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Inhibition of Lysophosphatidic Acid Receptor 2 Attenuates Neonatal Chronic Lung Disease in Mice by Preserving Vascular and Alveolar Development

Overview
Journal Eur J Pharmacol
Specialty Pharmacology
Date 2024 Nov 10
PMID 39522686
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Abstract

Aim: Bronchopulmonary dysplasia (BPD) is a common morbidity in extremely premature infants. Previous studies demonstrated the important role of lysophosphatidic acid (LPA) in inflammation in BPD. However, the role of LPA and its receptors in hyperoxia-induced vascular malformations in BPD remains to be elucidated.

Methods And Results: Elevated plasma LPA levels were observed in mice with BPD compared to controls (792 vs. 607 ng/mL, p < 0.05). Inhibition of LPA signaling protected against hyperoxia-induced lung injury in neonatal mice, demonstrated by a 2.8-fold increase in pulmonary vascular density and a 14% reduction in alveolar enlargement. In vitro studies showed that LPA suppressed tube formation in human umbilical vein endothelial cells (HUVECs) by approximately 50%. LPA receptor 2 (LPA) was identified as a functional LPA receptor in primary endothelial cells from the lungs of hyperoxic mice and in HUVECs under hyperoxic conditions. The LPA antagonist H2L5186303 enhanced the tube formation ability of HUVECs exposed to LPA, both under normoxia (4-fold) and hyperoxia (5-fold). Moreover, H2L5186303 significantly protected against hyperoxia-induced vascular malformation (2-fold) and improved alveolarization in neonatal mice (12% decrease in mean linear intercept, MLI). Early growth response 1 (EGR1) was characterized as a downstream target of LPA, silencing EGR1 restored tube formation in HUVECs exposed to LPA and hyperoxia.

Conclusions: Our in vitro and in vivo findings demonstrate that the inhibition of LPA/LPA signaling mitigates hyperoxia-induced pulmonary vascular malformations, suggesting the LPA/LPA-dependent signaling pathway has therapeutic potential for extremely premature infants with BPD.