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.

Prednisolone suppresses the immunostimulatory effects of 27‑hydroxycholesterol

“…We observed suppressed expression of 27OHChol-induced M1 markers, and upregulation of the transcription and cell surface expression of CD163 and CD206, without further enhancement of the 27OHChol-induced expression of molecules. These results are consistent with previous reports that glucocorticoids generate M2 macrophages (20) and enhance transdifferentiation of macrophages towards the immune regulatory M2 phenotype (32). Taken together with previous publications, our findings suggest that prednisolone differentially regulates M1/M2 polarization of monocytes/macrophages.…”

Lung inflation with hydrogen during the cold ischemia phase decreases lung graft injury in rats

“…Lung preservation solution, such as low-potassium dextran (LPD) solution, is the most commonly used lung protective method during the cold ischemia phase. 3,4 Different perfusion pressures and perfusion methods for the donor could also improve lung graft function, 5 as could by using anti-platelet/endothelial cell adhesion molecule-1, 6 relaxin, 7 and steroids 8 during IRI. Additionally, hypothermia (4-10 C) is an important method for donor lung perseveration during the ischemia phase, 9,10 but the donor lung still could not be stored for a longer time.…”

Ischemia/Reperfusion Injury: Pathophysiology, Current Clinical Management, and Potential Preventive Approaches

“…It can be speculated that the high doses used in such studies blocked the proliferative and remodeling stages of MIRS, along with the inflammatory phase that was initially the intended target. Nowadays, a protective role for corticosteroids in MIRS has been described in both experimental [122,123] and clinical settings. Concordantly, a metaanalysis by Giugliano et al [124] showed this cardioprotective effect for corticosteroids in MIRS in patients.…”