Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs

Abstract Ex-vivo lung perfusion (EVLP) systems like XVIVO are more and more common in the setting of lung transplantation, since marginal donor-lungs can easily be subjected to a performance test or be treated with corticosteroids or antibiotics in high dose regimes. Donor lungs are frequently posit...

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Autores principales:	Henning Carstens, Katharina Kalka, Rabea Verhaegh, Fabian Schumacher, Matthias Soddemann, Barbara Wilker, Simone Keitsch, Carolin Sehl, Burkhard Kleuser, Thorsten Wahlers, Gerald Reiner, Achim Koch, Ursula Rauen, Erich Gulbins, Markus Kamler
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0c13013009ad47569ac0c0d69a599ff6
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spelling	oai:doaj.org-article:0c13013009ad47569ac0c0d69a599ff62021-12-02T18:14:15ZInhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs10.1038/s41598-021-97708-32045-2322https://doaj.org/article/0c13013009ad47569ac0c0d69a599ff62021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97708-3https://doaj.org/toc/2045-2322Abstract Ex-vivo lung perfusion (EVLP) systems like XVIVO are more and more common in the setting of lung transplantation, since marginal donor-lungs can easily be subjected to a performance test or be treated with corticosteroids or antibiotics in high dose regimes. Donor lungs are frequently positive in bronchoalveolar lavage (BAL) bacterial cultures (46–89%) which leads to a donor-to-recipient transmission and after a higher risk of lung infection with reduced posttransplant outcome. We have previously shown that sphingosine very efficiently kills a variety of pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and epidermidis, Escherichia coli or Haemophilus influenzae. Thus, sphingosine could be a new treatment option with broadspectrum antiinfective potential, which may improve outcome after lung transplantation when administered prior to lung re-implantation. Here, we tested whether sphingosine has any adverse effects in the respiratory tract when applied into isolated ventilated and perfused lungs. A 4-h EVLP run using minipig lungs was performed. Functional parameters as well as perfusate measurements where obtained. Biopsies were obtained 30 min and 150 min after inhalation of sphingosine. Tissue samples were fixed in paraformaldehyde, embedded in paraffin and sectioned. Hemalaun, TUNEL as well as stainings with Cy3-coupled anti-sphingosine or anti-ceramide antibodies were implemented. We demonstrate that tube-inhalation of sphingosine into ex-vivo perfused and ventilated minipig lungs results in increased levels of sphingosine in the luminal membrane of bronchi and the trachea without morphological side effects up to very high doses of sphingosine. Sphingosine also did not affect functional lung performance. In summary, the inhalation of sphingosine results in an increase of sphingosine concentrations in the luminal plasma membrane of tracheal and bronchial epithelial cells. The inhalation has no local side effects in ex-vivo perfused and ventilated minipig lungs.Henning CarstensKatharina KalkaRabea VerhaeghFabian SchumacherMatthias SoddemannBarbara WilkerSimone KeitschCarolin SehlBurkhard KleuserThorsten WahlersGerald ReinerAchim KochUrsula RauenErich GulbinsMarkus KamlerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Henning Carstens Katharina Kalka Rabea Verhaegh Fabian Schumacher Matthias Soddemann Barbara Wilker Simone Keitsch Carolin Sehl Burkhard Kleuser Thorsten Wahlers Gerald Reiner Achim Koch Ursula Rauen Erich Gulbins Markus Kamler Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs
description	Abstract Ex-vivo lung perfusion (EVLP) systems like XVIVO are more and more common in the setting of lung transplantation, since marginal donor-lungs can easily be subjected to a performance test or be treated with corticosteroids or antibiotics in high dose regimes. Donor lungs are frequently positive in bronchoalveolar lavage (BAL) bacterial cultures (46–89%) which leads to a donor-to-recipient transmission and after a higher risk of lung infection with reduced posttransplant outcome. We have previously shown that sphingosine very efficiently kills a variety of pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and epidermidis, Escherichia coli or Haemophilus influenzae. Thus, sphingosine could be a new treatment option with broadspectrum antiinfective potential, which may improve outcome after lung transplantation when administered prior to lung re-implantation. Here, we tested whether sphingosine has any adverse effects in the respiratory tract when applied into isolated ventilated and perfused lungs. A 4-h EVLP run using minipig lungs was performed. Functional parameters as well as perfusate measurements where obtained. Biopsies were obtained 30 min and 150 min after inhalation of sphingosine. Tissue samples were fixed in paraformaldehyde, embedded in paraffin and sectioned. Hemalaun, TUNEL as well as stainings with Cy3-coupled anti-sphingosine or anti-ceramide antibodies were implemented. We demonstrate that tube-inhalation of sphingosine into ex-vivo perfused and ventilated minipig lungs results in increased levels of sphingosine in the luminal membrane of bronchi and the trachea without morphological side effects up to very high doses of sphingosine. Sphingosine also did not affect functional lung performance. In summary, the inhalation of sphingosine results in an increase of sphingosine concentrations in the luminal plasma membrane of tracheal and bronchial epithelial cells. The inhalation has no local side effects in ex-vivo perfused and ventilated minipig lungs.
format	article
author	Henning Carstens Katharina Kalka Rabea Verhaegh Fabian Schumacher Matthias Soddemann Barbara Wilker Simone Keitsch Carolin Sehl Burkhard Kleuser Thorsten Wahlers Gerald Reiner Achim Koch Ursula Rauen Erich Gulbins Markus Kamler
author_facet	Henning Carstens Katharina Kalka Rabea Verhaegh Fabian Schumacher Matthias Soddemann Barbara Wilker Simone Keitsch Carolin Sehl Burkhard Kleuser Thorsten Wahlers Gerald Reiner Achim Koch Ursula Rauen Erich Gulbins Markus Kamler
author_sort	Henning Carstens
title	Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs
title_short	Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs
title_full	Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs
title_fullStr	Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs
title_full_unstemmed	Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs
title_sort	inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0c13013009ad47569ac0c0d69a599ff6
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Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs

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