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Lysophosphatidic acid generation by pulmonary NKT cell ENPP-2/autotaxin exacerbates hyperoxic lung injury

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Abstract

Hyperoxia is still broadly used in clinical practice in order to assure organ oxygenation in critically ill patients, albeit known toxic effects. In this present study, we hypothesize that lysophosphatidic acid (LPA) mediates NKT cell activation in a mouse model of hyperoxic lung injury. In vitro, pulmonary NKT cells were exposed to hyperoxia for 72 h, and the induction of the ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP-2) was examined and production of lysophosphatidic acid (LPA) was measured. In vivo, animals were exposed to 100 % oxygen for 72 h and lungs and serum were harvested. Pulmonary NKT cells were then incubated with the LPA antagonist Brp-LPA. Animals received BrP-LPA prior to oxygen exposure. Autotaxin (ATX, ENPP-2) was significantly up-regulated on pulmonary NKT cells after hyperoxia (p < 0.01) in vitro. LPA levels were increased in supernatants of hyperoxia-exposed pulmonary NKT cells. LPA levels were significantly reduced by incubating NKT cells with LPA-BrP during oxygen exposure (p < 0,05) in vitro. Hyperoxia-exposed animals showed significantly increased serum levels of LPA (p ≤ 0,05) as well as increased pulmonary NKT cell numbers in vivo. BrP-LPA injection significantly improved survival as well as significantly decreased lung injury and lowered pulmonary NKT cell numbers. We conclude that NKT cell-induced hyperoxic lung injury is mediated by pro-inflammatory LPA generation, at least in part, secondary to ENPP-2 up-regulation on pulmonary NKT cells. Being a potent LPA antagonist, BrP-LPA prevents hyperoxia-induced lung injury in vitro and in vivo.

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Compliance with Ethical Standards

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Funding

This study was partially funded grant by NIH T32 GM007592-32 (PI Keith Miller) through M Nowak-Machen.

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Author contributions

MNM and SCR designed the study; AU, SW, and ML performed TLC experiments and analyzed the data; MNM performed the experiments; MNM and SCR analyzed the data and wrote the manuscript; and MAE advised on the project and edited the manuscript.

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Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Martina Nowak-Machen

  2. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Martina Nowak-Machen, Martin Lange, Sherry Wu, Anny Usheva & Simon C. Robson

  3. Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital, Eberhard Karls University Tübingen, Tübingen, Germany

    Martina Nowak-Machen

  4. Department of Medicine Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Mark Exley

  5. Medicine & Health Sciences, University of Manchester, Manchester, UK

    Mark Exley

Authors
  1. Martina Nowak-Machen
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  2. Martin Lange
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  3. Mark Exley
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  4. Sherry Wu
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  5. Anny Usheva
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  6. Simon C. Robson
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Correspondence to Martina Nowak-Machen.

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Nowak-Machen, M., Lange, M., Exley, M. et al. Lysophosphatidic acid generation by pulmonary NKT cell ENPP-2/autotaxin exacerbates hyperoxic lung injury. Purinergic Signalling 11, 455–461 (2015). https://doi.org/10.1007/s11302-015-9463-6

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  • DOI: https://doi.org/10.1007/s11302-015-9463-6

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