Preservation solution supplemented with biliverdin prevents lung cold ischaemia/reperfusion injury.
OBJECTIVE
Biliverdin (BV), one of the byproducts of heme catalysis through the heme oxygenase system, is a known scavenger of the reactive oxygen species. We hypothesized that adding BV to the perfusate and cold storage solution could protect rat lung grafts from oxidative injuries via its antioxidant efficacies.


METHODS
Orthotopic left lung transplantation was performed in a syngenic Lewis-to-Lewis rat combination under 100% oxygen. Grafts were preserved in low-potassium dextran (LPD; Perfadex) at 4°C for 6 h with or without supplementation of 1 or 10 μM of BV into LPD.


RESULTS
Prolonged cold storage and reperfusion resulted in a considerable deterioration of graft functions associated with massive apoptosis in the grafts after reperfusion. The untreated grafts exhibited the early up-regulations of mRNA for inflammatory mediators and an increase in a marker of lipid peroxidation, showing oxidative injuries. Although BV supplementation of LPD at a lower concentration (1 μM) did not improve the graft gas exchange, the grafts treated with BV (10 μM) showed a significant improvement of oxygenation and less inflammatory responses as well as reduced lipid peroxidation and apoptosis. Although the rapid activations of mitogen-activated protein kinases (MAPKs) were seen 30 min after reperfusion in the grafts stored in control LPD, BV treatment significantly reduced phosphorylated-MAPK protein expression.


CONCLUSIONS
This study demonstrates that the exposure of the lung grafts to BV during cold storage can impart potent cytoprotective effects to lung cold ischaemia/reperfusion injury and significantly improve the lung graft function following extended cold preservation and transplantation by the mechanism of a reduction in oxidative injury and following inflammatory events.
Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Ryujiro
R
Sugimoto
Yugo
Y
Tanaka
Kentaro
K
Noda
Tomohiro
T
Kawamura
Yoshiya
Y
Toyoda
Timothy R
TR
Billiar
Kenneth R
KR
McCurry
Atsunori
A
Nakao
D000818:Animals; D017209:Apoptosis; D001664:Biliverdine; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002951:Citrates; D050377:Cold Ischemia; D016166:Free Radical Scavengers; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D016040:Lung Transplantation / Q000379:methods*; D008297:Male; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions; D018384:Oxidative Stress; D051381:Rats; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D015415:Biomarkers; D002951:Citrates; D016166:Free Radical Scavengers; D018836:Inflammation Mediators; D019188:Organ Preservation Solutions; C070005:Perfadex; D001664:Biliverdine