© 2008 American Thoracic Society doi: 10.1164/rccm.200804-629ED
The Dysmorphic Pulmonary Circulation in Bronchopulmonary DysplasiaA Growing Story
Department of Pediatrics Bronchopulmonary dysplasia (BPD) is a chronic lung disease resulting from oxygen and respiratory therapies after premature birth and afflicts an estimated 10,000–15,000 infants each year in the United States alone. As initially described by Northway and his colleagues over 40 years ago, BPD is characterized as severe acute lung injury in modestly premature newborns due to the adverse effects of hyperoxia, inflammation, mechanical ventilation, and infection (1). These mechanisms are still recognized as major contributors to the pathogenesis of BPD. Over the past decades, however, changes in perinatal care, including antenatal steroid therapy, surfactant use, and changes in ventilator strategies, have altered the very nature of BPD. Infants who now survive with BPD have been born at far earlier gestational ages than in the past. The "new BPD" is believed to represent less the effects of severe lung injury and its repair and more a disruption or arrest of lung development (2). This is most clearly illustrated by changes in lung structure found at autopsy of infants dying with BPD. In comparison with the striking findings of fibroproliferation, current histologic features of BPD primarily include marked decreases in alveolarization and a dysmorphic vascular structure, leading to reduced surface area for gas exchange and increased risk for pulmonary hypertension. Although clinical abnormalities of airway function and structure persist during long-term follow-up, there has been increasing recognition of late cardiopulmonary complications of prematurity that are due to impaired structure of the distal lung and its vasculature (3, 4). There has been a growing story regarding the effects of premature birth and lung injury on the pulmonary circulation itself, especially the endothelial cell, which may contribute to the pathogenesis of BPD (5). The exact timing and relative roles of vasculogenesis, angiogenesis, vascular fusion, and remodeling during lung development remain uncertain. Similarly, little is known of the interplay between diverse signaling pathways, including transcription factors, growth factors, extracellular matrix, and mechanical forces, which must be precisely orchestrated for normal lung circulation. Data have consistently shown that early disruption of vascular growth not only sets the stage for late pulmonary hypertension but can actually contribute to impaired growth of the distal airspace, leading to reduced alveolarization (the so-called vascular hypothesis) (6). These concepts have been supported by many studies in animal models, including the fawn-hooded rat, hyperoxia, endotoxin, mechanical ventilation, hemodynamic stress, antiangiogenic agents, and genetic mouse models. Early work from the laboratories of Maniscalco and Perkett first suggested that vascular endothelial growth factor (VEGF) is decreased by neonatal hyperoxia (7, 8). Later studies showed that disruption of VEGF signaling reduces alveolarization in the normal rat pup and that VEGF treatment enhances lung structure in experimental BPD (5, 9–12). Most important, lung VEGF expression was markedly decreased in lungs from human infants dying with BPD, providing further support for the role of VEGF in this clinical setting (13). In this issue of the Journal (pp. 180–187), De Paepe and coworkers provide exciting new information that, in addition to alterations in VEGF expression, lung endoglin expression is increased in preterm infants who died after receiving mechanical ventilator support (14). Endoglin gene and protein levels were particularly elevated in early deaths, but such changes are less consistently found with more prolonged ventilation. mRNA levels for lung angiopoietin-1 and its receptor, tie-2, were also reduced with early and late deaths. These findings are especially important not only for being the first report to demonstrate the potential role of endoglin in the pathogenesis of human BPD but also for bringing forward the concept that the dysmorphic lung vasculature is likely due to disruption of diverse angiogenic signaling pathways. Although the emphasis is placed on associations with mechanical ventilation, perhaps other clinical correlates of BPD, such as the presence or absence of chorioamnionitis and hyperoxia, also contribute to altered endoglin expression. Endoglin is a transforming growth factor-β coreceptor that is predominantly expressed by vascular endothelium (15). Endoglin plays a critical role in angiogenesis in several settings, and dysregulation of its expression or activity has been implicated in several vascular diseases, including hereditary hemorrhagic telangiectasia, preeclampsia, and cancer. Mice with partial genetic endoglin deficiency have impaired tumor and injury-related angiogenesis and demonstrate impaired regulation of vascular tone as well as growth. While the biology of endoglin is complex, reports have suggested that endoglin has both pro- and antiangiogenic properties, depending on the relative expression of its isoforms and the experimental setting. As changes in lung vascular structure of infants with BPD are complex, the term "dysmorphic" is perhaps most appropriate to describe these findings (4, 16). Dr. De Paepe has previously shown a relative paucity of arteries with reduction in endothelial cell number after short periods of ventilation. Although vessel branches remained decreased, endothelial proliferation was noted in infants dying after more prolonged ventilation (16). Thus, despite sustained reduction of its vascular bed, the lung is further characterized by increased but poorly organized endothelial proliferation later in the course of BPD. The major impact of the current article will likely be to stimulate new areas of investigation that address key questions regarding the role of endoglin in BPD. Although lung endoglin expression is increased during ventilation of premature infants, basic studies are needed to determine whether endoglin primarily serves as a marker of the endothelial response to injury or whether it directly plays a role in the pathophysiology of BPD. As endoglin has a complex biology, much work is needed in models of normal lung development and experimental BPD to better characterize its function. Because diverse vascular stimuli are altered in BPD, much work is needed to specifically explore interactions between the multiple signaling pathways that modulate vascular growth and structure during development and how this signaling is altered in BPD. FOOTNOTES Conflict of Interest Statement: S.H.A. is a scientific advisor for INO Therapeutics (Ikaria) and is paid with honoraria of less than $10,000 per year; he also received a grant from Bayer for animal-related research. REFERENCES
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