INTRODUCTION:
Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, contributes to significant morbidities and mortality, especially in extremely low gestational-age newborns. Despite advances in perinatal care, BPD remains a major sequel of prematurity, often leading to the prolonged need for mechanical ventilation, pulmonary hypertension (PH), other co-morbidities, and mortality.1,2 Further, there has been a growing recognition that some preterm infants develop severe BPD (sBPD), and this subgroup has been identified as having a much higher risk for poor outcomes, including late mortality and PH.3-5
Compromised alveolar development with impaired lung vascular growth and hypertensive remodeling are histologic hallmarks of sBPD, as well as genetic lethal lung developmental disorders (LLDD), including alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV).6,7 Extensive work has shown that loss ofFOXF1 expression is the genetic basis for ACDMPV,.8 As with sBPD, ACDMPV is characterized by marked disruption of the alveolar capillary network, which causes severe neonatal respiratory distress and PH, leading to nearly uniform mortality despite aggressive cardiopulmonary therapies.6,7 Additional studies of ACDMPV have shown that the “MPV,” are actually bronchial veins and represent recruitment of intrapulmonary bronchopulmonary anastomoses (IBA), which connect the pulmonary vasculature with bronchial vessels.8 The presence of prominent IBAs have similarly been identified in fatal sBPD,11 suggesting that overlapping features between ACDMPV and sBPD exist, and that these conditions may share pathogenetic mechanisms. Such a link has been suggested in extensive laboratory studies that demonstrated impaired FoxF1 expression in neonatal mice exposed to hyperoxia, a common experimental model for BPD.12
Although multiple mechanisms are associated with high risk for BPD, outcomes remain highly variable and mechanisms that increase susceptibility for this challenging subgroup of preterm infants with sBPD and PH remain poorly understood.2 In this report, we present the case of a preterm infant who died with sBPD and PH, andhad striking histologic features compatible with the diagnosis of ACDMPV but had negative genetic findings for FOXF1 . We further demonstrate dramatic reductions in lung FOXF1 content in sBPD, suggesting common mechanistic links between ACDMPV and sBPD with impaired FOXF1 signaling.