Decreased ZONAB expression promotes excessive transdifferentiation of alveolar epithelial cells in hyperoxia-induced bronchopulmonary dysplasia.

Abstract

Previous studies by our group have confirmed excessive transdifferentiation of alveolar epithelial cells (AECs) in a hyperoxia‑induced bronchopulmonary dysplasia (BPD) model, but the underlying mechanism have remained elusive. The transcription factor zonula occludens 1‑associated nucleic acid binding protein (ZONAB) has the biological functions of inhibition of epithelial cell differentiation and promotion of epithelial cell proliferation. The aim of the present study was to explore the regulatory effect of ZONAB on the transdifferentiation and proliferation of AECs in a model of hyperoxia‑induced lung injury. Newborn Wistar rats were randomly allocated to a model group (inhalation of 85% O2) or a control group (inhalation of normal air), and ZONAB expression in lung tissues was detected at different time‑points. TypeII AECs (AECII) isolated from normal newborn rats were primarily cultured under an atmosphere of 85 or 21% O2, and ZONAB expression in the cells was examined. The primary cells were further transfected with ZONAB plasmid or small interfering (si)RNA and then exposed to hyperoxia, and the indicators for transdifferentiation and proliferation were measured. The present study indicated that ZONAB expression in AECII of the BPD rats was significantly decreased from 7days of exposure to hyperoxia onwards. In the AECII isolated from normal neonatal rats, ZONAB expression in the model group was also reduced compared with that in the control group. After transfection with the plasmid pCMV6‑ZONAB, the expression of aquaporin 5 (typeI alveolar epithelial cell marker) decreased and the expression of surfactant proteinC (AECII marker), proliferating‑cell nuclear antigen and cyclinD1 increased, which was opposite to the effects of ZONAB siRNA. Transfection with pCMV6‑ZONAB also alleviated excessive transdifferentiation and inhibited proliferation of AECII induced by hyperoxia treatment. These results suggest that ZONAB expression in AECII decreases under hyperoxia conditions, which promotes transdifferentiation and inhibits proliferation of AECs. This may, at least in part, be the underlying mechanism of lung epithelial injury in the hyperoxia-induced BPD model.