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This research investigates how neuropeptide Y (NPY) affects lung growth and immune responses in a BPD model using neonatal mice exposed to hyperoxia.

July 3, 2026Respiratory Research0 citationsOpen Access

The autonomic nervous system-lung interface in experimental BPD: NPY modulates immune response, alveolar growth and vascular muscularizationin neonatal mice exposed to oxidative stress

CNClemens O. NiesUniversity Hospital Cologne CZCaroline ZeitounyUniversity of Cologne CKCelien Kuiper-MakrisUniversity of Cologne

Key Points

This research investigates how neuropeptide Y (NPY) affects lung growth and immune responses in a BPD model using neonatal mice exposed to hyperoxia.
Neonatal wild-type (WT) and NPY knockout (NPY −/−) mice were exposed to 85% O2 or 21% O2 from birth to postnatal day 14.
Tyrosine hydroxylase (TH) protein and NPY mRNA levels were measured in lungs to assess sympathetic nervous system signaling.
Quantitative histomorphometry was used to evaluate alveolar growth and vascular muscularization.
WT mice exposed to hyperoxia had a 7-fold increase in TH protein and over 40-fold increase in NPY mRNA compared to those not exposed.
NPY −/− mice under hyperoxia exhibited reduced TH levels and worsened alveolar growth and septal thickening compared to WT mice.
NPY −/− mice showed higher levels of inflammatory markers (Il6, Il1b) but lower macrophage recruitment during hyperoxia.

Abstract

Abstract Oxygen supplementation triggers inflammation and disrupts alveolar and microvascular growth in preterm infants, often leading to bronchopulmonary dysplasia (BPD). The autonomic nervous system (ANS) is critical in lung tissue homeostasis and repair. The sympathetic co-neurotransmitter neuropeptide Y (NPY) emerges as a central regulator of the ANS-organ interface with immune-modulatory function. Here, we studied sympathetic nervous system (SNS) signaling and the contribution of NPY to a hyperoxia-based model of BPD. To this end, neonatal wild-type (WT) and NPY knockout mice (NPY −/− ) were exposed to 85% O 2 (HYX) or 21% O 2 (NOX) from birth to postnatal day 14. Prolonged hyperoxia caused a 7-fold increase of tyrosine hydroxylase (TH) protein, an enzyme characteristic for the SNS, and NPY mRNA (> 40-fold) in neonatal WT lungs. The analysis of lung scRNA-seq revealed an upregulation of NPY in alveolar macrophages of WT HYX when compared to WT NOX . In contrast, NPY −/− HYX showed lower amount of TH than WT HYX , indicating reduced sympathetic-associated signaling. Quantitative histomorphometry demonstrated an aggravated hyperoxia-induced alveolar growth arrest and septal thickening in NPY −/− HYX , whereas vascular muscularization and proliferation of vascular smooth muscle cells (SMC) were attenuated compared to WT HYX . Additionally, NPY −/− HYX were protected from hyperoxia-induced CD68 + macrophage recruitment, despite exhibiting higher lung expression of Il6 (20-fold) and Il1b (4-fold) than WT HYX . In summary, our data demonstrate a dual role of NPY in neonatal lungs in response to hyperoxia, preserving alveolarization while promoting immune cell recruitment and vascular muscularization, highlighting the importance of ANS-lung interface in lung maturation and injury.

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