Alan H. Jobe and Eduardo Bancalari
Children’s Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio; and Department of Pediatrics, University of Miami, Miami, Florida
Background and Reason for Workshop
Bronchopulmonary Dysplasia (BPD) was first described by
Northway and colleagues in 1967 as a lung injury in preterm infants
resulting from oxygen and mechanical ventilation (1). A
National Heart, Lung, and Blood Institute (NHLBI)-sponsored
workshop further defined the disease and suggested research initiatives
in 1978 (2). The pathophysiology of BPD was extensively
reviewed by O’Brodovich and Mellins in 1985 (3). Subsequent
research with animal models has shown that the very preterm
lung can be acutely injured by either oxygen or mechanical ventilation,
resulting in interference with or inhibition of lung alveolar
and vascular development (4, 5). A change in the pathology
of the lungs of infants who have died of BPD has also been
found as smaller and more immature infants have come to constitute
the majority of the infants who develop BPD (6, 7). A recently
published book contains multiple reviews of all aspects of
BPD (8). This workshop was organized by the National Institute
of Child Health and Human Development (NICHD) and
the NHLBI, together with the Office of Rare Diseases (ORD),
to review the definition of BPD and lung injury in very preterm
infants, to identify gaps in knowledge about lung development
and the best indicators of outcome for infants with BPD, and to
determine priorities for future research.
BPD is now infrequent in infants of more than 1,200 g birth
weight or with gestations exceeding 30 week (9). Gentler ventilation
techniques, antenatal glucocorticoid therapy, and surfactant
treatments have minimized severe lung injury in larger
and more mature infants. However, some patients who develop
BPD are more enigmatic. These consist of very low
birth weight infants who initially have minimal or no lung disease
but who develop increasing oxygen and ventilatory needs
over the first several weeks of life (9, 10). Some of these infants
with minimal lung disease that progresses to BPD may
have been exposed to chronic chorioamnionitis (11). The incidence
of BPD defined as an oxygen need at 36 week postmenstrual
age is about 30% for infants with birth weights <
(6). Some of these infants have severe lung disease requiring
ventilation and/or supplemental oxygen for months or years.
Pathology of the New BPD
Burri reviewed normal lung development and identified a number
of questions and controversies surrounding it (12, 13). The concept
that only conducting airways are formed during the pseudoglandular
period of lung development may not be correct, because future
gas-exchanging airways can already be identified at this point.
Burri proposed that a mantle of mesenchyme over the saccular
lung may be producing undifferentiated cells that become integrated
in the differentiating lung. The alveolar stage of lung development
in the human is from about 36 week gestation to 18 monthspostnatally,
but the majority of alveolarization occurs within 5 to 6 months
of term birth. The current concept is that primary septation forms
saccules and that secondary septal crests indicate alveolarization.
Burri questions whether these are separable processes rather than
a continuum of septation, with some potential for alveolar development
even after most alveolarization has ceased. The arborization
of the pulmonary microvasculature is intense as the lung
grows, even after completion of the major phase of alveolarization
(14). An in-depth understanding of the interdependence of alveolization
and microvascular development is needed for a better understanding
of the pathophysiology of BPD.
Hussain characterized the “new” BPD on the basis of pathology
found in infants dying from BPD (15). Before the surfactant
treatment era, airway injury, inflammation, and parenchymal fibrosis
were the prominent findings in BPD. More recently, the
lungs of infants dying from BPD have shown less fibrosis and
more uniform inflation. The large and small airways are remarkably
free of epithelial metaplasia, smooth-muscle hypertrophy,
and fibrosis. However, there are fewer and larger alveoli, indicating
an interference with septation despite an increase in elastic
tissue that is proportionate to the severity and duration of the
respiratory disease before death (16). Some specimens also have
decreased pulmonary microvascular development. The few biopsy
specimens available from surviving infants show a similar
decrease in alveolarization (5). More information is needed
about the progression of the lung injury in survivors of BPD.
Mechanical ventilation and oxygen can interfere with alveolar
and vascular development in preterm baboons and sheep
(5, 17). Coalson demonstrated that 7 d of mechanical ventilation
of preterm baboons of 140 d gestation with 100% oxygen
severely reduced the numbers of alveoli (4). The same interference
with septation of the more preterm 125-d–gestation
baboon lung occurs after surfactant treatment and ventilation
but without exposure to large amounts of supplemental oxygen
(5). The large decrease in surface area is associated with a decreased
and dysmorphic pulmonary microvasculature. These
anatomic changes are associated with persistent increases in
white blood cells and cytokine levels in airway samples. Although
ventilation of preterm baboons from birth with high-frequency
oscillatory ventilation resulted in somewhat better gas
exchange, better lung mechanics, and lower proinflammatory
cytokine levels than did conventional ventilation, both ventilation
techniques interfered with septation (18). The relationships
between the lung injury and inflammatory responses and lung
vascular and alveolar hypoplasia need to be better characterized.
Infants with severe BPD have pulmonary hypertension and
abnormal vascular development. In model systems of pulmonary
hypertension caused by chronic hypoxia in calves, Stenmark
has identified vascular adventitial fibroblasts that proliferate
and migrate into the media of resistance vessels in the
presence of hypoxia (19). These hypoxia-sensitive cells express
matrix metalloproteinase-2, and inhibitors of this metalloproteinase
block migration of the cells into the vessels. These fibroblasts
of adventitial origin may be sentinel cells that can
transdifferentiate and contribute to pulmonary hypertension.
The molecular signals causing hypoxic activation of adventitial
fibroblasts are being identified (20). The relationship between
the decrease in septation and vascular development in
BPD is not understood, nor is the potential for recovery from
either of these abnormalities.
Genetics may contribute to BPD at multiple levels. Genetic
polymorphisms in the population may result in increased risks
for developing BPD, as was recently shown for respiratory distress
syndrome in the Finnish population (21). Through the
use of gene ablation in animal models, factors such as fibroblast
growth factor-10, Bmp-4, and NKx2.1 were shown to be
essential for early lung development (22). This signaling circuitry
of morphoregulators of early lung development is likely
to be equally important and more complex in location and in
developmental timing for alveolar and vascular development.
Newly developed techniques to regulate genes at precise times
during development will provide critical information about the
effects of specific genes on lung developmental stages relevant
to BPD. Minoo emphasized that there will undoubtedly be
complex interactions between morphoregulators of lung development
and the inflammatory mediators present in the injured
lung (23). Factors such as transforming growth factor (TGF)-
exhibit sexual dimorphism and may predict the development of
BPD of sufficient severity as to need home oxygen therapy (24).
Advances in expression technology and proteinomics should be
applied to lung injury in the preterm infant to begin to identify
those genes that contribute to the injury sequence.
Mechanisms of Lung Injury
Multiple factors contribute to BPD, and probably act additively
or synergistically to promote injury. The traditional view has
been that BPD is caused primarily by oxidant- and ventilation-mediated
injury. Oxygen alone can arrest septation of lungs that
are in the saccular stage of development (4, 25). Infants with
BPD who were exposed to higher levels of supplemental oxygen
to achieve higher levels of oxygen saturation were found to have
more persistent lung disease (26). Mechanical ventilation of preterm
animals without simultaneous exposure to high levels of
supplemental oxygen also results in the pathologic lesion of
BPD (5, 17). The initiation of mechanical ventilation in surfactant-treated preterm animals causes a proinflammatory response,
suggesting that any mechanical ventilation of the preterm
lung may be injurious (27). The avoidance of intubation
and mechanical ventilation with the use of continuous positive
airway pressure (CPAP) in the delivery room was associated
with a lower incidence of BPD, although this has not been validated
by randomized trials (28). Therefore, the development of
ventilation and oxygen-exposure strategies that minimize lung
injury is a priority for improving outcomes.
Continuing the theme of the possible importance of early
postnatal events as contributors to lung injury in the preterm
fetus, D. Carlton noted that the preterm lung contains very
few mature macrophages or granulocytes, and that granulocytes
appear in the lung soon after the initiation of ventilation
in animal models (29). The appearance of granulocytes in alveolar
washes correlates with pulmonary edema and with the
appearance of early indicators of injury, and occurs in parallel
with a decrease in circulating granulocytes. Preterm infants
who have a decrease in circulating granulocytes at about 1 h of
age have an increased risk of developing BPD (30). Proteases
produced by activated white blood cells in the lungs may contribute
to the progression of lung injury, as suggested by initial
α1-antitrypsin to decrease the risk of BPD (31).
The recruitment of neutrophils to the lungs soon after birth indicates
that the events surrounding birth have consequences
that can increase the risk of BPD. More information is needed
about what modulates neutrophil sequestration in the preterm
lung and about the downstream events that result in lung injury.
The theme that inflammation is central to the development
of BPD was further developed by Speer. Multiple proinflammatory
and chemotactic factors are present in the air spaces
of ventilated preterm infants, and these factors are found in
higher concentrations in the air spaces of infants who subsequently
develop BPD (32). Factors such as macrophage inflammatory
protein-1 and interleukin (IL)-8 persist in the air
spaces, and counterregulatory cytokines such as IL-10 may be
decreased, resulting in unregulated and persistent inflammation.
Infants exposed to antenatal infection/inflammation or
fetal colonization with
indicators in their air spaces at delivery (33). Inflammatory
cells are prominent in the interstitium as well as in
the air spaces, and lung epithelial cells also may synthesize inflammatory
mediators. Free radical production, enhanced by
free iron in the air spaces, can result in production of TGF-β
production and fibrosis. The relative importance of the different
factors discussed here to the pathophysiology of BPD remains to
be defined, and multiple pathways to injury are plausible.
Sunday has evaluated bombesin-like peptides (BLP) produced
by neuroendocrine cells as mediators in BPD (34). Infants
and baboons with BPD have increased numbers of neuroendocrine
cells, mast cells, and eosinophils in their lungs,
and treatment of preterm baboons with an anti-BLP blocking
antibody decreases the numbers of these “immunologic” cells
and results in less lung injury. BLP and other factors may elicit
or promote proinflammatory responses that progress to BPD.
Urinary BLP levels correlate with the severity of BPD in preterm
baboons, and infants destined to develop BPD have increased
urinary levels of BLP. BLP may be a useful early indicator
for the identification of infants at risk for BPD.
Because decreased numbers of alveoli are so striking in the
lungs of very preterm infants who die of BPD, understanding
the developmental regulation of septation and alveolarization is
a high priority in understanding the pathology of BPD. In experimental
models, hyperoxia, hypoxia, or poor nutrition can
decrease septation, as can glucocorticoid treatment (35). In
transgenic mice, overexpression of the cytokines tumor necrosis
, IL-6, or IL-11 also can interfere with alveolarization,
suggesting that the proinflammatory environment
of the air space of the preterm infant may contribute to the altered
septation (7). Massaro noted that all-trans
can increase septation in newborn rodents, and promote septation
in adult rats with elastase-induced emphysema (36).
These findings have been extended to the observations that
mice lacking the retinoic acid receptor (RAR)β
septation, and that treatment of rats with an RARβ
inhibits septation (37). There are several classes of RAR,
and their signaling relative to septation will need to be understood.
The inhibition of septation induced by glucocorticoids
in neonatal rats also can be reversed with retinoic acid (38).
These studies demonstrate that alveolarization can be regulated
once the signaling pathways involved in it are understood.
Interventions for BPD
Nutrition plays an important supportive role in the process of normal lung
development and maturation. Sosenko noted that
general undernutrition, and specifically insufficient protein intake,
may increase the vulnerability of the preterm infant to
oxidant-induced lung injury. Decreased glutathione levels may
impair the response to oxidant-induced lung injury, and protein
undernutrition may interfere with lung growth and DNA
synthesis. A protective effect of polyunsaturated fatty acids
against lung injury was reported in experimental animals (39).
However, several randomized, controlled clinical trials of polyunsaturated
fatty acid administration soon after birth failed to
show protection against BPD in preterm infants (40). The lack
of effect may have been related to the presence of toxic lipid
peroxidation products in the lipid preparations. The commercial
lipid preparations now available have reduced hydroperoxide
contents, and new trials may be justified. Vitamin A is a
nutrient that is important to cell growth and differentiation
and to airway epithelial cell integrity. In a recent randomized,
controlled multicenter clinical trial, vitamin A supplementation
caused a small but significant reduction in BPD (41). Additional
nutrients, such as inositol, sulfur-containing amino acids,
and selenium may provide the premature infant with additional
protection against the development of BPD (42). Evaluations
of nutritional interventions are warranted.
Many premature infants are exposed to increased oxygen
concentrations, and endogenous antioxidant enzyme activity
is relatively deficient at birth. Hyperoxic lung injury can be
ameliorated both in cell culture and in animals by the administration
of recombinant human superoxide dismutase (rhSOD)
(43). Davis reviewed a placebo-controlled multicenter trial of
the safety and efficacy of rhSOD in preventing BPD (44). Placebo
or rhSOD was instilled into the trachea after the first
dose of exogenous surfactant, and the treatment was continued
for up to 28 d or for as long as infants were ventilated. Although
there was no difference in the primary outcome of
death and/or BPD, the administration of rhSOD was associated
with less severe intraventricular hemorrhage and periventricular
leukomalacia. At 6 months and at 12 months of corrected age,
infants treated with rhSOD had a reduced need for respiratory
medications as compared with infants receiving placebo
(45). Antioxidant administration for the prevention and treatment
of BPD will need to be further evaluated.
Ballard (46) noted that lung development results from the
balance between stimulatory and inhibitory influences, and that
two of the key regulators are glucocorticoids and TGF-β. Glucocorticoids
accelerate the maturation of parenchymal structure,
increase surfactant production and lung compliance, reduce
vascular permeability, and increase lung water clearance.
The net results are improved lung function, better responses to
surfactant, and improved survival (46). Glucocorticoids modulate
both the transcriptional and posttranscriptional regulation
of surfactant components, and the effects are reversible after
treatment (47). Maturation of the surfactant system is also induced
by analogs of cyclic adenosine monophosphate. In contrast,
is an inhibitor of lung development (48). TGF-β
isoforms and receptors are expressed by fibroblasts and epithelial
cells in lung during early gestation. In cultured fetal lung,
inhibits branching and blocks differentiation of type II
increases in tracheal aspirates on the first day of life
in premature infants who subsequently develop BPD, suggesting
is involved in initiation of the injury in BPD.
Watterberg discussed the role of postnatal glucocorticoid
therapy for BPD. Many infants at risk for developing BPD are
treated with high doses of glucocorticoids, a therapy associated
with adverse effects, such as gastrointestinal perforation,
cardiac hypertrophy, short- and long-term growth failure, and
the possibility of neurodevelopmental compromise (49). Glucocorticoids
impair alveolar septation in animal models. Wattenberg
questioned the rationale for the high doses of dexamethasone
frequently used in BPD. Cortisol is a key factor in the
response of the lung to injury, and cortisol synthesis is suppressed
until relatively late in fetal life. Very preterm infants
may lack the capacity to produce enough cortisol to respond
to extrauterine stress, and infants who develop BPD have low
cortisol levels and a decreased response to adrenocorticotropic
hormone (50). In a pilot study, low-dose hydrocortisone, when
begun shortly after birth and given for 12 d, increased survival
without BPD at 36 week postmenstrual age (51). Further studies
are needed to evaluate low dose glucocorticoid therapy.
Pulmonary vascular resistance (Rpv) is often increased in infants
with BPD, and decreased vascular development may be an
important component of the pathophysiology of the disease (52).
Abman reported that the administration of antiangiogenesis
drugs such as fumagillin and thalidomide impaired pulmonary
vascular and alveolar development in rats, demonstrating that
angiogenesis can be a regulator of alveolar septation (53). Nitric
oxide (NO) is an important regulator of pulmonary vascular
tone, and NO synthase is expressed in the vascular endothelium
and bronchiolar epithelium. NOS increases in the early canalicular
stage of development, and inhaled NO increases pulmonary
blood flow and decreases Rpv in fetal lambs. NO also decreases
Rpv in infants with severe RDS and can improve oxygenation
(54). Although possible side effects of NO in the preterm infant
have not been adequately evaluated, NO may decrease the risk
of BPD by decreasing intrapulmonary and extrapulmonary
shunting and by decreasing inflammation in infants with severe
hyaline membrane disease. Clinical trials are needed to evaluate
NO therapy to prevent and treat BPD.
Mechanical ventilation alone can cause severe lung injury.
Carlo noted that insufficient positive end-expiratory pressure
(PEEP) and large tidal volumes are the main causes of acute
lung damage with mechanical ventilation (55). In adults with
acute respiratory distress syndrome, ventilation at low tidal
volume (VT) was associated with improved outcomes and decreased
mortality (56). This ventilation strategy has not been
evaluated in infants. No detrimental effects were observed in
an initial randomized, controlled trial of permissive hypercapnia
in preterm infants, although no benefit was demonstrated
(57). Because arterial carbon dioxide tension may not be a
good substitute for VT
, a prospective study, assessing varying
levels of VT
and PEEP, will be required.
Epidemiology and Evaluations of BPD
Preterm births continue to be the major challenge in obstetrics
and neonatology, accounting for most of the perinatal mortality
and long-term neurologic morbidity among newborns (58). Andrews
noted that approximately half of all preterm births result
from the spontaneous onset of preterm labor and that about a
third result from preterm premature rupture of the amniotic
membranes. The remaining 20% of preterm births are medically
indicated for specific maternal or fetal conditions. The rate
of clinically asymptomatic colonization of the chorioamnion
and the amniotic fluid increases as the gestational age at delivery
decreases. In one study, positive cultures of chorioamnion
were reported in 73% of women with spontaneous preterm
births occurring prior to 30 week gestation, and in 83% who had
newborns with birth weights under 1 kg. The colonizing bacteria
initiate an inflammatory cascade and the release of numerous
cytokines, chemokines, prostaglandins, and other bioactive
substances that can induce cervical ripening, preterm labor, and
membrane rupture (59). This inflammatory response may also
cause adverse neonatal outcomes, such as neurologic damage
and cerebral palsy, necrotizing enterocolitis, and BPD.
Palta presented the results at 8 years of a six-center follow-up of
infants with birth weights below 1.5 kg in an effort to identify
predictive factors for early and late respiratory and functional
outcomes (60, 61). Radiographic evidence of BPD at 36 week was
predictive for rehospitalization at ages 0 to 1 year, of the need for
asthma medications, and of wheezing at age 8 years, but the predictive
value of the radiographic changes diminished as the children
became older. On the other hand, patent ductus arteriosus increased
in predictive importance as the children aged. Oxygen
use at 36 weeks was not predictive of outcomes after 2 years of age. A
family history of asthma was predictive of most respiratory outcomes
among children without BPD. Many infants with BPD
seem to recover without long-term respiratory problems.
Tepper reviewed techniques to evaluate pulmonary outcomes.
The main determinant of chronic morbidity in patients
with BPD is the development of obstructive airway disease. This
is demonstrated by a decreased forced expiratory flow (FEF),
increased airway reactivity, and increased RV with a normal
TLC (62–64). In addition, carbon monoxide diffusion capacity
may be decreased. All abnormalities may normalize during the
first 3 years of life, except for that in FEF, which may remain decreased
to adulthood (65). Patients with BPD have increased
airway reactivity to bronchoconstricting agents, as well as persistent
respiratory symptoms. Curves of FEF versus volume, generated
with the squeeze or the forced suction method, are helpful
in detecting airway abnormalities even in patients who are clinically
asymptomatic. High-resolution computed tomographic
scans may provide information on airway size, wall thickness,
and hyperinflation caused by gas trapping, and on heterogeneity
within the airways and lung parenchyma. Longitudinal studies of
large cohorts of infants with BPD, from the neonatal period
through infancy, childhood, and to adulthood, are needed. The
development of new techniques to evaluate pulmonary structure
and function in different age groups will be crucial to identifying
the underlying mechanisms for persistent lung-functional abnormalities
in survivors of BPD.
With the change in clinical presentation of BPD, the original
description now applies only to a minority of patients (1).
A variety of definitions of BPD have been used in the literature.
The most widely used was that of the 1979 BPD workshop,
which defined BPD as 28 d of oxygen therapy with radiographic
changes (2). The oxygen requirement at 36 weeks
postmenstrual age was suggested as a better predictor of long-term
respiratory outcomes (66). These definitions have the
limitation that oxygen administration may vary according to
clinical practice among different centers. In an attempt to find
a better definition, Ehrenkranz analyzed the NICHD Neonatal
Network data base for all infants with birth weights under
1 kg and gestational ages under 32 weeks who were born between
January 1995 and December 1997. Oxygen administration for
the first 28 d resulted in the highest sensitivity, specificity, and
positive and negative predictive values for oxygen administration
at 36 weeks. With respect to predicting oxygen use at discharge,
oxygen administration at 36 weeks postmenstrual age had
the highest values for sensitivity, specificity, and the percent of
infants correctly classified. Rehospitalization for respiratory
causes, and the use of pulmonary medications after discharge,
were predicted similarly by the 28-d and the 36 weeks oxygen requirements.
Given the importance of a consistent definition of
BPD, a subcommittee was asked to develop a new definition.
General Discussion, New Definition of BPD,
and Research Priorities
All workshop participants contributed to a discussion of gaps
in knowledge and research priorities relating to BPD. The
best name of the disease referred to as BPD in the older literature,
and more recently as chronic lung disease, was discussed.
The consensus was to retain the name BPD because it
is clearly distinct from the multiple chronic lung diseases of
later life. A new definition, which categorizes the severity of
BPD, is proposed (Table 1). The definition for infants with
gestational ages <
32 weeks was validated preliminarily with the
NICHD Neonatal Network data base and Palta’s data (61),
but extensive validation will be needed to determine whether
this definition is superior to previous definitions of BPD. Radiographic
findings of BPD are inconsistently interpreted and
not routinely available at precise ages, and did not contribute
to the resolution of the new definition.
Research and training initiatives that are critical to better
understanding of the pathophysiology of BPD, and for exploring
therapies for it, are outlined in Table 2. The rapid progress
in understanding the developmental biology of the lung will
provide the essential information about the major signaling
pathways for lung-structural development. The stages of particular
interest for BPD will be saccular-to-alveolar development,
with the associated extracellular matrix and vascular development.
Once signaling pathways for alveolar and vascular
development are identified, studies of how oxidants, mechanical
stress, and inflammation may alter that signaling will be
critical to understanding BPD. Expression arrays developed
with preterm models of BPD and from human tissue should
complement mouse models in which manipulation of specific
genes is possible. Such studies will ultimately define what happens
when lung injury is superimposed on a prealveolized and
minimally vascularized developing lung.
Table 1. Definition of Bronchopulmonary Dysplasia: Diagnostic Criteria
||< 32 weeks
||≥ 32 weeks
|Time point of assessment
||36 weeks PMA or discharge to home, whichever comes first
||> 28 d but < 56 d postnasal age or discharge to home, whichever comes first
Treatment with oxygen > 21% for at least 28 d plus
||Breathing room air at 36 weeks PMA or discharge, whichever comes
||Breathing room air by 56 d postnatal age or discharge, whichever comes
||Need* for < 30% oxygen at 36 weeks PMA or discharge, whichever comes first
||Need* for < 30% oxygen at 56 d postnatal age or discharge, whichever
||Need* for ≥ 30% oxygen and/or positive pressure, (PPV or NCPAP) at 36 weeks PMA or discharge, whichever comes first
||Need* for ≥ 30% oxygen and/or positive pressure (PPV or NCPAP) at 56 d postnatal age or discharge, whichever comes first
Definition of abbreviations: BPD bronchopulmonary dysplasia; NCPAP
positive airway pressure; PMA
postmenstrual age; PPV
* A physiologic test confirming that the oxygen requirement at the assessment time
point remains to be defined. This assessment may include a pulse oximetry saturation
BPD usually develops in neonates being treated with oxygen and positive pressure
ventilation for respiratory failure, most commonly respiratory distress syndrome. Persistence
of clinical features of respiratory disease (tachypnea, retractions, rales) are considered
common to the broad description of BPD and have not been included in the
diagnostic criteria describing the severity of BPD. Infants treated with oxygen
and/or positive pressure for nonrespiratory disease (e.g., central apnea or diaphragmatic
paralysis) do not have BPD unless they also develop parenchymal lung disease
and exhibit clinical features of respiratory distress. A day of treatment with oxygen
means that the infant received oxygen >
21% for more than 12 h on that day. Treatment
21% and/or positive pressure at 36 weeks PMA, or at 56 d postnatal
age or discharge, should not reflect an “acute” event, but should rather reflect the infant’s
usual daily therapy for several days preceding and following 36 weeks PMA, 56 d
postnatal age, or discharge.
Table 2. Priorities for Better Characterizing the Pathophysiology of and Developing Effective Preventive
and Treatment Strategies for Bronchopulmonary Dysplasia
Understand the developmental processes of septation,
alveolarization, and vascularization
Learn how inflammation and injury are expressed by the
Differential gene expression in uninjured and injured lungs
Identify modulators of inflammation and injury
Use animal models of BPD to test new treatments
Clinical research priorities
Characterization of BPD
Establish a resource for tissue from infants dying with BPD
Develop new clinical tests for lung function in infants and children
Study genetic contributors to BPD in human populations
Prevention of BPD
Develop standards of care as a basis for clinical trials
Evaluate delivery room procedures and ventilation techniques
Evaluate nutritional, antioxidant, and anti-inflammatory interventions
Train physicians and physiologists with expertise in evaluating lung function
in infants and children
Definition of abbreviations: BPD bronchopulmonary dysplasia.
New insights into how the lung develops may yield useful
strategies for maturing the preterm lung that are more selective
and have fewer adverse effects than glucocorticoids. Also,
knowledge of the specific signaling pathways that interfere with
normal alveolar and vascular development should yield treatment
options to better promote lung development despite preterm
birth and the inevitable oxygen and ventilation exposures
necessary for clinical care. Optimizing this information will require
research targeted toward the specific abnormalities of
BPD, including unique characteristics of inflammation and tissue
responses in the preterm infant. These studies will require
animal models that are appropriate to the questions being
asked. Ultimately, the biological question is whether normal
lung development can be altered by injury or by treatment
strategies without adversely affecting subsequent development.
A risk is that interventions targeted at one component of the
system (e.g., the type II cell) may have a dichotomous effect
and adversely alter another component such as vascular development.
Animal models of BPD will be critical for testing treatment
strategies that affect lung-developmental sequences.
Clinical research is needed to better characterize the long-term
outcomes of infants with BPD as newly defined. Airway
disease and reactivity can be measured from early infancy.
However, there are no tests with which to evaluate the abnormalities
resulting from the arrested alveolar and vascular development
in BPD, or for monitoring how these abnormalities
change with time. Tests of gas diffusion with exercise may provide
information about the function of the alveolar–capillary
barrier. High-resolution imaging techniques may be useful.
Poor neurodevelopmental outcomes are associated with BPD,
and their possible pathophysiologic link to the disease via
proinflammatory mediators needs to be explored (58). Surrogate
indicators for the anatomic and functional consequences
of early lung injury resulting in BPD need to be developed to
facilitate treatment-directed clinical research.
Because BPD results from multiple insults to the preterm
lung that probably cause additive or synergistic injurious responses,
multiple aspects of care need careful assessment.
Given the wide variation in incidence of BPD among neonatal
care units (28), different elements of care in current use need
to be identified and subsequently evaluated with intervention
trials. Factors that are thought to contribute to BPD (delivery-room
care, oxygen, ventilation, macro- and micronutrient deficiencies,
antenatal and postnatal infection) will need to be
evaluated with clinical trials.
The pathologic description of the new BPD is based on tissue
from infants who have died. Much of this tissue is not optimally
collected and prepared. Better pathologic information
depends on the careful collection of tissue from infants who
die of BPD and infants with BPD who die from other causes.
The collection of tissue prepared according to protocol by a
centralized tissue bank could provide tissue with which investigators
could test for possible pathophysiologic factors as
they are identified in experimental models. The clinical research
and development of tests of pulmonary function for infants,
and the wide application of such tests, require trained
personnel. There is a severe lack of physicians with expertise
in the evaluation of lung function of infants and children, and
training programs in this area are needed.
Participants of the Conference
Soraya Abassi, M.D., Pennsylvania Hospital; Steven Abman,
M.D., University of Colorado; Duane Alexander, M.D., Institute
of Child Health and Human Development; Bill Andrews,
M.D., Ph.D., University of Alabama at Birmingham; Phillip
Ballard, M.D., Ph.D., Children’s Hospital of Philadelphia;
Roberta Ballard, M.D., Children’s Hospital of Philadelphia;
Eduardo Bancalari, M.D., University of Miami; Beverly
Banks, M.D., The Children’s Hospital of Philadelphia; Charlie
R. Bauer, M.D., University of Miami; Mary Anne Berberich,
Ph.D., NHLBI; Richard Bland, M.D., University of Utah; Peter
H. Burri, M.D., University of Bern; Waldemar Carlo,
M.D., University of Alabama at Birmingham; David P. Carlton,
M.D., University of Utah; Reese H. Clark, M.D., Pediatrix
Medical Group, Inc.; Jacqueline Coalson, Ph.D., University
of Texas; Jonathan Davis, M.D., State University of NY at
Stony Brook; Francesco J. DeMayo, Ph.D., Baylor College of
Medicine; Mary Demory, Office of Rare Diseases, NIH; Shahnaz
Duara, M.D., University of Miami; Manuel Durand, M.D.,
University of Southern California; Edmund A. Egan, M.D.,
Children’s Hospital at Buffalo; Richard A. Ehrenkranz, M.D.,
Yale University; Dorothy Gail, Ph.D., NHLBI; Fabio Ghezzi,
M.D., University of Insubria-Varese; Thomas Hazinski, M.D.,
Vanderbilt University; William A. Hodson, M.D., University of
Washington; Aliya Hussain, M.D., Loyola University Medical
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