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Published on: October 19, 2013
Neonatal hyperoxia promotes macrophage senescence and lung injury via a p38MAPK-dependent secretome
Sorel V Y Ouonkap1, Bethany McGonnigal1, Joselynn Wallace2
1Department of Molecular Biology, Cellular Biology, and Biochemistry, Brown University, Providence, RI, USA.
Insights
Hyperoxia induces alveolar macrophage senescence via increased glycolysis, impairing lung function and causing injury. Inhibiting macrophage glycolysis and p38MAPK offers a potential therapeutic strategy for bronchopulmonary dysplasia.
Area of Science:
- Neonatal lung injury
- Cellular senescence
- Immunometabolism
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants, characterized by lung simplification and linked to cellular senescence.
- Alveolar macrophages (AMs) show predominant senescence after neonatal hyperoxia, but mechanisms and injury contribution are unclear.
Purpose of the Study:
- Investigate mechanisms of hyperoxia-induced AM senescence.
- Determine effects of senescence/hyperoxia on AM function.
- Characterize the secretome's contribution to lung injury.
Main Methods:
- scRNA-seq analysis of neonatal mouse AMs exposed to hyperoxia.
- Analysis of metabolic shifts, motility, and phagocytosis in AMs.
- Proteomic characterization of the senescent AM secretome and assessment of lung injury models with p38MAPK inhibition.
Main Results:
- Hyperoxia significantly increased AM senescence markers, driven by enhanced glycolysis.
- Senescent AMs exhibited reduced motility and phagocytosis.
- The secretome from senescent/hyperoxic AMs induced alveolar and vascular simplification, which was reduced by p38MAPK inhibition.
Conclusions:
- Hyperoxia reprograms AM glycolysis, promoting senescence and dysfunction.
- The resulting secretome drives lung injury, suggesting therapeutic targets.
- Inhibiting macrophage glycolysis and p38MAPK pathways are promising strategies for preventing neonatal lung injury.
Rationale:
Bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants exposed to ventilatory support and hyperoxia, involves alveolar and vascular simplification and is linked to cellular senescence. We previously found senescence predominantly in alveolar macrophages (AMs) after neonatal hyperoxic exposure, but the specific mechanisms driving this and its role in neonatal lung injury remain poorly understood.
Objectives:
This study investigated the mechanisms driving hyperoxia-induced AM senescence, the effects of senescence/hyperoxia on AM function and how the resulting secretome contributes to lung injury.
Methods:
scRNA-seq datasets from hyperoxia-exposed neonatal mice were used to score AM senescence and characterize senescent/hyperoxia-induced AM clusters. Hyperoxia-induced metabolic shifts were analyzed alongside AM motility and phagocytosis. Proteomics characterized the senescent AM secretome. Finally, the effects of senescent and hyperoxic secretomes on lung injury were assessed with and without p38MAPK inhibition.
Results:
scRNA-seq analysis confirmed that hyperoxia significantly increases senescence markers in AMs. This induction occurs via increased glycolysis and leads to reduced AM motility and phagocytosis. Proteomics identified p38MAPK-regulated proteins in the AM secretome including upregulated pro-fibrotic factors and downregulated structural regulators. Intranasal administration of senescent and/or hyperoxia-conditioned media caused alveolar and vascular simplification in neonatal mice, which was attenuated by p38MAPK inhibition.
Conclusions:
Hyperoxia causes glycolytic reprogramming in AMs, increasing senescence markers and impairing function. This also leads to a secretome that drives lung injury. Inhibiting macrophage glycolysis and p38MAPK pathways represent novel, promising therapeutic approaches to prevent lung injury.
