title: Prednisolone as preservation additive prevents from ischemia reperfusion injury in a rat model of orthotopic lung transplantation.
abstract: The lung is, more than other solid organs, susceptible for ischemia reperfusion injury after orthotopic transplantation. Corticosteroids are known to potently suppress pro-inflammatory processes when given in the post-operative setting or during rejection episodes. Whereas their use has been approved for these clinical indications, there is no study investigating its potential as a preservation additive in preventing vascular damage already in the phase of ischemia. To investigate these effects we performed orthotopic lung transplantations (LTX) in the rat. Prednisolone was either added to the perfusion solution for lung preservation or omitted and rats were followed for 48 hours after LTX. Prednisolone preconditioning significantly increased survival and diminished reperfusion edema. Hypoxia induced vasoactive cytokines such as VEGF were reduced. Markers of leukocyte invasiveness like matrix metalloprotease (MMP)-2, or common pro-inflammatory molecules like the CXCR4 receptor or the chemokine (C-C motif) ligand (CCL)-2 were downregulated by prednisolone. Neutrophil recruitment to the grafts was only increased in Perfadex treated lungs. Together with this, prednisolone treated animals displayed significantly reduced lung protein levels of neutrophil chemoattractants like CINC-1, CINC-2α/β and LIX and upregulated tissue inhibitor of matrix metalloproteinase (TIMP)-1. Interestingly, lung macrophage invasion was increased in both, Perfadex and prednisolone treated grafts, as measured by MMP-12 or RM4. Markers of anti-inflammatory macrophage transdifferentiation like MRC-1, IL-13, IL-4 and CD163, significantly correlated with prednisolone treatment. These observations lead to the conclusion that prednisolone as an additive to the perfusion solution protects from hypoxia triggered danger signals already in the phase of ischemia and thus reduces graft edema in the phase of reperfusion. Additionally, prednisolone preconditioning might also lead to macrophage polarization as a beneficial long-term effect.
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, Goethe-University Hospital Frankfurt, Frankfurt am Main, Germany. Patrick.Paulus@kgu.de
authors.forename: Patrick
authors.initials: P
authors.lastname: Paulus
authors.forename: Johannes
authors.initials: J
authors.lastname: Holfeld
authors.forename: Anja
authors.initials: A
authors.lastname: Urbschat
authors.forename: Haitham
authors.initials: H
authors.lastname: Mutlak
authors.forename: Pia Alexandra
authors.initials: PA
authors.lastname: Ockelmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Tacke
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Christin
authors.initials: C
authors.lastname: Reissig
authors.forename: David
authors.initials: D
authors.lastname: Stay
authors.forename: Bertram
authors.initials: B
authors.lastname: Scheller
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D054338:Cell Transdifferentiation / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000860:Hypoxia; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation / Q000009:adverse effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D011239:Prednisolone / Q000008:administration & dosage*; D011292:Premedication; D055031:Primary Graft Dysfunction / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1; D011239:Prednisolone