DISCUSSION
We report the case of an extremely preterm infant who developed progressive ventilator-dependent sBPD with refractory PH, who died at 10 months of age despite aggressive interventions after a prolonged course in the NICU. Clinical and radiographic features were characteristic of sBPD, as classified in the category of type 2 sBPD3 or Grade 3 BPD,4 which is associated with poor outcomes. Lung histology demonstrated classic features of sBPD, including increased interstitial thickening, decreased alveolarization, and hypertensive pulmonary arterial remodeling with reduced vessel density. The lungs further demonstrated striking findings associated with ACDMPV.7 These include the presence of prominent thin-walled and engorged vascular structures, which have been characterized as IBA, that generally share a common sheath with small pulmonary arteries, and have been shown by 3D reconstruction and Synchotron imaging to represent connections between the pulmonary and bronchial ciruclations.9-11 Due to these features, additional genetic studies were performed but these failed to render the diagnosis of ACDMPV. However, measurements of lung FOXF1 andTMEM100 expression were dramatically reduced to levels observed in ACDMPV patients. These findings suggest that disruption ofFOXF1 and TMEM100 signaling, as observed in ACDMPV,13,14 may also contribute to the pathobiology of disruption of lung development in sBPD.
Recent advances have identified the genetic basis for diverse LLDD, including point mutations or copy-number variant deletions involvingFOXF1 , TBX4 , and other genes, which have enabled clinicians to better discriminate these disorders by identifying factors beyond clinical and histopathologic features alone.7Past studies have shown that expressions of FOXF1 andTMEM100 are decreased in lung tissue in infants dying with proven genetic cases of ACDMPV.13,14 Dysregulation of genes from FOXF1 -related pathways are essential for epithelial branching and vascular patterning, including the lung-specificTMEM100 gene, which is known to be crucial in vascular morphogenesis.13 Most recently, these data were corroborated in the Foxf1 mouse model, which further demonstrated the role of FOXF1 in mediating endothelial progenitor cell stimulation of angiogenesis via BMP9 signaling15Findings from this report support the proposal that in some infants with sBPD, down-regulation of FOXF1 and TMEM100 signaling may contribute to the pathogenesis of severe impairment of lung alveolar and vascular growth, including prominent IBAs with PH.
Genetic deletion of Foxf1 reduces pulmonary endothelial cell growth and angiogenesis during development and increases susceptibility to lung injury in mice.12 Past animal studies have demonstrated that early disruption of angiogenesis, including decreased VEGF signaling, impairs airspace development, suggesting an important role of angiocrine signaling for promoting alveolar as well as vascular growth.16 Overall, these findings remind us that the pathogenesis of ACD and other rare but lethal LLDD in term neonates is highly relevant to more common multifactorial disorders of lung hypoplasia, such as sBPD.12 This case report supports the proposal that pulmonary vascular growth is a critical driver of lung maturation and suggests that therapeutic strategies to preserve the survival and function of endothelial cells may effectively stimulate lung vascular growth, improve alveolarization, and reduce the risk of PH in preterm infants. Future preclinical and clinical studies are needed to define the potential roles of impaired FOXF1 andTMEM100 signaling in the subgroup of preterm infants with severe BPD and PH, which will likely enhance our understanding of early pathogenetic mechanisms underlying sBPD and the failure of recovery from severe lung injury.