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.