lung injury resulting from mechanical ventilation and oxygen supplementation, and was seen mostly
in premature infants born at 26–30 weeks PMA (5–7). The introduction of major interventions
such as maternal corticosteroids (8, 9) and surfactant replacement therapy (10–12) resulted in a
changed disease phenotype that was seen in preterm infants that could survive at younger gestational
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New Concepts in BPD
ages (24 to 26 weeks PMA). As a result, “new” BPD, defined as
the requirement of supplemental oxygen at 36 weeks PMA or
treatment with supplemental oxygen for more than 28 days
(4), was characterized based on impaired alveolar and capillary
development of the immature lungs (13). It is now becoming clear
that BPD survivors continue to have respiratory morbidity after
they leave the neonatal intensive care unit (NICU) [see comprehensive review by Islam et al. (14)], underlining that BPD really
is a disease of disrupted lung development. Understanding how
the alveoli and underlying capillary network develop and how
these mechanisms are disrupted in BPD is critical for developing efficient therapies, which currently are lacking. Moreover,
the nature of lung injury and consequently BPD is perpetually
changing as treatment strategies evolve in an attempt to prevent
injury to the premature lungs. Combined with increasing insight
into the pathophysiology of BPD, this has started a discussion
on yet a newer definition of what BPD is, basing it more on biomarkers, pulmonary hypertension and the underlying vascular
basis of BPD (15–17). In this review, we provide an overview of
emerging new pathophysiological concepts in the understanding
of perinatal lung development and injury from a molecular and
cellular point of view and how this is paving the way for new
therapeutic options to prevent or treat BPD, as well as a reflection
on how this compares with current treatment procedures.
and Kool et al. (21)]. Far less is known about the molecular and
cellular processes that direct saccular and alveolar development,
the very stages that are clinically relevant after preterm birth and
BPD pathogenesis. VEGF, which is expressed by alveolar epithelial type II cells in response to hypoxia-induced factor (HIF), is
crucial in directing pulmonary microvascular development and
alveolar development (22). Moreover, VEGF plays an important
role in BPD pathogenesis as BPD patients express little or no VEGF
in their lung epithelium, and lack expression of VEGF receptors
in pulmonary microvascular endothelium (23). Multiple studies
have demonstrated that platelet derived growth factor (PDGF)
and FGF signaling is crucial for myofibroblast differentiation and
subsequent onset of secondary septation (24–29). WNT, BMP,
and TGFβ signaling components have also been implicated to
play a role in fibroblast differentiation during alveolarization
(30–32). Additionally, correct deposition of extracellular matrix
(ECM) proteins by myofibroblasts, like elastin and collagen, plays
a crucial role during secondary septation (33, 34). These and
other ECM components may exert their role in lung development
by functioning as a scaffold for the growth factors to coordinate
the growth interactions of cells (35).
BPD IN 2017
Current Understanding of Perinatal Risk
Factors
Overview of Lung Development
To understand BPD pathophysiology, it is important to understand how the lung normally develops. Despite the large body of
knowledge concerning the morphogenesis of the lung (18, 19),
research on the intercellular communications that regulate
growth, migration, and differentiation during lung development
is still unfolding. Among the best characterized growth factors
and their signaling components in early lung development are
fibroblast growth factor (FGF), transforming growth factor β
(TGFβ), bone morphogenetic protein (BMP), sonic hedgehog
(SHH), wingless-type MMTV integration site family (WNT),
vascular endothelial growth factor (VEGF), and retinoic acid
signaling pathways [reviewed by Hogan and Morrissey (20)
Because BPD is still very much a functional diagnosis, which
is made when preterm infants have already been exposed to a
wide variety of perinatal stressors [Figure 1; (36)], it is hard to
pinpoint exactly which exposure is more detrimental for lung
development. Most of these insights have been obtained through
decades of work on animal models [reviewed by Jobe (37)] and
correlations found through epidemiological research. Already
before preterm birth, intrauterine conditions can have a profound
impact on lung development and susceptibility to BPD. Risk factors established by statistical correlation are first and foremost
maternal risk factors associated with preterm birth, such as
FIGURE 1 | The pathogenesis of bronchopulmonary dysplasia (BPD) is highly multifactorial in nature, with a wide variety of pre- and postnatal
exposures influencing lung development. Depending on the timing and combinations of exposures, BPD likely exists of multiple different pathophysiologies that
manifest themselves in a similar way clinically. The top arrow represents exposures that may to a certain extent protect from BPD pathogenesis and promote repair,
while the bottom arrow indicates exposures that injure the preterm lung and contribute to BPD pathogenesis. Figure reprinted from Hütten et al., originally published
by Springer (36).
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smoking and socioeconomic background (38). Intrauterine
growth restriction increases the risk of BPD threefold in infants
born before 29 weeks (2, 39), while chorioamnionitis and preeclampsia trigger the release of cytokines and growth factors that
directly inhibit alveolar and microvascular development of the
fetal lungs (2, 36, 40). Placental abnormalities, such as gestational
hypertension, pre-eclampsia, and eclampsia, are emerging as an
important antenatal risk factor for BPD. A French prospective
cohort study found that placenta-mediated pregnancy complications with fetal consequences are associated with moderate to
severe BPD in very preterm infants (41). The maternal administration of corticosteroids prior to preterm birth leads to thinning
of the primary septa, which narrows the air blood barrier, stimulates the production of surfactant, which stabilizes the alveolar
sacs and prevents collapse after exhalation, and stimulates the
clearance of fetal lung fluid (42). Although this accelerated
development improves neonatal outcome and survival of the
infant, antenatal corticosteroids have the unwanted side effect of
inhibiting secondary septation and impairing microvasculature
development (28, 43–45).
Postnatally, inflammation is also considered to be an
important risk factor for the development of BPD [reviewed
in Ref (46)], either as a result of lung injury caused by invasive
mechanical ventilation and supplemental oxygen or in the form
of sepsis. Due to their lung immaturity and apnea of prematurity,
preterm infants are also frequently exposed to hypoxia, which
just like hyperoxia leads to impaired alveolar and microvascular
development (47). Recently, the presence of oxygen-sensitive
intrapulmonary bronchopulmonary anastomoses (IBA) was
discovered in preterm infants with BPD and other infants with
chronic lung diseases, which may stay patent in the setting of
persistent hypoxia (16, 48–52). Thus, IBA may in itself lead to
persistent hypoxemia and contribute to the pulmonary hypertension that is often seen in conjunction with BPD, and could
therefore be a significant risk factor for BPD (16). Considering
that not all infants that are born very or extremely preterm go
on to develop BPD, multiple pre- and/or postnatal hits are probably needed for lung development to be significantly affected,
especially since the incidence of BPD has not decreased despite
advances in neonatal care (2).
of administration and dosing (42). Similarly, there is discussion
as to whether surfactant therapy should be prophylactic or only
selectively administered upon diagnosed RDS, as a result of the
increased use of non-invasive ventilation methods such as nasal
continuous positive airway pressure (CPAP) (53, 55). Without the
application of routine CPAP, prophylactic surfactant treatment
reduces neonatal mortality. However, the routine application of
CPAP reduces the risk of BPD and neonatal death, and in these
infants selective administration of surfactant is more beneficial
(55). The INSURE method (intubate-surfactant-extubate to
CPAP) is therefore now the recommended technique to avoid
lung injury (56).
An alternative method of surfactant administration that builds
on this is less invasive surfactant administration (LISA), which
circumvents the need of endotracheal intubation and mechanical
ventilation all together while improving pulmonary outcome in
extreme premature infants (57–59). A more high-tech approach
that is now being tested in the NICU is surfactant administration
through aerosolization, nebulization, or atomization (60–67). It
has proven technically challenging to achieve sufficient delivery
of surfactant in the distal lung compared to bolus administration of surfactant, although the recent development of vibrating
membrane nebulizers seems promising (67). Switching from
animal-derived surfactants to new generation synthetic surfactants, which are more resistant to inactivation and even antiinflammatory in cell culture and animal studies, may be another
step forward (11, 68–75). Several clinical trials are testing two
promising synthetic surfactants to combat RDS in the NICU. A
multicenter phase 2 study is comparing the safety and efficacy of
CHF5633, a synthetic surfactant with surfactant protein (SP)-B
and SP-C analogs, with poractant alfa in preterm infants with RDS
(ClinicalTrials.gov identifier NCT02452476). In addition, two
multicenter phase 2 studies are assessing the safety and efficacy of
aerosolized lucinactant (also known as KL4 surfactant, Aerosurf,
and Surfaxin) in preterm neonates 26 to 32 weeks PMA receiving
nasal CPAP (ClinicalTrials.gov identifiers NCT02636868 and
NCT02528318). Optimizing ventilation strategies and surfactant
therapy are therefore seen as the most easily achievable targets in
the prevention of BPD.
Besides ventilation strategies, surfactant therapy and corticosteroids, there are a few therapies that have a profound effect in the
prevention of BPD. Prophylactic caffeine therapy is recommended
to counter apnea of prematurity and is now common practice
after it was shown to be effective in reducing BPD and subsequent
neurodisability (56, 76–78). The protective effect of caffeine
therapy appears greater when given earlier rather than later,
although there is still discussion among experts as early therapy
is also associated with slightly greater mortality in some studies
(79–81). This effect has been attributed to infants receiving earlier
extubation and subsequently shorter mechanical ventilation
times, alleviating the injury burden on the developing premature
lung (76, 79). Multiple recent animal studies have attempted to
elucidate whether caffeine itself can promote or protect alveolar
development directly, with mixed results. Using the hyperoxia
model of experimental BPD, caffeine could protect against alveolar simplification and inflammation in rats (82, 83) and rabbits
(84), but not in mice (85, 86). Potential mechanisms include its
Current Treatment Procedures
In this complex multifactorial setting, current therapies are aimed
to not only support the survival of the preterm infant, but also to
limit or prevent further damage as much as possible [see review by
Jain and Bancalari (53)]. In this regard, the most direct approach
is to prevent the need for aggressive, prolonged invasive ventilation. The first treatment of choice to prevent respiratory distress
syndrome (RDS) is still antenatal maternal corticosteroid administration, followed by prophylactic surfactant therapy through
endotracheal bolus administration after birth. The maternal
administration of a single or repeated intramuscular injection of
betamethasone or dexamethasone within a time window of 24 h
to 7 days prior to preterm birth can significantly increase survival
of the preterm infant and decrease the incidence and severity of
RDS (9, 54). However, there is no consensus yet on how the use
of antenatal steroids can be optimized by improving the timing
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abilities to amplify glucocorticoid-mediated SP-B expression in
alveolar type 2 cells (87, 88), to modulate connective tissue growth
factor (CTGF) expression (89) and TGFβ pathway members
(85), and to attenuate endoplasmic reticulum (ER) stress (82).
Conflictingly, both up- and downregulation of alveolar apoptosis
has been reported (82, 86). Caffeine is however primarily known
as a methylxanthine, which is a non-selective phosphodiesterase
(PDE) inhibitor (78). PDE inhibitors have potent immunomodulatory and vascular effects and are therefore still interesting
targets for neonatal intensive care medicine. Animal studies
using the neonatal rodent hyperoxia model of experimental BPD
have shown promise for non-selective PDE inhibitor pentoxyfilline (90), PDE4 inhibitors rolipram, piclamilast, and cilomilast
(91–93), and PDE5 inhibitor sildenafil (94), which were able
to ameliorate pulmonary inflammation and hypertension and
improve lung alveolarization. Inhaled nitric oxide (iNO) therapy,
which has a complementary mode of action to PDE inhibitors
by boosting cyclic guanosine monophosphate (cGMP) (95), has
long been the subject of clinical trials after promising results in
animal models of BPD. Although iNO decreases inflammatory
mediators in tracheal aspirates of treated preterm infants (96),
systematic reviews show no protective effect in the development
of BPD (97). Interestingly, iNO therapy was effective in reducing
BPD incidence when combined with vitamin A therapy (98).
Supplementation with vitamin A improved alveolarization in
neonatal rats and lambs (99, 100), while in clinical studies, supplementation with vitamin A in preterm infants significantly
reduced the risk of BPD (101–103). Unfortunately, these studies
have not lead to the adoption of vitamin A supplementation in
clinical practice, as the treatment benefits were deemed too small
and the intramuscular route of administration too cumbersome
in tiny preterm infants (104, 105). Other administration routes
must be investigated for these promising therapies to become
commonplace in the clinic.
For all currently used therapies, there is still ground to be
gained through clinical trials and evidence-based medicine to
ascertain optimal dosing, timing, and administration methods
for maximum efficiency. It is essential that risk stratification
takes place within the trial design to identify the real potential
advantage of the different interventions. Despite all efforts at
reducing lung injury through current treatment procedures,
the incidence of BPD has remained stable over the past two
decades (2). This is in part explained by the increased survival
of extremely preterm infants born between 22 and 26 weeks
PMA but probably also reflects the highly multifactorial nature
of BPD. Prematurity is often not the first complication leading
to BPD pathogenesis, as infants have already been exposed to
a disadvantageous intrauterine environment, either through
severe intrauterine growth restriction resulting from severe
pre-eclampsia or chorioamnionitis. This is then followed by
various exposures and comorbidities in the NICU, which in a
substantial portion of these extreme premature infants leads
to BPD with a similar phenotype, even though the underlying
pathogenesis might have been quite different. It should not be
forgotten that an astonishing portion of these infants does not
go on to develop BPD, despite experiencing similar exposures.
A better understanding of the pathophysiology leading to BPD
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is therefore crucial to create a better tailored treatment regimen
for premature infants.
CURRENT UNDERSTANDING OF BPD
PATHOPHYSIOLOGY, NEW
PATHOPHYSIOLOGICAL CONCEPTS,
AND POTENTIAL THERAPIES
Infants at greatest risk of developing BPD are born when their
developing lungs are still transitioning from the canalicular to
saccular phase. Given the complexity of lung development and
the wide variety of perinatal insults leading to BPD, there is
likely no single pathophysiology of BPD. Because of a paucity of
histopathological data from preterm infants and BPD patients,
our current understanding of BPD pathophysiology has mostly
been generated from various small and large animal models
looking at the effect of perinatal inflammation, oxygen toxicity,
and mechanical ventilation on lung development [reviewed by
Jobe (37)]. Although these simplified animal models of BPD only
approximate the actual disease in humans, they have helped us
immensely to better understand the pathophysiology of BPD. A
number of recent reviews have generated a detailed overview of
the various pathophysiological mechanisms implicated in BPD
that have been uncovered through these models [see review by
Niedermaier and Hilgendorff (106) and Hilgendorff and O’Reilly
(107)], focusing on the role of perinatal infection and inflammation (46, 108, 109), pulmonary vascular development (17), the
mesenchyme (110), the extracellular matrix (111), and oxygen
(112) [Figure 2 (107)]. For the remainder of this review, we will
highlight new pathophysiological concepts that are promising
avenues for potential future therapies for BPD. Because of the
inherent intertwinement of the pathophysiological mechanisms
and potential therapies, we have chosen to present these side by
side for each pathophysiological concept.
Stem Cells in Development and for
Therapy of BPD
In the past decade, the field of stem cell biology has advanced
significantly, especially with respect to tissue resident stem cells
in development and repair. A wide variety of lung epithelial stem/
progenitor cells has been described but also multipotent mesenchymal stromal cells (MSCs) and endothelial colony forming
cells (ECFCs) [reviewed in Ref (113)]. In the developing lung,
where an extensive microvasculature is crucial for lung function,
resident lung MSCs (L-MSCs) are a heterogeneous progenitor
population, which orchestrate the formation of the alveolar
microvasculature, repair/regeneration, and tissue maintenance
[reviewed in Ref (114, 115)]. Already at the beginning of lung
budding, a multipotent cardiopulmonary mesoderm progenitor
has been described, based on expression of Wnt2, Gli1 and Isl1,
giving rise to pulmonary vascular and airway smooth muscle,
proximal vascular endothelium and pericyte-like cells (116).
During pseudoglandular lung development early Tbx4+ multipotent MSCs give rise to a wide variety of distinct mesenchymal cell
populations including airway and vascular smooth muscle and
early fibroblast-like cells (117), reminiscent of quintipotential
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FIGURE 2 | A schematic overview of the pathophysiology of bronchopulmonary dysplasia (BPD). Pre- and postnatal risk factors lead to lung injury,
resulting in apoptosis of distal lung cells, inflammation, extracellular matrix remodeling and altered growth factor signaling. These have long term effects on lung
growth and function, including vascular and immune function, resulting in an increased disposition for chronic lung disorders. Figure reprinted from Hilgendorff and
O’Reilly, originally published by Frontiers in Medicine (107).
MSCs in bone marrow (118). During saccular and alveolar lung
development, Pdgfrα+, Shh+, and Fgf10+ L-MSCs give rise to
myofibroblasts and lipofibroblasts, which are crucial for alveolar
Frontiers in Medicine | www.frontiersin.org
development (119–122). Importantly, Pdgfrα + L-MSCs are supportive of lung epithelial progenitor cells, which are unable to form
colonies in their absence or in the presence of more differentiated
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Pulmonary Macrophages Contribute to
Alveolar Development and Repair
myofibroblasts (123, 124). There is mounting evidence from both
human patients and animal models that L-MSCs are perturbed
in BPD, potentially actively contributing to BPD pathogenesis.
The presence of L-MSCs in tracheal aspirates from ventilated
preterm infants could predict the subsequent development of
BPD (125). In vitro, these L-MSCs showed signs of dysfunction
through reduced PDGFRα expression, a propensity toward
myofibroblast differentiation and impaired migration capacity
(126, 127). This is supported by a recent study in neonatal mice,
where suppression of Fgf10 expression left alveolar epithelial
type 2 cells (AEC2) unable to regenerate after hyperoxia damage,
leading to increased AEC1 differentiation (128). Combined with
prior observations in parabronchial smooth muscle cells upon
naphthalene injury (129), the secretion of FGF10 to stimulate
epithelial repair may be one of the ways through which L-MSCs
exert their regenerative capacities in the distal lung following
injury (130).
Similarly, lung resident ECFCs, which are important for
the development of the pulmonary microvasculature, were
shown to be dysfunctional in a neonatal rat model of BPD
(131). Moreover, the cord blood of preterm infants who go on
to develop BPD contains lower numbers of circulating ECFCs,
which are more vulnerable to hyperoxia-induced oxidative
stress and dysfunction (132). Understanding how these resident progenitor populations are affected in BPD, but also how
they normally mediate development, repair, and regeneration
in the lung, will provide an insight into how we may mobilize
these cells to actively engage in repair and normalize lung
development.
Arguably the most important immune cells to participate in wound
repair are alternatively activated macrophages. Besides peripheral
blood derived macrophages, the pulmonary microenvironment contains three distinct resident pulmonary macrophage
populations: alveolar macrophages, interstitial macrophages
and primitive macrophages (140). Alveolar macrophages are the
best-studied subset and are most abundantly present in the lung.
They reside in the alveolar spaces where they phagocytose foreign
particles and have a crucial role in the surfactant metabolism
that facilitates alveolar function and gas exchange. Interstitial
macrophages (IMF) reside on the other side of the epithelial
barrier, among mesenchymal cells and capillaries. They have a
distinct phenotype and behavior from alveolar macrophages and
are geared more toward tissue repair and maintenance, antigen
presentation and influencing dendritic cell functions to prevent
allergy (140, 141). The third population, primitive macrophages,
has only very recently been identified as a distinct subtype. These
macrophages are the first to colonize the fetal lungs, and persist in
adult lungs in the parenchyma of the peripheral alveoli. Because
of their location in peripheral and perivascular spaces, which have
been described as hotspots for alveolar regeneration, they are
speculated to promote or be attracted to stem cell activity (140).
The influx of these macrophages, which display an alternatively
activated or M2 phenotype, and localization at the branching
sites of the developing lung, suggest they potentially contribute
to alveolar lung development (142). Conversely, if fetal lung
macrophages are activated by an inflammatory stimulus, they
actively inhibit expression of genes critical for lung development,
leading to disrupted airway development and perinatal death in
mice (143).
Potential Therapies
Tapping into and stimulating the regenerative properties of
L-MSCs and ECFCs through cell-based therapy may be a central
way to ameliorate the lung injury leading to BPD pathogenesis. To this end, important lessons will come from exogenous
stem cell therapy. In a neonatal rat hyperoxia model of BPD,
intratracheal installation of either bone marrow or umbilical
cord derived MSCs, or their conditioned media, could nearly
completely repair experimental BPD, both on a histological and
on a functional level (133, 134). The mode of action appears to
be largely paracrine, as injection with MSC conditioned medium
could promote alternatively activated (M2) macrophages (135).
Exosomes, which are extracellular vesicles containing a cocktail
of proteins, RNAs and even mitochondria, are secreted by a wide
variety of cells including MSCs and likely play an active role in
the paracrine therapeutic effects of MSCs (136). Their potential as
a carrier of therapeutic paracrine factors makes them appealing
and promising targets for cell-free MSC based therapy. However,
several technical challenges must be overcome to ensure their
safety, such as a robust reproducible isolation technique and
their ability to facilitate infectious or damaging particles (137).
The next decade will likely see large advances in the development of exogenous stem cell therapy for BPD and a vast array
of other diseases, either by injecting stem cells themselves, their
conditioned medium or through exosomes [see recent reviews
by Möbius and Thébaud (138), O’Reilly and Thébaud (139), and
Mitsialis and Kourembanas (136)].
Frontiers in Medicine | www.frontiersin.org
Potential Therapies
These insights provide new support for anti-inflammatory treatments. Furthermore, exogenous MSC therapy may be beneficial
in regulating pulmonary macrophage activity. As cells with potent
immunomodulatory capacities, MSCs can regulate macrophage
function and polarization (144). Steady-state MSCs drive macrophages toward a wound healing or M2 phenotype through the
production of IL-6 and inhibit differentiation toward dendritic
cells (145, 146). However, in a proinflammatory environment
MSCs stimulate macrophages toward a pro-inflammatory M1
phenotype (147). Using cell-based therapy to activate resident
L-MSCs may therefore also be effective in promoting an M2
phenotype in pulmonary macrophages.
The Lung Microbiome: An Important
Emerging Field of Interest
Although there has been a surge in interest in the microbiome
thanks to the Human Microbiome Project, the lung was not
included in this research project. Research interest in the lung
microbiome is now however on the rise, uncovering that not
only the upper but also the lower airways are colonized, with
numbers of 10–100 bacterial cells per 1,000 human cells being
reported (148). The six most commonly detected bacterial phyla
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are found throughout the body, but composition varies per organ.
In the lung, composition varies between different areas, making
consistent sampling of the same area extremely important when
comparing between groups. The lungs of newborn infants are
already colonized at birth with a variety of bacterial phyla, most
predominately Acinetobacter (149). The composition of the lung
microbiome changes and stabilizes in the first month of life,
but is decidedly different in lungs of children and adult patients
with lung disease (148, 149). Interestingly, amniotic fluid and
the placenta harbor their own microbiota, suggesting that fetal
tissues already get colonized in utero, potentially having an effect
on early immune cell maturation (148).
Inflammation frequently occurs in preterm infants, both
antenatal (chorioamnionitis) and postnatal (sepsis), and can
strongly perturb lung development (150). In the neonatal period,
the immune system is still immature, and evidence is mounting
that host-microbial interactions are necessary for development
and homeostatic control of the immune system (151). Recently,
a strong correlation was found between decreased diversity of
the lung microbiome at the time of birth in preterm infants and
the development of BPD (149, 152). Other studies correlated
prolonged antibiotics use during the first week of life and BPD
(153, 154). The protective effect of bacterial exposure in early life
on asthma and allergy development, the “hygiene hypothesis,”
is extensively studied, and a greater microbial diversity of commensal bacteria seems to underlie this protective effect (148).
Beyond microbial diversity and exposure, the role of the lung
microbiome in the regulation and maturation of the immature
immune system and the developing neonatal lung is less clear.
One route of how the lung microbiome might train the immature
immune system is by inducing expression of programmed death
ligand 1 (PD-L1) in pulmonary dendritic cells. Lack of microbial
colonization, or blocking pulmonary PD-L1 during the first
2 weeks of life in mice, induced a disproportionate inflammatory
response to allergens later in life (155).
An imbalanced microbiome, called dysbiosis, may further
impact the inflammatory and tissue repair response to oxygen
exposure, as beneficial bacteria are lost or overrun by other
bacteria. An important emerging mechanism through which the
microbiome can influence cell function is through the production of microbial metabolites, such as short chain fatty acids or
tryptophane catabolites (156, 157). Tryptophane catabolites are
produced via the enzyme indoleamine 2,3-dioxygenase 1 (IDO1)
and function as agonists for the aryl hydrocarbon receptor (AhR).
AhR activation leads to an immune suppressive response through
the production of interleukin (IL) 22 and promotes development
of regulatory T-cells (158). One genus of bacteria capable of
metabolizing tryptophane into AhR agonists are Lactobacilli. The
beneficial effects of tryptophane metabolites and Lactobacilli have
been shown to inhibit inflammation and promote health in the
gut, central nervous system and the lung (156, 157). Treatment
of COPD patients with emphysema with the anti-inflammatory
macrolide antibiotic azithromycin, resulted in increased levels
of tryptophane catabolites in bronchoalveolar lavages, which
decreased macrophage production of proinflammatory cytokines
(156). In mice, intranasal administration of Lactobacilli was more
potent in reducing allergic airway inflammation than intragastric
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administration, possibly linked to an increase in regulatory
T lymphocytes in the lungs (159). Interestingly, Lactobacilli were
found to be significantly less abundant in the lungs of preterm
infants who develop BPD compared to preterm infants who are
BPD resistant (152). Within this cohort, Lactobacilli abundance
was particularly low in infants born to mothers with chorioamnionitis. Coincidentally, azithromycin treatment could reduce the
risk of BPD in preterm infants (160), particularly those colonized
with Ureaplasma spp., which have been associated with chorioamnionitis and BPD (161, 162). The beneficial impact of the lung
microbiome and specifically Lactobacilli on lung development is
supported by a study in mice, where there was a positive correlation between microbial abundance and lung development (163).
Injection of Lactobacilli into the lungs of germ-free mice could
improve alveolar development (163).
Potential Therapies
In the near future, a potentially interesting avenue of therapy for
the prevention or treatment of BPD may be the further exploration of the benefits of azithromycin. Following the bacterial lung
microbiome, the lung virome and mycobiome are now slowly also
becoming unraveled, which may provide further insights and
treatment opportunities (148, 164, 165). Additionally, the benefits
of pre- or probiotics to promote a healthy growth promoting lung
microbiome should be investigated, and in particular the presence
of Lactobacilli. d-Tryptophane was recently identified as a potent
probiotic that could ameliorate allergic airway inflammation in a
mouse model of allergic airway disease, and may therefore also
be of interest in the setting of BPD (166). One possible way to
achieve the same effect as tryptophane catabolites may be through
the proton pump inhibitor omeprazole, which induces detoxification enzyme cytochrome P540 (CYP)1A1 possibly through an
AhR-mediated process (167). AhR signaling is protective against
hyperoxic injury in human fetal pulmonary microvascular cells
and neonatal mice, likely because of its potent effects on the gene
expression of immunomodulatory and developmental pathways
(168). Combined pre- and postnatal omeprazole administration
could attenuate hyperoxic lung injury in preterm rabbits even at
low doses, making omeprazole an interesting potential therapeutic intervention to prevent BPD (167). Further studies are needed
to validate its effects and to ascertain that it has no adverse effects
on other developing organs.
Anti-inflammatory Agents
Bronchopulmonary dysplasia is primarily considered to be a
developmental disease resulting from perinatal inflammation,
and therefore specialists in the field have for the past decade
called for a special focus on the development and improvement
of anti-inflammatory therapies in BPD (169). Currently there
are multiple anti-inflammatory therapies under investigation.
Interleukin 1 receptor antagonist (IL1RA) is particularly promising, as it can prevent the development of experimental BPD when
administered at a low dose in the neonatal rodent “double hit”
model of BPD, consisting of hyperoxia and perinatal inflammation (170–172). In a sheep model for prenatal inflammation,
intra-amniotic IL1RA could partially prevent the effects that
lipopolysaccharide (LPS) had on lung maturation, measured as
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New Concepts in BPD
Reactive Oxygen Species (ROS) and
Mitochondrial Dysfunction
surfactant protein gene expression and lung compliance (173).
Interestingly, preterm infants who go on to develop BPD have
elevated levels of IL1RA in their tracheal aspirates (174). A more
recent study in preterm ventilated baboon and human infants
suggested however that an increased IL1β:IL1ra ratio on days
1 to 3 of life is more predictive of BPD (172). The same study
provided compelling animal data that early IL1RA or glyburide
therapy, which prevents the formation of the NLR family, pyrin
domain containing 3 (NLRP3) inflammasome upstream of IL1β,
can indeed ameliorate BPD development (172). IL1RA, also
called anakinra or Kineret, and glyburide, also known as Diabeta,
are both already approved by the Federal Drug Administration
(FDA) for treatment in rheumatoid arthritis and type 2 diabetes,
respectively, making them attractive treatment options. Future
studies will have to show whether their use would also be safe in
the neonatal setting.
Postnatal use of corticosteroids such as dexamethasone and
hydrocortisone, which are potent anti-inflammatory compounds,
can effectively reduce the incidence of BPD (175, 176). Despite this
positive effect, there are significant adverse effects associated with
systemic administration of corticosteroids. Short-term adverse
effects include intestinal perforation, gastrointestinal bleeding,
hypertension, hypertrophic cardiomyopathy, hyperglycemia, and
growth failure, while follow-up studies pointed to adverse effects
on neuronal development (175, 176). Experts in the field have
therefore questioned whether the beneficial effects of reducing
BPD and death can be weighed up to these significant adverse
effects (175, 176), and are reluctant to recommend postnatal
systemic corticosteroids for the prevention of BPD (177). A perhaps more compelling alternative would be to more specifically
target the lung through intratracheal administration. Early results
obtained with inhaled corticosteroids have been mixed (178, 179),
likely due to its efficiency to reach the lung parenchyma. However,
as more studies are being done, there is increasing evidence that
inhaled corticosteroids prevent BPD and death when administered early, but long term follow-up studies are needed to assess
the risk-benefit ratio (180–182). Recent in vitro studies in human
fetal lungs attributed budenoside more potent anti-inflammatory
effects than dexamethasone, swiftly decreasing gene expression
of chemokines IL8 and CCL2 (MCP1) in whole lungs even in
the presence of exogenous surfactant (183). Future validation
studies should however closely monitor the combined effect of
intratracheal corticosteroids and pre-existing pulmonary inflammation, as combined antenatal exposure of fetal sheep to LPS and
corticosteroids had much stronger effects on lung inflammation
and developmental pathways than either agent alone (184–187).
Additionally, it will be important to validate with combined
budenoside and surfactant treatment also has the potential to
prevent BPD in premature infants that initially present with mild
RDS and do not receive surfactant therapy (188).
Although BPD pathogenesis has a very multifactorial nature, with
oxygen exposure, mechanical ventilation and inflammation as
some of the most widely accepted causes, one common pathway is
shared by these insults: the generation of ROS. In animal models,
exposure of neonatal animals to hyperoxia within a specific time
period is sufficient to induce a pathophysiology similar to BPD
(189). Underlying this pathophysiology is an exaggerated mitochondrial oxidant stress in response in newborn mice compared
to adults, with an overall lower expression of antioxidant enzymes
(190). The response to hyperoxia is developmentally regulated,
leading specifically to the production of mitochondrial ROSdependent NADPH oxidase 1 (NOX1) expression in neonatal
animals (191). Expression of antioxidant enzymes is controlled
by AhR, as AhR-deficient fetal human pulmonary microvascular
cells displayed significantly attenuated antioxidant enzyme
expression and increased hyperoxic injury (192). Deficiency
of another key antioxidant enzyme, extracellular superoxide
dismutase (EC-SOD), was sufficient to impair alveolar development and induce pulmonary hypertension in mice (193). This
phenotype was worsened by additional oxidative stress caused by
bleomycin exposure, which was also associated with decreased
VEGF signaling (193). Further support for the hypothesis that
ROS formation also plays a role in human BPD development
has come from a genetic study in very low birth weight infants,
which found an association between single nucleotide polymorphisms (SNPs) in antioxidant response genes and an increased
or decreased risk for the development of BPD (194). The role of
antioxidant enzymes in neonatal chronic lung disease is reviewed
in depth by Berkelhamer and Farrow (195).
Mitochondria play a central role in oxygen metabolism, and
mitochondrial abundance as measured by mitochondrial protein
expression peaks around birth to facilitate the transition to the
oxygen-rich world outside the womb (196, 197). Preterm infants
are born before this peak, making them less prepared to deal with
this shift in bioenergetics. Besides this mitochondrial immaturity,
the exposures leading to chronic lung diseases have been linked to
mitochondrial dysfunction (198, 199). Both hyperoxia exposure
and mechanical ventilation of neonatal mice caused pulmonary
mitochondrial dysfunction (200, 201). Moreover, direct inhibition of mitochondrial oxidative phosphorylation significantly
impaired alveolar development, comparable to hyperoxia or
mechanical ventilation. In vitro experiments indicate that
elevated CO2 levels, called hypercapnia, a common occurrence in
BPD patients, also causes mitochondrial dysfunction (202). One
potential mechanism through which mitochondrial dysfunction
and ROS generation potentially lead to impaired alveolar development in hyperoxia exposed neonatal mice is through endoplasmic
reticulum (ER) stress, which can cause apoptosis (82).
Potential Therapies
Potential Therapies
As outlined above, IL1RA, glyburide, and inhaled budenoside are
currently the most promising anti-inflammatory therapies that
have the potential to prevent BPD in premature infants. However,
more studies will have to look into the safety and potential longterm effects in human neonates.
In animal studies, several potential treatments have been identified to decrease ROS generation. In neonatal mice, treatment with
a specific mitochondrial antioxidant, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium
chloride (mitoTEMPO), could protect against hyperoxia-induced
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lung injury (191). Another promising treatment compound is
GYY4137, a slow-releasing H2S donor, which could decrease
ROS generation and thus protect and restore normal alveolar and
microvascular development after neonatal hyperoxia injury in
rats (203). Targeting the AhR would appear to be another promising approach considering it also has potent anti-inflammatory
properties, as described above. Although omeprazole is generally
seen as a potentiator of AhR activation, omeprazole treatment of
hyperoxia-exposed newborn mice counterintuitively decreased
functional AhR activation, worsening hyperoxic injury (204).
Other approaches to promote AhR activation may however prove
to be more effective. An entirely different approach in treating
mitochondrial dysfunction may be through mitochondrial transfer, a process that has been reported as one of the therapeutic
mechanisms of MSC therapy (205). In human BPD patients, most
neonatal antioxidant trials have unfortunately not shown any
benefit in the prevention of BPD, with the exception of vitamin A
therapy (195). However, none of these antioxidant therapies were
specifically targeted against mitochondrial ROS or dysfunction.
More targeted approaches, as those outlined in the animal studies, may prove to be more promising.
date no study has been able to show a significant reduction in the
development of BPD following LF supplementation (214).
A pathophysiological mechanism of BPD that is slowly
gaining more attention is the link between pre-eclampsia and
BPD. Pre-eclampsia a proven risk factor for BPD (41), and the
underlying impact on the developing fetus may be three-fold.
Firstly, maternal preeclampsia is a frequent cause of preterm
birth before 28 weeks (215). Secondly, severe preeclampsia can
lead to intrauterine growth restriction, which in itself is a strong
risk factor for BPD (38, 39). Thirdly, the placental dysfunction
that lies at the root of pre-eclampsia leads to an overproduction
of soluble VEGF receptor 1 [also known as soluble fms-like
tyrosine kinase-1 (sFlt-1)], which inhibits VEGF signaling
(216, 217). This not only leads to increased sVEGFR-1 in maternal
serum, but also in amniotic fluid (218). By giving pregnant rats
intra-amniotic injections with sVEGFR-1, Steven Abman’s group
demonstrated a link between pre-eclampsia and BPD, as neonatal
rats presented with impaired alveolar and microvascular development and right and left ventricular hypertrophy (40). Moreover,
intrauterine exposure to excess sVEGFR-1 led to increased
apoptosis of endothelial and mesenchymal cells in neonatal rat
lungs. Placental dysfunction and subsequent overexpression of
sVEGFR-1 may therefore be a potential therapeutic target to
improve fetal outcome and prevent development of BPD. At the
very least, the diagnosis of maternal pre-eclampsia should be considered as a serious predisposition for the development of BPD.
From a developmental biology perspective, developmental
molecular pathways that are downregulated in BPD provide other
potential targets for the amelioration of BPD pathogenesis. These
include the Wnt signaling pathway (187, 219, 220), SHH signaling (185, 221–223), axonal guidance cues semaphorin 3 C and
ephrin B2 (224, 225), Notch signaling (226, 227), and HIFs (228).
In addition, a wealth of new molecular insights on mouse and
human lung development has been and will be published in the
upcoming years by the LungMAP consortium (1U01HL122638),
funded by the National Heart, Lung, and Blood Institute (NHLBI)
(http://www.lungmap.net) (229, 230). BPD is generally considered to be caused by environmental factors, but in recent years
studies have uncovered that a genetic component may also be
at play [reviewed in Ref (231, 232)]. Although associations are
not conclusive, these studies suggest that genetic variants of
genes in well-known lung development and repair pathways may
predispose for severe BPD or mild/moderate BPD (232). microRNAs have emerged as both a pathophysiological mechanism
and a tempting tool to target transcription of multiple of these
developmental signaling pathways at once. Although multiple
human and animal studies have reported an association between
altered microRNA levels and BPD, valid concerns have been
raised about the lack of a causal link between altered microRNA
levels and BPD pathogenesis [reviewed in Ref (233)]. However,
if such a causal link can be confirmed, as was recently seen in a
study which demonstrated the regulation of alveolar septation by
microRNA-489 (234), the use of specific microRNA antagonists
or agonists may be considered as a potential therapy for BPD.
Caution should however be exercised when directly modulating
potent developmental pathways, either directly or through microRNA therapy. Further exploration of such therapeutic targets
Other Promising Therapeutic Options
Based on Novel Pathophysiological
Insights
Inflammation associated with BPD pathogenesis affects many
molecular pathways, which by themselves can be interesting
therapeutic targets. One of these is the ceramide pathway, which
is upregulated in both hyperoxia and antenatal inflammation animal models (206–208) and also in other chronic lung diseases such
as asthma, cystic fibrosis and COPD (209). Increased ceramide
levels lead to increased apoptosis, both in epithelial cells of BPD
patients and in animal models of BPD (208, 209). Intervention
with a sphingosine-1-phosphate (S1P) analog in the mouse
hyperoxia model of BPD could successfully ameliorate ceramide
levels and hyperoxia-induced alveolar hypoplasia (208). In a more
complex piglet model of lung injury by lavage, LPS instillation
and injurious ventilation, tracheal installation with surfactant and
d-myo-inositol-1,2,6-trisphosphate (IP3) could achieve a similar
effect in reducing ceramide levels and improving oxygenation
(210). In a different approach to decrease sensitivity to apoptosis
in hyperoxia-exposed epithelial cells, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) could
prevent hyperoxia-induced lung injury in neonatal mice (211).
Based on these studies, selective pharmacological interventions
which temporarily reduce apoptosis could be a promising way to
prevent or repair neonatal lung injury and reduce BPD severity.
An intervention that has garnered attention in neonatal care
is lactoferrin (LF), an iron-binding protein that is a normal
component of human colostrum and milk (212). It has potent
antimicrobial activity, can stimulate the innate immune system
and promote epithelial proliferation and differentiation of the
immature gut (213). Recent studies have identified LF supplementation as a promising agent for the reduction of late onset
sepsis and necrotizing enterocolitis (214). Although the properties of LF may also be desirable for the prevention of BPD, to
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FIGURE 3 | Continued
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New Concepts in BPD
FIGURE 3 | Continued
Summary of new pathophysiological concepts in bronchopulmonary dysplasia (BPD). In normal alveolar lung development, a diverse microbiome is
necessary to train the pulmonary immune system and secrete metabolites that support lung development. Pulmonary M2 interstitial macrophages (M2 IMφ) are
present and likely play an active role in lung development. L-MSCs support M2 IMφ, alveolar epithelial cells and the microvasculature. In BPD (bottom panel),
pre- and postnatal risk factors lead to decreased microbiome diversity, a proinflammatory environment, dysfunctional L-MSCs, epithelial and endothelial injury and
impaired repair. LF, lipofibroblast; EC, endothelial cell; AMΦ, alveolar macrophage; L-MSC, lung mesenchymal stromal cell; AEC2, alveolar epithelial cell type 2; M1/
M2 IMΦ, type 1/2 interstitial macrophage; DC, dendritic cell.
• Cell-based therapies, either through administration of stem
cells and their products or by promoting the regenerative
potential of resident lung stem cells.
• The commensal role of the pre- and postnatal (lung) microbiome in the normal and perturbed lung development, and its
potential as a therapeutic target.
• The role of placental dysfunction in the pathogenesis of BPD,
and its potential as a therapeutic target in the prevention of
BPD.
• The role of the immune system not only as an adverse factor
in BPD pathogenesis, but its importance in supporting normal
lung development and repair.
should perhaps be combined with slow releasing microparticles
or capsules to ensure a more physiological release and prevent
pathological side effects.
Conclusion and Future Directions
The pathophysiology of BPD is extremely multifactorial, which is
underlined by the emerging role of cell types that have only recently
been acknowledged, such as the microbiome, macrophages, and
tissue stem cells (Figure 3). Our knowledge on the pathophysiology is poised to move forward rapidly in the next decade, due to
exciting new technological advances in the research field, and
is opening avenues for the pursuit of therapeutic options. In
addition, there is still promise for new and better applications of
existing therapies, which have not yet fulfilled their promise in
a clinical setting. In the next decade of BPD research, the most
promising therapies and pathophysiological concepts that should
be pursued for new therapeutic options are as follows:
AUTHOR CONTRIBUTIONS
Conception and outline of review: JC, DT, and RR. Writing of
the manuscript: JC. Drafting of the manuscript: JC, DT, and RR.
Critical revision of manuscript: JC, DT, IK, IR, and RR. Final
approval of manuscript: JC, DT, IK, IR, and RR.
• Animal models investigating the pathogenesis of BPD should
identify different sub-pathophysiological processes that arise
because of different combinations of pre-and postnatal exposures (e.g. pre-eclampsia, dysbiosis), as opposed to only looking at hyperoxia or inflammation models. Moreover, better
appreciation of extrapulmonary issues related to BPD might
be instructive, particularly neurodevelopmental outcome and
retinopathy, which are frequent long-term outcomes resulting
from BPD (235).
• Different routes of administration for effective therapies such
as vitamin A and postnatal corticosteroids, in particular
non-invasive intratracheal routes.
FUNDING
JC is supported by the Sophia Children’s Hospital Research
Foundation (S16-17) and by a Dirkje Postma Talent Award
from the Lung Foundation Netherlands (project 11.1.16.152).
IMK is supported by a VENI grant from the Dutch Scientific
Organization (NWO). RR is supported by the Sophia Children’s
Hospital Research Foundation (S17-20, S16-17, S15-11, S14-12,
678) and the Lung Foundation Netherlands.
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Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be
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