000K utf8 1100 2021$c2021-09-20 1500 eng 2050 urn:nbn:de:hbz:465-20220729-140741-7 2051 10.1038/s41598-021-97708-3 3000 Carstens, Henning 3010 Gulbins, Erich 3010 Kalka, Katharina 3010 Kamler, Markus 3010 Keitsch, Simone 3010 Kleuser, Burkhard 3010 Koch, Achim 3010 Rauen, Ursula 3010 Reiner, Gerald 3010 Schumacher, Fabian 3010 Sehl, Carolin 3010 Soddemann, Matthias 3010 Verhaegh, Rabea 3010 Wahlers, Thorsten 3010 Wilker, Barbara 4000 Inhaled sphingosine has no adverse side effects in isolated ventilated and perfused pig lungs [Carstens, Henning] 4209 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. 4950 https://doi.org/10.1038/s41598-021-97708-3$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:hbz:465-20220729-140741-7$xR$3Volltext$534 4961 https://duepublico2.uni-due.de/receive/duepublico_mods_00076359 5051 610