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Development of a Neonatal Piglet Acute Lung Injury Model Recreating the Early Environment of Preterm Infant Lungs
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The Postnatal Lung Maturation Disrupted by Increased Pulmonary Blood Flow and Its Clinical Implications

Sixie Zheng1, Zheng Wang1, Yiting Xue1

  • 1Department of Thoracic and Cardiovascular Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

JACC. Asia
|March 26, 2026
PubMed

Insights

Increased pulmonary blood flow in newborns impairs lung development by disrupting cell cycle and immune pathways. Targeting these pathways, along with circadian and neural mediators, offers potential therapeutic strategies for lung maldevelopment.

Area of Science:

  • Pediatric Cardiology
  • Neonatal Physiology
  • Pulmonary Medicine

Background:

  • Congenital heart diseases can cause increased pulmonary blood flow (IPF) in neonates, leading to pulmonary hypertension and respiratory distress.
  • The impact of IPF on postnatal lung maturation is not well understood.
  • This study investigates the effects of IPF on lung development in a neonatal model.

Purpose of the Study:

  • To establish a neonatal model of increased pulmonary blood flow (IPF).
  • To elucidate the molecular mechanisms of IPF-induced impaired lung maturation.
  • To identify potential therapeutic targets for IPF-related lung maldevelopment.

Main Methods:

  • A neonatal mouse model of IPF was created using surgical aortocaval fistula.
  • Bulk RNA sequencing was employed to compare lung transcriptomes at different postnatal ages.
  • Histological analysis and assessment of immunosuppression effects (cyclosporine A) were performed.

Main Results:

  • IPF significantly altered gene expression, downregulating extracellular matrix organization and cell cycle pathways.
  • IPF led to specific dysregulation of cell cycle genes (e.g., Birc5, CENPE) and hyperactive immunity (e.g., NLRP3, IL23R), hindering alveolar and capillary development.
  • Normal lung maturation pathways, including circadian (Per2) and neural (Nr1d1) components, were suppressed in the IPF model.
  • Cyclosporine A treatment improved alveolar structure, reduced vascular remodeling, and enhanced alveolar epithelial differentiation.

Conclusions:

  • A neonatal model for studying increased pulmonary blood flow (IPF) and its impact on lung development was successfully established.
  • Key molecular targets for therapeutic intervention were identified, including immune modulators (NLRP3/IL23R inhibitors), cell cycle regulators (Birc5/CENPE agonists), and neural/circadian mediators (Nr1d1/Per2 activators).
  • These findings provide a framework for developing strategies to mitigate lung maldevelopment caused by IPF.
Abstract

Keywords:
increased pulmonary blood flowleft-to-right shuntlungneonatal animal modelspediatric

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