Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in preterm neonates. Extracellular matrix (ECM) abnormalities reshape lung development, contributing to BPD progression. In the present study, we first discovered that the ECM component fibronectin was reduced in the pulmonary tissues of model mice with BPD induced by lipopolysaccharide (LPS) and hyper-oxygen. Meanwhile, interleukin-33 (IL-33) and other inflammatory cytokines were elevated in BPD lung tissues. LPS stimulated the production of IL-33 in alveolar epithelial cells via myeloid differentiation factor 88 (MyD88), protein 38 (p38), and nuclear factor-kappa B (NF-κB) protein 65 (p65). Following the knockout of either IL-33 or its receptor suppression of tumorigenicity 2 (ST2) in mice, BPD disease severity was improved, accompanied by elevated fibronectin. ST2 neutralization antibody also relieved BPD progression and restored the expression of fibronectin. IL-33 induced the formation of neutrophil extracellular traps (NETs), which degraded fibronectin in alveolar epithelial cells. Moreover, DNase-mediated degradation of NETs was protective against BPD. Finally, a fibronectin inhibitor directly decreased fibronectin and caused BPD-like disease in the mouse model. Our findings may shed light on the roles of IL-33-induced NETs and reduced fibronectin in the pathogenesis of BPD.
Keywords: Immune cell death; Innate immunity.
© The Author(s) 2020.