Proinflammatory monocyte-derived granulocyte-macrophage colony-stimulating factor fuels airway inflammation in bronchopulmonary dysplasia

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a leading cause of morbidity and long-term respiratory complications in preterm neonates. Effective strategies for moderate-severe BPD are currently lacking. METHODS: monocytes were isolated and purified from the TA samples for transcriptomic sequencing analysis. Cytokine arrays and enzyme-linked immunosorbent assays were utilized in the cytokine level detection from TA samples. Finally, we evaluated the efficacy of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor in alleviating lung inflammation resembling BPD in a neonatal rat model of hyperoxia lung injury. RESULTS: monocytes in TA samples from patients with BPD were significantly increased, and exhibited a pro-inflammatory transcriptomic profile, producing large amount of GM-CSF in the airway. Upregulated toll-like receptor 9 (TLR9) expression in these monocytes was observed. Baricitinib, a JAK1/JAK2 inhibitor, effectively reduced lung inflammation induced by hyperoxia and GM-CSF in a neonate rat model mimicking BPD. CONCLUSIONS: GM-CSF derived from airway pro-inflammatory monocytes exacerbated inflammation in preterm neonates with BPD, particularly in moderate-severe cases. Baricitinib emerges as a promising therapeutic option, offering new hope for mitigating the inflammatory burden associated with moderate-severe BPD. IMPACT: Moderate-to-severe bronchopulmonary dysplasia in preterm infants is closely linked to the sustained production of high levels of GM-CSF (granulocyte-macrophage colony-stimulating factor) by airway inflammatory monocytes. We propose a local GM-CSF-driven inflammatory positive-feedback loop in airway of patients with BPD. Interrupting the downstream GM-CSF signaling pathway may hold promise as the next effective therapeutic strategy.