Inhibition of lysophosphatidic acid receptor 2 attenuates neonatal chronic lung disease in mice by preserving vascular and alveolar development.

Autor: Chen X; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China; Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, China., Han D; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China., Zeng Y; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China., Li H; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China., Wang X; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China., Huang Z; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China., Yang L; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China., Wagenaar GTM; Faculty of Science, VU University Amsterdam, Amsterdam, the Netherlands., Lin B; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China. Electronic address: pureice1998268@126.com., Yang C; Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, The First School of Medicine, Southern Medical University, Shenzhen, China; Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, China. Electronic address: yangczgd@smu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Dec 15; Vol. 985, pp. 177120. Date of Electronic Publication: 2024 Nov 09.
DOI: 10.1016/j.ejphar.2024.177120
Abstrakt: 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 2 ) 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 2 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 2 , 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 2 signaling mitigates hyperoxia-induced pulmonary vascular malformations, suggesting the LPA/LPA 2 -dependent signaling pathway has therapeutic potential for extremely premature infants with BPD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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