SFRP2 is involved in hyperoxia-induced bronchopulmonary dysplasia in newborn mice by suppressing Nrf2/HO-1 pathway

Bronchopulmonary dysplasia (BPD), characterized by inflammation, is a severe pulmonary condition of preterm infants. This study aimed to investigate the role of secreted frizzled related protein 2 (SFRP2) in BPD and to elucidated its underlying mechanisms, focusing on inflammation, apoptosis, and the Nrf2/HO-1 signaling pathway. In vivo neonatal mouse models and in vitro murine lung epithelial-12 (MLE-12) models were established by hyperoxia induction. Administration of recombinant SFRP2 (rSFRP2) aggravated hyperoxia-induced lung injury, reduced alveolation, and increased inflammatory cytokines (TNF-α, IL-1β, and IL-6) in both lung tissues and cells (all P  < 0.05). This demonstrated that SFRP2 aggravated hyperoxia-induced inflammation. These results were also evidenced by elevated numbers of inflammatory cells in the BALF and increasing counts of MAC-3 positive cells in the lung tissues of rSFRP2-treated BPD mice (all P  < 0.05). rSFRP2 treatment promoted hyperoxia-induced apoptosis of lung tissue in mice and MLE-12 cells, reflected in increased count of TUNEL-positive cells. The Nrf2/HO-1 pathway was inhibited in the lung tissues of mice and MLE-12 cells after hyperoxia induction, and rSFRP2 therapy further suppressed its activity. Rescue experiments demonstrated that the activation of Nrf2 expression mitigated rSFRP2-induced inflammation and apoptosis in MLE-12 cells. Mechanically, SFRP2 promoted competitive binding of BACH1 to the ARE sequence of HO-1, impaired Nrf2 binding, and suppressed antioxidant signaling. We concluded that SFRP2 might exacerbate lung inflammation and apoptosis by inhibiting the Nrf2/HO-1 pathway, thus promoting the progression of BPD.