Sixie Zheng, Zheng Wang, Yiting Xue, He Zhang, Yingying Xiao, Yuqing Hu, Debao Li, Qing Cui, Chenxi Liu, Jing Wang, Lincai Ye, Lisheng Qiu
Shanghai Children’s Medical Center and Shanghai Jiao Tong University School of Medicine. Women and Children’s Hospital of Ningbo University. Children’s Hospital of Fudan University and National Children’s Medical Center.
China
Journal of the American College of Cardiology: Asia
JACC Asia 2026;
DOI: 10.1016/j.jacasi.2026.02.013
Abstract
Background: Increased pulmonary blood flow (IPF) from congenital heart diseases causes pediatric pulmonary hypertension and respiratory distress, yet its impact on postnatal lung maturation remains unknown.
Objectives: This study aimed to establish a neonatal model of IPF and elucidate the molecular mechanisms underlying impaired lung maturation, thereby identifying potential therapeutic targets.
Methods: Neonatal mice underwent surgical creation of an aortocaval fistula to induce IPF. Bulk RNA sequencing compared lung transcriptomes at postnatal day (P)14 (alveolar stage) and P30 (maturity) in IPF vs sham-operated controls. Histological validation was performed, and the effects of immunosuppression (cyclosporine A) were assessed.
Results: IPF generated 2,272 differentially expressed genes vs 943 in controls, revealing the following: 1) shared downregulation of extracellular matrix organization and cell cycle pathways; 2) IPF-specific cell cycle dysregulation (downregulated Birc5/CENPE) and hyperactive immunity (upregulated NLRP3/IL23R) impairing alveolar/capillary development; 3) suppressed circadian (Per2) and neural pathways (Nr1d1) unique to normal maturation. Cyclosporine A treatment mitigated alveolar simplification, attenuated vascular remodeling, and improved alveolar epithelial differentiation.
Conclusions: This study establishes the first neonatal IPF model and identifies actionable therapeutic targets, including immune modulators (NLRP3/IL23R inhibitors), cell cycle regulators (Birc5/CENPE agonists), and neural/circadian mediators (Nr1d1/Per2 activators). These findings provide a roadmap for mitigating IPF-driven lung maldevelopment.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Acquired Patient Factors Associated with Pulmonary Vascular Disease
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes