Bronchopulmonary Dysplasia
"A Vascular Hypothesis"

Steven H. Abman, M.D.

Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado

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Despite major advances in perinatal medicine, including the introduction of surfactant therapy and new ventilator strategies, the premature newborn remains at risk for mortality and late morbidity due to the development of bronchopulmonary dysplasia (BPD). BPD is the chronic lung disease of infancy that follows ventilator and oxygen therapy for acute respiratory failure after premature birth (1, 2). Traditionally, BPD has been defined by the presence of persistent respiratory signs and symptoms, the need for supplemental oxygen to treat hypoxemia, and an abnormal chest radiograph at 36 wk corrected age. During long-term follow-up, children with BPD have variable degrees of persistent respiratory problems, including airflow limitation, gas trapping, exercise intolerance, pulmonary hypertension, and others. Recently, there has been growing recognition that infants with chronic lung disease after premature birth have a far different clinical course and pathology than had been observed in infants with BPD in the past (3, 4). Infants with BPD are now far less mature and have markedly lower birth weights than originally described over 30 yr ago. In addition to its changing epidemiology, the nature of BPD has also evolved, such that pathological signs of severe chronic lung injury with striking fibrosis and cellular proliferation are far less common. Infants with BPD now have less severe acute respiratory disease, and at autopsy, lung histology is predominantly characterized by arrested lung development, including impaired alveolar and vascular growth (2). That is, perinatal lung injury in neonates who are born during the late canalicular stage (at 24-27 wk gestation) disrupts the normal sequence of lung development, resulting in the histological pattern of alveolar simplification and "dysmorphic" vascular growth. Similar structural abnormalities have been demonstrated in animal models of BPD caused by chronic ventilation of premature lambs (6) and baboons (7). Thus, decreased alveolarization and abnormal vascular growth are the central hallmarks of the "new BPD," but mechanisms that inhibit lung growth in premature infants with severe BPD remain poorly understood.

During normal intrauterine development, lung volume and surface area dramatically increase during the late canalicular and early saccular stages (8). Secondary septation forms new alveoli in the late fetus and newborn, and continues at a slower rate during the first 2-3 yr of life. Parallel increases in vascular growth are closely synchronized with alveolarization during the same time periods, but molecular signals that link distal airspace growth with angiogenesis are uncertain. Of several angiogenic factors, vascular endothelial growth factor (VEGF) has been shown to play a central role in vascular development. VEGF is a potent endothelial cell-specific mitogen and survival factor that stimulates angiogenesis, promotes vessel remodeling, and enhances endothelial survival (9). VEGF signaling is absolutely critical for vascular development and embryonic survival (10), and appears to protect against hyperoxia or cytokine-induced endothelial cell injury (9, 11). Whether disruption of VEGF signaling impairs lung vascular growth and contributes to the pathogenesis of BPD has been uncertain.

Two papers in this issue of the American Journal of Respiratory and Critical Medicine provide new insights into the potential role of impaired VEGF signaling in the pathogenesis of severe BPD. First, Bhatt and coworkers studied the expression and cell-specific localization of VEGF and its receptors, as well as other angiogenic factors, in lung tissue from human infants dying with BPD (see pp. 1971-1980). In the BPD group, autopsy findings confirmed the typical patterns of alveolar simplification with "dysmorphic" microvasculature, as characterized by decreased vessel growth and the appearance of dilated vessels located deep within thickened septae, without extensive network organization. These authors convincingly demonstrate reduced lung VEGF mRNA and protein expression, as well as reduction of the VEGF receptor, flt-1 (VEGFR-1), in the lungs of infants with fatal BPD. They also report decreased expression of other endothelial markers, including PECAM-1 and tie-2, but no changes in lung angiopoietin 1 and VEGFR-2 content. In a second paper, Lassus and coworkers measured changes in lung, tracheal fluid, and plasma levels of VEGF in human premature newborns with acute respiratory distress syndrome (RDS) and BPD, and in term infants with severe pulmonary hypertension (pp. 1981-1987). They report that premature neonates who died with severe acute RDS have lower lung VEGF than survivors, that infants with BPD have lower tracheal VEGF levels, and that plasma VEGF is decreased in term infants with severe pulmonary hypertension.

Interpretation of data from both studies is partly limited due to the small number of study patients, problems with delays in preparing autopsy tissue for mRNA measurements, and an inability to distinguish markers of decreased vessel density and endothelial cell number from specific changes in gene and protein regulation. However, these findings provide strong support for the hypothesis that lung VEGF expression is decreased in infants with BPD, and that impaired VEGF signaling contributes to the vascular pathology of BPD. Because growth of small pulmonary arteries is closely linked with alveolarization and the premature lung circulation may be particularly susceptible to injury, it has recently been speculated that inhibition of vascular growth itself may directly impair alveolarization (13). Treatment of newborn rats with a VEGF receptor inhibitor, SU5416, or with less specific antiangiogenesis drugs (thalidomide and fumagillin), inhibits vascular growth and decreases alveolarization in infants (14). These findings suggest that angiogenesis is necessary for alveolarization during normal lung development, and that injury to the developing pulmonary circulation during a critical period of growth can also contribute to lung hypoplasia.

More information is needed regarding the contribution of abnormal vascular growth to impaired distal airspace development, and whether therapies that protect vascular growth will improve long-term outcome. As we learn more about specific mechanisms by which lung injury disrupts lung development, it has become evident that damage to the developing vessels, as well as the airway and distal airspaces, contributes to the late sequelae of BPD. Novel approaches to protect the immature endothelium and enhance lung vascular growth may decrease the risk for clinical problems such as impaired gas exchange, exercise intolerance, pulmonary hypertension, and abnormal lung mechanics.

	Footnotes

	References

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