Abstract
Objective
The study aimed to elucidate the role and the underlying mechanism of human epididymis protein 4 (HE4) in the pathogenesis of hyperoxia-induced bronchial dysplasia in newborn rats.
Methods
Forty neonatal Sprague–Dawley (SD) rats were separated into two groups: a normal control group (20.8% oxygen concentration) and a hyperoxia-induced group (85% oxygen concentration). Three time intervals of 24 h, 3 days and 7 days were chosen for each group. Haematoxylin–eosin staining was used to identify the pathological alterations in the lung tissue of the SD rats. Enzyme-linked immunosorbent assay was used to evaluate plasma protein levels. Real-time reverse transcription polymerase chain reaction was used to determine messenger RNA (mRNA) expression.
Results
In newborn SD rats, hyperoxia intervention within 7 days may result in acute lung damage. In the plasma and tissue of newborn SD rats, hyperoxia induction may raise levels of HE4, matrix metalloproteinases (MMP) 9 and tissue inhibitors of metalloproteinases (TIMP) 1. We discovered that the HE4 protein activates the phosphorylation of extracellular regulated protein kinases (ERK) and p65, activates the downstream MMP9 signalling pathway, inhibits MMP9 mRNA expression, inhibits protein activity, reduces type I collagen degradation, increases collagen secretion and promotes matrix remodelling and fibrosis in neonatal rat primary alveolar type II epithelial cells by overexpressing and silencing the HE4 gene.
Conclusion
Through the ERK, MMP9 and TIMP1 signalling pathways, HE4 mediates the pathophysiological process of hyperoxia-induced lung damage in rats. Lung damage and lung basal remodelling are mediated by HE4 overexpression.
Acknowledgments
The manuscript has been shared as a preprint on bioRxiv, the link: https://biorxiv.org/cgi/content/short/2022.09.22.509120v1.
Author contributions
(I) Conception and design, both collection and assembly of date: Yan XF and Feng X.
(II) Administrative support: Gao Y.
(III) Provision of study materials or patients: Liu DW.
(IV) Collection and assembly of data:Bai L.
(V) Data analysis and interpretation: Xu L.
(VI) Manuscript writing: All authors.
(VII) Final approval of manuscript: All authors.
Animal studies
This experiment was approved by the Experimental Animal Ethics Committee of Children’s Hospital of Soochow University.
Disclosure statement
All of the authors had no any personal, financial, commercial, or academic conflicts of interest separately.
Availability of data and materials
All data generated or analysed during this study are included in this article.