© 2003 American Thoracic Society
Bronchopulmonary DysplasiaOne Disease or Two?Departments of Paediatrics and Physiology University of Toronto Toronto, Ontario, Canada The successful introduction in the 1960s of positive pressure ventilation for newborn infants (1) heralded the modern era of neonatal intensive care. This approach enabled the survival of premature infants who would otherwise have died from neonatal respiratory distress syndrome. Shortly thereafter, Northway and coworkers (2) described a new syndrome of acute, subacute, and chronic lung disease appearing in some premature infants supported by oxygen and positive pressure ventilation. This syndrome was named bronchopulmonary dysplasia (BPD) secondary to the major pathologic features evident at autopsy, which included necrotizing bronchiolitis, vascular changes of pulmonary hypertension, inflammatory cell infiltration, and alveolar changes of alternating overinflation and atelectasis with pulmonary fibrosis (3). Northway and colleagues later attributed these changes, in major part, to pulmonary oxygen toxicity and immaturity (4). Other groups believed that ventilator-induced lung injury was the principal initiating factor in the development of BPD (5). Despite the initiation of this debate more than 25 years ago, and the subsequent recognition of other factors, including proinflammatory cytokines (6), which can contribute in an additive or synergistic fashion, the relative importance of oxygen toxicity and ventilator-induced lung injury in the development of BPD has remained unclear. In this issue of AJRCCM (pp. 57–64), Chang and colleagues (7) show unequivocally, through the use of an antioxidant intervention, that generation of reactive oxygen/nitrogen species during pulmonary oxygen toxicity is responsible for many of the pathologic features observed in a premature baboon model of BPD. Increased mucus plugging of small airways, collagen deposition, alveolar tissue and septal thickness, airspace overinflation and atelectasis, as well as reduced alveolar surface area, in animals exposed to 100% oxygen were all attenuated by the antioxidant intervention. These pathologic features are remarkably similar to those originally described for BPD in the human infant (3). This study would seem to settle at least one aspect of the longstanding debate alluded to previously: supplemental oxygen alone, through the generation of reactive oxygen species in excess of antioxidant defenses, can cause many or all of the pathologic changes of BPD as originally described by Northway and colleagues. Unfortunately, therein also lies the rub. In the 35 years since BPD was originally described, the clinical, radiologic, and pathologic features of the disease and the susceptible patient population have all changed dramatically. Indeed, the pathogenesis of BPD as seen then and now cannot be assumed to be identical. The patient population originally described by Northway and coworkers were delivered at an average gestational age of 32 weeks. It is uncommon for infants of that degree of immaturity to develop BPD in the current era. The reasons for this loss of susceptibility are not entirely clear but are likely to include the use of antenatal steroids to mature the lung surfactant system, and possibly the antioxidant enzyme system, the use of exogenous surfactant after birth, improved parenteral nutrition, and the development of ventilators and ventilator strategies more suited to premature infants. By far the majority of infants now seen with BPD have been delivered at 23 to 28 weeks gestation, a population that was largely nonviable at the time of the original report of BPD. The hallmark of BPD in this population is an arrest of alveologenesis. Airway injury and pulmonary fibrosis are no longer major features of lung pathology at autopsy or lung biopsy (8). Are the findings of Chang and colleagues (7) therefore only of historic interest, in that they address a disease variant, or even a different disease, which is no longer of major clinical significance? We would argue not. Despite the fact that the authors could not clearly address the effect of the antioxidant intervention on alveolar formation in this model, there are several valuable points to be taken from this study. After the seminal observation that oxygen-mediated mortality in laboratory animals could be prevented by parenteral injection of liposome-entrapped antioxidant enzymes (9), various antioxidant interventions have been shown to protect against the lethal effects of hyperoxia in both adult and newborn animals. Very few of these studies, however, have examined the lung pathology, as done by Chang and associates (7), to determine whether antioxidant interventions also confer protection against alterations in lung architecture. This study has also provided valuable dosimetric and distribution information for the use of the catalytic antioxidant metalloporphyrin in the newborn. Lastly, and most importantly, this study can be viewed as preliminary work leading to a study in a more clinically relevant model. The preterm baboon delivered at 125 days of gestation, after prenatal steroid treatment of pregnant dams and treatment with exogenous surfactant and respiratory support with oxygen and ventilation to maintain normal blood gases, develops a picture of BPD with arrested lung development comparable with that currently seen in extremely immature human infants (10). This model of BPD therefore has the advantage of occurring "naturally" in a setting comparable with that experienced by the extremely immature human infant where prolonged exposure to high concentrations of inspired oxygen is not required to arrest lung development. This does not preclude oxygen toxicity being a major determinant of abnormal lung development because oxidant stress, due to extreme immaturity of antioxidant defenses and a relative excess of reactive oxygen species formation, may occur even with minimal amounts of supplemental oxygen. It is clear from the reported studies in the 140-day gestation premature baboon (7) that the authors have the tool necessary to determine the role of oxygen in the 125-day model, and it is apparent from their manuscript that such studies are already underway. Interventional studies in the 125-day baboon model are of enormous clinical relevance. So far the only therapy widely believed to be effective, at least in the short term, in the human infant with evolving BPD has been the use of dexamethasone. Unfortunately, there have been worrying reports of an association between the use of dexamethasone and adverse neurodevelopmental outcome, such that its use has been severely curtailed. Safe and effective replacements are urgently needed. We eagerly await the results of the next trial of the catalytic antioxidant metalloporphyrin in the 125-day baboon. REFERENCES
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