Sixie Zheng, Hao Li, Siqi She, Yiting Xue, Debao Li, Jiapei Wang, Jing Wang, Yuqing Hu, Lincai Ye
Shanghai Children’s Medical Center and Shanghai Jiao Tong University School of Medicine. Children’s Hospital of Fudan University and National Children’s Medical Center. Affiliated Women and Children’s Hospital of Ningbo University.
China
Frontiers in Immunology
Front Immunol 2026; 17:
DOI: 10.3389/fimmu.2026.1780303
Abstract
Background: Approximately 70% of pediatric pulmonary arterial hypertension (PAH) is associated with congenital heart disease causing increased pulmonary blood flow (IPF). The developing neonatal lung is highly susceptible to hemodynamic stress, yet the direct causal link and mechanisms of neonatal IPF-induced pulmonary vascular remodeling remain poorly understood due to the lack of suitable animal models that recapitulate this critical developmental window.
Methods: We established a novel neonatal mouse model of IPF by performing an aortocaval fistula (ACF) on postnatal day 7(P7). Pulmonary hemodynamics were assessed by ultrasound at P30. Vascular remodeling was evaluated through histology (H&E, α-SMA immunofluorescence) and molecular analysis of phenotypic markers (Spp1, Myh11). Transcriptomic profiling (RNA-seq) and pathway enrichment analysis were employed to uncover underlying mechanisms, with flow cytometry and immunosuppression (Cyclosporin A) and type I interferon receptor blocker (MAR1-5A3) used for functional validation.
Results: The neonatal ACF model successfully induced a left-to-right shunt, resulting in significant IPF and right ventricular volume overload. IPF mice exhibited pronounced pulmonary small vessel remodeling, evidenced by increased α-SMA intensity, elevated synthetic-phenotype marker (Spp1) expression, and decreased contractile-phenotype marker (Myh11). Transcriptomic analysis revealed a dominant immune signature, with the most enriched pathways being antiviral and interferon-response related (response to virus and IL-17 signaling). This was corroborated by a significant increase in pulmonary CD4+ and CD8+ T cells. Crucially, immunosuppressive treatment and type I interferon receptor blocker attenuated vascular remodeling.
Conclusions: We provide the direct experimental evidence that neonatal IPF alone is sufficient to drive pulmonary small vessel remodeling. The process is fundamentally mediated by an activated immune response characterized by an antiviral-like signature, a mechanism distinct from those reported in classic adult PAH models. This novel model offers a critical platform for investigating the developmental-specific pathogenesis of pediatric PAH and bridging the translational “valley of death.”
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Class I. Pulmonary Hypertension Associated with Inflammation
Pulmonary Vascular Pathology
Medical Therapy. Efficacy or Lack of Efficacy
Animal Models of Pulmonary Vascular Disease and Therapy
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