Keywords
lung injury - injury repair - postnatal steroids - injury tolerance
Definition and Epidemiology of BPD
Definition and Epidemiology of BPD
Although the definition of bronchopulmonary dysplasia (BPD) has evolved as the surviving
preterm infants that develop BPD have become more immature, the definition provides
minimal insight into the pulmonary abnormalities.[1] The incidence of BPD in surviving infants ≤ 28 weeks gestational age has been approximately
40% for over 20 years.[2] The lack of decrease of incidence in part results in survival of smaller or more
compromised infants that are more likely to develop BPD. The incidence and severity
of BPD increase based on variables available at or shortly after birth—birth weight,
gestational age, sex, growth restriction, and lung function. These variables relate
to the fetal state of lung development/maturation at birth ([Fig. 1]). However, the definitions of BPD depend only on lung-directed therapy with supplemental
oxygen and/or ventilator support with positive pressure at 36-weeks gestational age.
Thus, the disease is defined by its therapy and not by pathology, radiology, or injury
markers. Based on the multiple variables that contribute to lung injury in the preterm,
it is likely that there are multiple pathologies in the airways, of epithelial surfaces,
mesenchyme, and the pulmonary vasculature that are variably contributing to an infant
being classified as having BPD. For example, traditional BPD definitions that rely
on supplemental oxygen are problematic for infants that require pressure (continuous
positive airway pressure, high flow nasal catheters) but no oxygen.[3] The lung functional abnormalities may include decreased saccular/alveolar septation,
decreased microvascular cross-sectional area with or without pulmonary hypertension,
airway injury with or without increased airway reactivity, and abnormalities of control
of breathing in various combinations. This complexity is not captured by the clinical
definitions of BPD, and different phenotypes of BPD have not been well characterized
in individual infants.
Fig. 1 A diagram of some of the factors that can contribute to bronchopulmonary dysplasia.
The focus is on how long development is modulated by multiple injuries and repair
over time.
Injury Mechanisms in BPD
I find a helpful concept to be that BPD is an injury syndrome superimposed on the
essential lung growth and maturation (development) required for survival ([Fig. 1]).[4] Counteracting the injury is a poorly understood repair program that must support
repair of injury and lung development for the infant to survive. What are the injuries
and are their common elements that might identify treatment options? The substrate
for BPD is the very preterm lung that is certainly structurally immature even if there
is sufficient maturation (saccularization and surface area plus surfactant) to support
gas exchange. Chorioamnionitis can cause lung inflammation before birth; growth restriction
can interfere with lung structural development, and maternal vascular diseases such
as preeclampsia can disrupt fetal lung vascular development to increase the risk of
BPD.[1] The major injury drivers for the fetal lung are inflammation and developmental disruptions
such as growth restriction and nicotine exposure.
The assisted ventilation required to initiate breathing at birth in the very preterm
lung can injure the lung by exposure to high pressures, volumes, and oxygen. Both
ventilation and oxygen-mediated injury initially activate inflammatory pathways that
can amplify preexisting injury (chorioamnionitis) or be amplified by continued exposure
to oxygen and ventilation-mediated injury.[5]
Subsequent oxygen exposure and mechanical ventilation will cause continuous injury
to the very preterm lung, primarily mediated by inflammatory mechanisms. In term rodent
models of BPD, blocking multiple inflammatory pathways (granulocyte recruitment, cytokines,
prostanoids, oxidants) will prevent much of the inhibition of airway septation and
microvascular injury. These experiments are proof of principle that multiple inflammatory
pathways contribute to the pathology, although translation to clinical treatments
has been disappointing.[6]
Postnatal Corticosteroids: Revisited
Postnatal Corticosteroids: Revisited
Common threads through the mechanisms responsible for BPD are multiple inflammatory
mediators and pathways. Corticosteroids are potent and pleiotropic anti-inflammatory
drugs that are also developmental disruptors that interfere with airway septation
and microvascular development. However, in numerous clinical trials corticosteroids
decrease BPD when given either soon after birth to decrease BPD or later in the clinical
course to decrease injury progression.[7] There has been a particular concern about using corticosteroids soon after birth
because of gut and brain developmental complications. However, and consistent with
the rodent models, three recent trials have demonstrated that corticosteroids can
decrease BPD when given soon after birth, a proof of principle that inflammation initiated
before or soon after birth is central to BPD progression. In large randomized controlled
trials, Bassler et al[8] decreased BPD with a budesonide aerosol, Baud et al[9] decreased BPD using a 10-day low-dose hydrocortisone infusion beginning on the first
day after birth, and Yeh et al[10] mixed surfactant with budesonide for the initial surfactant treatments of infants
with respiratory distress syndrome and decreased BPD by 21%. The Yeh et al's trial
is particularly intriguing as the corticosteroid is targeted to the lung soon after
birth and results in minimal systemic exposure of the infant to the steroid. While
anti-inflammatory therapies that are targeted to specific inflammatory mediators would
be desirable, the clinicians should reconsider postnatal corticosteroid treatments
along with continued efforts to minimize oxygen and ventilation injury in very preterm
infants to decrease the incidence and severity of BPD.
BPD Is Complex: Interactions
BPD Is Complex: Interactions
The simultaneous and continuous need to promote lung development, minimize injury,
and optimize repair is a complex goal for which the field has insufficient information
to optimize. Lessons from observations in other systems may provide some insight into
the complexity of the pathophysiology that may be driving BPD. In immunology, a pathogen
can directly damage tissue, induce host resistance (immunity) or induce a host inflammatory/immune
response that may cause more injury that the initial pathogen exposure. The host also
may have tolerance responses that can modulate the injury response.[11] Other variables are the effects of pre-exposures that can precondition or tolerize
to a second more injurious stimulus ([Fig. 2]).[12] Based primarily on studies of the fetal/newborn brain, a low-grade insult, such
as hypoxia, hyperoxia, lipopolysaccharide or specific cytokines can greatly modulate
the injury response to a second insult, which can be the same or a different insult.
That initial exposure can increase or decrease the response to the second exposure
depending on the time interval between exposures. I suspect that the variability in
injury and repair in infants at risk of BPD results from modulation of responses.
These complex interactions remain to be explored.
Fig. 2 Schematic of how exposure or increase to low grade injury mechanisms can modulate
a secondary larger injury to decrease the injury by inducing protective mechanisms
or by augmenting the injury.
