SOX4 arrests lung development in rats with hyperoxia‑induced bronchopulmonary dysplasia by controlling EZH2 expression

Pan,Bingting; Xue,Xindong; Zhang,Dan; Li,Mengyun; Fu,Jianhua

doi:10.3892/ijmm.2017.3171

SOX4 arrests lung development in rats with hyperoxia‑induced bronchopulmonary dysplasia by controlling EZH2 expression

Authors:
- Bingting Pan
- Xindong Xue
- Dan Zhang
- Mengyun Li
- Jianhua Fu
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Affiliations: Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
Published online on: October 3, 2017 https://doi.org/10.3892/ijmm.2017.3171
Pages: 1691-1698
Copyright: © Pan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bronchopulmonary dysplasia (BPD) is currently the most common severe complication in premature infants and is characterized by the arrest of alveolar and vascular growth. Alveolar type II cells play an important role in the pathological foundation of BPD. An association of BPD with epithelial‑to‑mesenchymal transition (EMT) in type II cells exposed to hyperoxia was previously identified. SOX4, a transcription factor that is indispensable to embryogenesis, including lung development, participates in regulating EMT and cell survival, affecting tumorigenesis. The aim of the present study was to investigate the involvement of SOX4 in the occurrence of BPD, which, to the best of our knowledge, has not been previously determined. For this purpose, newborn rats were randomly divided into two treatment groups: The model group was exposed to hyperoxia (80-85% O2), while the control group was kept under normoxic conditions (21% O2). Lung tissues were collected on postnatal days 1, 3, 7, 14 and 21 and morphological changes in the lungs were examined by hematoxylin and eosin staining. The location of SOX4 in type II cells was detected by double immunofluorescence. The expression of SOX4 and enhancer of zeste homolog 2 (EZH2) in type II cells and lung tissues were detected by immunochemistry, western blotting and quantitative polymerase chain reaction analysis. The results demonstrated that, compared with the control group, the radial alveolar count decreased rapidly in the model group, accompanied by increased mean alveolar diameter and alveolar septal thickness. SOX4 and EZH2 were highly expressed in type II cells exposed to hyperoxia. However, in total lung tissues, SOX4 and EZH2 expression was profoundly decreased in the early stages and increased in the late stages following exposure to hyperoxia. The expression of the EZH2 protein was positively correlated with that of the SOX4 protein. In conclusion, at the alveolar stage, which is a critical period after birth for lung development, hyperoxia induced dysregulation of SOX4 and EZH2 in rat lungs, indicating that SOX4 may contribute to the disruption of lung development in BPD by regulating EZH2 expression.

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