# NR4A1 Mediates Bronchopulmonary Dysplasia-Like Lung Injury Induced by Intrauterine Inflammation in Mouse Offspring

## TL;DR

This study shows that NR4A1 plays a key role in lung injury caused by intrauterine inflammation in mice, offering a potential target for treating BPD.

## Contribution

The study identifies the NR4A1-EREG-EGFR signaling pathway as a novel mechanism linking intrauterine inflammation to lung injury.

## Key findings

- NR4A1 intervention reversed IUI-induced neonatal lung injury in mice.
- NR4A1 overexpression reduced cell proliferation and affected EMT-related gene expression.
- Blocking EREG's receptor recovered EMT-related gene expression in lung cells.

## Abstract

Intrauterine inflammation (IUI) is involved in the development of bronchopulmonary dysplasia (BPD). Previously, we observed BPD-like pathological changes in a mouse model of IUI. This study aimed to identify the key molecules involved in IUI-induced lung injury, focusing on NR4A1. Pregnant C57BL/6 mice were randomly divided into control and IUI groups. To verify the intervention effects, Nr4a1 siRNA was administered intranasally on postnatal day 3, while an NR4A1 overexpression plasmid was applied in MLE-12 cells to investigate downstream molecules. We found that the lungs of IUI-induced offspring exhibited a simplified structure on postnatal day 1 and excessive collagen fiber deposition by day 90. Postnatal NR4A1 intervention reversed IUI-induced neonatal lung injury. NR4A1 overexpression reduced cell proliferation and AKT and ERK1/2 phosphorylation levels, while also affecting the expression of the key epithelial–mesenchymal transition (EMT)-related gene TGF-β. EREG is a downstream target with potential NR4A1 binding sites in its promoter region. The expression of EMT-related genes can be recovered by blocking the receptor of EREG. Our findings imply that IUI induces BPD-like lung injury in neonates and fibrosis-like lung lesions in adult mice. The NR4A1-EREG-EGFR signaling pathway in pulmonary epithelial cells is crucial in IUI-induced lung injury, highlighting a key therapeutic target for mitigating BPD-like injury.