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Neonatal Hyperoxia Induces Metabolic Reprogramming in Senescent Alveolar Macrophages, Leading to Persistent Lung
Fanjie Lin1, Elena Pineda2,3, Bethany McGonnigal4
1State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 510120 Guangzhou, Guangdong, China.
Frontiers in Bioscience (Landmark Edition)
|February 28, 2026
Summary
Neonatal hyperoxia causes lung cell senescence, primarily in macrophages. Targeting these senescent cells with senolytics can mitigate lung injury, offering a potential therapeutic strategy for bronchopulmonary dysplasia.
Area of Science:
- Pulmonary Medicine
- Neonatology
- Cellular Biology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting premature infants.
- Neonatal hyperoxia exposure in rodents induces a BPD-like lung phenotype and cell senescence.
- Senescent lung macrophages are predominant in a hyperoxia model, peaking at postnatal day 7 (pnd7).
Purpose of the Study:
- To define the molecular and functional characteristics of senescent lung macrophages induced by neonatal hyperoxia.
- To investigate the role of these senescent macrophages in lung injury development and persistence.
- To evaluate therapeutic interventions targeting senescent cells in a hyperoxia-induced lung injury model.
Main Methods:
- Reanalysis of scRNA-seq data from senescent lung cells following neonatal hyperoxia.
- Identification and characterization of senescent macrophage clusters using hierarchical clustering and manual annotation.
- In vivo validation using dichloroacetate (DCA) and a senolytic cocktail (quercetin and dasatinib) in neonatal mice.
Main Results:
- Macrophages constituted 65.90% of senescent cells, with M1-like and alveolar phenotypes identified.
- Senescent macrophages showed altered metabolism (glycolysis, pentose phosphate, glutamine pathways) and upregulated innate immunity/DNA damage genes.
- Dichloroacetate (DCA) treatment reduced macrophage senescence and lung injury; senolytic cocktail mitigated persistent lung injury.
Conclusions:
- Neonatal hyperoxia induces heterogeneous senescent macrophages with metabolic reprogramming and dysregulated signaling.
- These senescent macrophages contribute to the development and persistence of lung injury.
- Targeting senescent macrophages presents a potential therapeutic avenue for BPD and related lung injuries.
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