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Metabolism of a synthetic compared with a natural therapeutic pulmonary surfactant in adult mice

Metabolism of a synthetic compared with a natural therapeutic pulmonary surfactant in adult mice
Metabolism of a synthetic compared with a natural therapeutic pulmonary surfactant in adult mice
Copyright © 2018 Madsen et al. Published by The American Society for Biochemistry and Molecular Biology, Inc. Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells, catabolism by alveolar macrophages, and loss up the bronchial tree. We compared the in vivo metabolism of animal-derived poractant alfa (Curosurf) and a synthetic surfactant (CHF5633) in adult male C57BL/6 mice. The mice were dosed intranasally with either surfactant (80 mg/kg body weight) containing universally 13C-labeled dipalmitoyl PC (DPPC) as a tracer. The loss of [U13C]DPPC from bronchoalveolar lavage and lung parenchyma, together with the incorporation of 13C-hydrolysis fragments into new PC molecular species, was monitored by electrospray ionization tandem mass spectrometry. The catabolism of CHF5633 was considerably delayed compared with poractant alfa, the hydrolysis products of which were cleared more rapidly. There was no selective resynthesis of DPPC and, strikingly, acyl remodeling resulted in preferential synthesis of polyunsaturated PC species. In conclusion, both surfactants were metabolized by similar pathways, but the slower catabolism of CHF5633 resulted in longer residence time in the airways and enhanced recycling of its hydrolysis products into new PC species.
acyl remodeling, mass spectrometry, molecular species, phosphatidylcholine synthesis, stable isotopes
0022-2275
1880-1892
Madsen, Jens
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Panchal, Madhuriben H.
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Mackay, Rose Marie A.
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Echaide, Mercedes
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Koster, Grielof
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Koster, Grielof
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Aquino, Giancarlo
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Pelizzi, Nicola
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Perez-Gil, Jesus
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Salomone, Fabrizio
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Clark, Howard W.
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Clark, Howard W.
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Postle, Anthony D.
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Postle, Anthony D.
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Madsen, Jens
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Panchal, Madhuriben H.
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Mackay, Rose Marie A.
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Echaide, Mercedes
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Koster, Grielof
e404c38a-6f48-430a-adf0-5208228cb9e7
Koster, Grielof
e404c38a-6f48-430a-adf0-5208228cb9e7
Aquino, Giancarlo
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Pelizzi, Nicola
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Perez-Gil, Jesus
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Salomone, Fabrizio
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Clark, Howard W.
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Clark, Howard W.
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Postle, Anthony D.
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Postle, Anthony D.
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Madsen, Jens, Panchal, Madhuriben H., Mackay, Rose Marie A., Echaide, Mercedes, Koster, Grielof, Koster, Grielof, Aquino, Giancarlo, Pelizzi, Nicola, Perez-Gil, Jesus, Salomone, Fabrizio, Clark, Howard W., Clark, Howard W., Postle, Anthony D. and Postle, Anthony D. (2018) Metabolism of a synthetic compared with a natural therapeutic pulmonary surfactant in adult mice. Journal of Lipid Research, 59 (10), 1880-1892. (doi:10.1194/jlr.M085431).

Record type: Article

Abstract

Copyright © 2018 Madsen et al. Published by The American Society for Biochemistry and Molecular Biology, Inc. Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells, catabolism by alveolar macrophages, and loss up the bronchial tree. We compared the in vivo metabolism of animal-derived poractant alfa (Curosurf) and a synthetic surfactant (CHF5633) in adult male C57BL/6 mice. The mice were dosed intranasally with either surfactant (80 mg/kg body weight) containing universally 13C-labeled dipalmitoyl PC (DPPC) as a tracer. The loss of [U13C]DPPC from bronchoalveolar lavage and lung parenchyma, together with the incorporation of 13C-hydrolysis fragments into new PC molecular species, was monitored by electrospray ionization tandem mass spectrometry. The catabolism of CHF5633 was considerably delayed compared with poractant alfa, the hydrolysis products of which were cleared more rapidly. There was no selective resynthesis of DPPC and, strikingly, acyl remodeling resulted in preferential synthesis of polyunsaturated PC species. In conclusion, both surfactants were metabolized by similar pathways, but the slower catabolism of CHF5633 resulted in longer residence time in the airways and enhanced recycling of its hydrolysis products into new PC species.

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J. Lipid Res. 2018 Madsen 1880 92 - Version of Record
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Submitted date: 28 March 2018
Accepted/In Press date: 9 July 2018
e-pub ahead of print date: 14 August 2018
Published date: 1 October 2018
Keywords: acyl remodeling, mass spectrometry, molecular species, phosphatidylcholine synthesis, stable isotopes

Identifiers

Local EPrints ID: 425065
URI: http://eprints.soton.ac.uk/id/eprint/425065
ISSN: 0022-2275
PURE UUID: 3ac55304-4d93-4bf8-be00-f371967e2015
ORCID for Jens Madsen: ORCID iD orcid.org/0000-0003-1664-7645
ORCID for Rose Marie A. Mackay: ORCID iD orcid.org/0000-0002-9493-9654
ORCID for Anthony D. Postle: ORCID iD orcid.org/0000-0001-7361-0756
ORCID for Anthony D. Postle: ORCID iD orcid.org/0000-0001-7361-0756

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Date deposited: 10 Oct 2018 16:30
Last modified: 07 Oct 2020 01:54

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Contributors

Author: Jens Madsen ORCID iD
Author: Madhuriben H. Panchal
Author: Rose Marie A. Mackay ORCID iD
Author: Mercedes Echaide
Author: Grielof Koster
Author: Grielof Koster
Author: Giancarlo Aquino
Author: Nicola Pelizzi
Author: Jesus Perez-Gil
Author: Fabrizio Salomone
Author: Howard W. Clark
Author: Howard W. Clark

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