Infants who develop bronchopulmonary dysplasia have an airway endotype defined by vimentin expression and ciliary loss.

RATIONALE: Bronchopulmonary dysplasia (BPD) arises from disrupted lung development after preterm birth and produces structural deficits at every level of the respiratory tree. Lower airway disease is emerging as a clinically significant BPD phenotype with increased mortality, yet the molecular mechanisms whereby preterm birth disrupts airway development remain poorly defined.

OBJECTIVES

To develop a human model of lower airway disease following preterm birth and to define a molecular endotype of evolving BPD (eBPD) at baseline and in response to injury.

METHODS

An ex vivo organotypic airway epithelial cell (AEC) model was combined with well-characterized pathologic and transcriptomic patient samples for quantitative immunohistochemistry and RNA-sequencing analyses.

MEASUREMENTS AND MAIN

RESULTS

Compared to AECs from healthy controls, eBPD-derived AECs exhibited reduced proliferation, impaired differentiation to ciliated epithelium, and expansion of a vimentin-positive population with a transcriptional profile associated with impaired AEC differentiation. Following hyperoxia exposure, eBPD-derived AECs mounted a robust vimentin response ex vivo, paralleling increased vimentin expression observed in airway cells from lung tissue of human infants with BPD.

CONCLUSIONS

Using an organotypic model of neonatal airway differentiation, we demonstrate eBPD is associated with impaired AEC differentiation, increased vimentin-expression and concomitant loss of ciliated cells, and an exaggerated vimentin response to hyperoxic injury. These findings mimic the effects of prematurity in airway cells in human patients. These data support a mechanism whereby hyperoxia leads to impaired epithelial differentiation and associated lower airway dysfunction in BPD and inform future mechanistic studies interrogating the role of intermediate filaments in maladaptive epithelial repair.