Deficiency of SPP1 alleviates hyperoxia-induced bronchopulmonary dysplasia in neonatal mice

Abstract Bronchopulmonary dysplasia (BPD) is a common chronic lung disorder characterized by impaired proximal airway and bronchoalveolar development in premature births. SPP1 is involved in lung development and lung injury events, while its role was not explored in BPD. In the current study, the hyperoxiainduced lung injury animal models were generated by exposing neonatal mice to hyperoxia for 7 days after birth, and alveolar myofibroblasts (AMYFs) were treated with hyperoxia to establish the in vitro models of BPD. Based on the scRNA-seq analysis of lungs of mice housed under normoxia or hyperoxia conditions, mouse macrophages and fibroblasts were main different cell clusters between the two groups, and differentially expressed genes in fibroblasts were screened. Further GO and KEGG enrichment analysis revealed that these differentially expressed genes were mainly enriched in the pathways related to cell proliferation, apoptosis as well as the PI3K-AKT and ERK/MAPK pathways. SPP1 was found up-regulated in the lung tissues of hyperoxia mice. We also demonstrated the up-regulation of SPP1 in the BPD patients as well as hyperoxiainduced lung injury mouse models and cells. SPP1 deficiency was revealed to reduce the hyperoxia-induced apoptosis, oxidative stress and inflammation and increase the viability of AMYFs. In the hyperoxiainduced lung injury mouse models, SPP1 deficiency was demonstrated to reverse the hyperoxia-induced alveolar growth disruption, oxidative stress and inflammation. Overall, SPP1 exacerbates BPD progression in vitro and in vivo by regulating oxidative stress and inflammatory response via the PI3K-AKT and ERK/MAPK pathways, which might provide novel therapeutic target for BPD therapy.