Caffeine inhibited the hyperoxia-induced A2AR-ERK/p38 MAPK-IL-8 pathway in type II alveolar epithelial cells to suppress NETs formation in bronchopulmonary dysplasia.

BACKGROUND: To investigate how caffeine inhibited hyperoxia-induced NET formation and protected against bronchopulmonary dysplasia (BPD). METHODS: The impact of caffeine on NETs secretion in neutrophils triggered by hyperoxia-induced A549 cells was examined. The role of the IL-8/CXCR2 axis in inducing NETs was evaluated using IL-8 and anti-CXCR2 antibody. The impact of caffeine on ERK/p38 MAPK signaling induced by hyperoxia was explored. Finally, a BPD animal model was established to observe the effect of caffeine on hyperoxia-induced lung injury. RESULTS: Caffeine reduced hyperoxia's inhibitory effect on A549 cell activity and apoptosis, and suppressed the increased secretion of NETs by hyperoxia-induced A549 cells. The IL-8/CXCR2 axis was found to enhance NETs secretion to injury A549 cell. Caffeine inhibited IL-8 secretion in hyperoxia-induced A549 cells, suppressing NETs formation. It also inhibited the A2AR-ERK/p38 MAPK pathway to reduce IL-8 secretion. In the BPD animal model, caffeine alleviated hyperoxia-induced lung injury, lowered inflammatory factors and levels of ERK/p38 MAPK phosphorylation, NETs. However, CGS21680 and IL-8 treatment lessened caffeine's effects. CONCLUSION: Caffeine inhibited A2AR-ERK/p38 MAPK-IL-8 pathway to suppress the formation of NETs for alleviating hyperoxia-induced A549 cell injury. This provides a theoretical basis for developing therapeutic strategies targeting NETs to improve the prognosis of premature infants. IMPACT: Caffeine inhibited hyperoxia-induced NETs formation and exerts a protective effect on bronchopulmonary dysplasia (BPD). Caffeine reduces hyperoxia-induced A549 cell injury and NETs secretion by inhibiting the A2AR-ERK/p38 MAPK-IL-8 pathway. This research offers a new theoretical foundation for comprehending how caffeine improves neonatal BPD. These findings provide a theoretical basis for developing therapeutic strategies targeting NETs. This research offers new insights for improving the prognosis of premature infants with BPD.