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Bronchopulmonary dysplasia demonstrates dysregulated autotaxin/lysophosphatidic acid signaling in a neonatal mouse model

Pediatric Research volume 97, pages 2462–2474 (2025)Cite this article

Abstract

Background

Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting premature infants who require oxygen supplementation and ventilator therapy to support their underdeveloped lungs. Autotaxin (ATX), an enzyme that generates the bioactive phospholipid lysophosphatidic acid (LPA), which acts via G-protein coupled receptors, has been implicated in numerous pulmonary diseases. In this study, we explored the pathophysiological role of the ATX/LPA signaling pathway in BPD.

Methods

Neonatal mice were exposed to normoxia or hyperoxia (85%) for 14 days from birth while being treated with vehicle, ATX inhibitor or LPA receptor 1 (LPA1) inhibitor. In vitro studies utilized human lung fibroblast (HLF) cells exposed to room air, 85% oxygen, or LPA for varying time periods. Supernatants and cells were collected for assays and Western blotting.

Results

Animals exposed to hyperoxia showed elevated expression of ATX, ATX activity, and LPA1. Inhibiting ATX or LPA1 improved alveolarization, reduced inflammation, and mitigated extracellular matrix deposition and lysyl oxidase (LOX) expression. LPA1 inhibition leading to reduced LOX expression was associated with a reduction in phosphorylation of AKT.

Conclusion

Hyperoxia increases the expression of ATX and LPA1 associated with increased LOX in the lungs. Targeting the ATX/LPA1 pathway could be a potential therapeutic approach to BPD.

Impact

  • Exposure to hyperoxia increases the expression and activity of autotaxin (ATX), as well as expression of LPA receptor 1 (LPA1).

  • Increased expression of ATX influences extra cellular matrix (ECM) remodeling.

  • Inhibitors targeting the ATX/LPA pathway could offer a new therapeutic approach to bronchopulmonary dysplasia (BPD), potentially mitigating ECM deposition and improving lung development.

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Fig. 1: ATX expression is elevated in human patients with BPD.
Fig. 2: ATX expression is elevated in lung tissue of neonatal mice following 85% oxygen exposure.
Fig. 3: Inhibiting ATX activity with GLPG1690 improves alveolarization in neonatal mouse pups following HYX-induced lung injury.
Fig. 4: Inhibiting ATX activity with GLPG1690 attenuates HYX-induced inflammatory responses.
Fig. 5: Inhibiting ATX activity with GLPG1690 improves lung function following hyperoxia exposure.
Fig. 6: Treatment with GLPG1690 attenuates HYX-induced ECM deposition.
Fig. 7: Inhibiting ATX activity ameliorates HYX-induced LOX expression in neonatal mice.
Fig. 8: Exogenous addition of LPA increases expression of ECM proteins and can induce alveolar arrest ECM proteins, similar to that seen in HYX.
Fig. 9: LPA1 is elevated following hyperoxia exposure.
Fig. 10: Antagonizing LPA1, with BMS-986278, protects neonates from HYX-induced lung injury.
Fig. 11: Antagonizing LPA1 attenuates hyperoxia-induced ECM deposition in neonatal mice.
Fig. 12: Signaling via LPA1 activates PI3K/AKT to induce expression of LOX.
Fig. 13: Proposed signaling pathway for the role of ATX/LPA in the pathogenesis of BPD.

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Data availability

All data generated or analyzed during this study are included in the published article along with the supplementary information files. No other data sets were generated or analyzed.

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Acknowledgements

The authors would like to thank Dr. Xiaoyun Tang and Dr. David N. Brindley from the University of Alberta for sharing their ATX activity assay protocol, as well as providing valuable technical support. The authors would also like to thank David Fletcher and Dr. Tracey Bonfield from Case Western Reserve University’s Bioanalyte Core for their assistance with the Mouse Luminex Discovery Assay. Lastly, the authors would like to thank University Hospitals Rainbow Babies and Children’s Hospital in Cleveland for providing the lung tissue samples.

Funding

This work was supported in part by #18TPA34230095/American Heart Association and R01HD090887/Eunice Kennedy Shriver National Institute of Child Health and Human Development to A.H.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL, USA

    Alison W. Ha

  2. Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Tara Sudhadevi, Cathy Mayer, Peter M. MacFarlane & Anantha Harijith

  3. Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Anjum Jafri

  4. Department of Pharmacology, University of Illinois, Chicago, IL, USA

    Viswanathan Natarajan

  5. Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Viswanathan Natarajan

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  1. Alison W. Ha
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Contributions

A.W.H., V.N., and A.H. conceived, and designed research; A.W.H, T.S, A.J., C.M., and A.H. performed experiments; A.W.H., P.M.M., V.N., and A.H. analyzed data and interpreted results of experiments; A.W.H. and A.H. drafted manuscript; A.W.H., V.N., and A.H. edited and revised manuscript; All authors read and approved final version of the manuscript.

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Correspondence to Anantha Harijith.

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Ha, A.W., Sudhadevi, T., Jafri, A. et al. Bronchopulmonary dysplasia demonstrates dysregulated autotaxin/lysophosphatidic acid signaling in a neonatal mouse model. Pediatr Res 97, 2462–2474 (2025). https://doi.org/10.1038/s41390-024-03610-9

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