OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in preterm infants. Although dexmedetomidine (Dex) has been shown to exert lung-protective effects in experimental BPD models, the underlying molecular mechanisms remain incompletely understood. This study aimed to investigate whether Dex confers protection against hyperoxia-induced lung injury through regulation of the mitophagy-NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-pyroptosis axis.
METHODS: A neonatal mouse model of BPD and a hyperoxia-induced injury model in primary alveolar type II epithelial (AECII) cells were established. Gain- and loss-of-function approaches targeting PINK1/Parkin-mediated mitophagy and NLRP3 were applied. Mitophagy, inflammasome activation, mitochondrial integrity, inflammatory responses, and cell injury were evaluated using molecular, imaging, and functional assays.
RESULTS: Dex significantly alleviated hyperoxia-induced lung injury in neonatal mice and improved the survival of AECII cells under oxidative stress. Dex treatment enhanced PINK1/Parkin-mediated mitophagy, preserved mitochondrial structure and function, suppressed NLRP3 inflammasome activation, reduced inflammatory cytokine release, and attenuated pyroptosis-related protein expression. Notably, genetic silencing of PINK1 abolished the protective effects of Dex, while NLRP3 overexpression partially reversed Dex-mediated anti-inflammatory and cytoprotective effects, indicating a mechanistic link between mitophagy activation and inflammasome inhibition.
CONCLUSION: Dex protects against hyperoxia-induced lung injury by activating PINK1/Parkin-dependent mitophagy, maintaining mitochondrial homeostasis, inhibiting NLRP3 inflammasome activation, and suppressing pyroptosis. These findings provide mechanistic insight into the therapeutic potential of Dex for the prevention and treatment of BPD.
