Endothelial MLKL Inhibition Reduces Hyperoxia-Induced Bronchopulmonary Dysplasia in Neonatal Mice.

Abstract

Bronchopulmonary dysplasia (BPD) remains a severe complication in premature infants requiring prolonged oxygen therapy, with vascular endothelial dysfunction recognised as a critical contributor to disease progression. Mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis, an essential form of regulated cell death implicated in various pulmonary disorders, has not been fully investigated in the context of BPD. Here, we utilised a neonatal mouse model of hyperoxia exposure to elucidate the role and mechanisms of MLKL-mediated necroptosis in BPD pathogenesis. Our analysis demonstrated morphological characteristics of necroptosis in pulmonary vascular endothelial cells (ECs) under hyperoxic conditions, accompanied by significant elevation of MLKL protein levels and marked upregulation of MLKL gene expression specifically in vascular ECs. Administration of the MLKL inhibitor necrosulfonamide (NSA), either immediately postnatally or at postnatal day 7, effectively mitigated lung injury, preserved alveolar structure and partially restored pulmonary vascular growth. Moreover, MLKL conditional knockout in ECs significantly attenuated both structural and functional pulmonary abnormalities induced by hyperoxia. Collectively, our findings indicate that MLKL-mediated necroptosis in vascular ECs plays a pivotal role in hyperoxia-induced BPD. Therapeutically targeting MLKL to maintain endothelial integrity presents a promising approach to prevent or alleviate BPD in premature infants.