Bilirubin rinse of the graft ameliorates ischemia reperfusion injury in heart transplantation.
Ischemia and reperfusion contribute to substantial organ damage in transplantation. Clinically feasible measures for the prevention thereof are scarce. We tested whether rinsing rodent hearts with the antioxidant bilirubin ameliorates ischemia reperfusion injury (IRI). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDevP), rate per pressure product (RPP), coronary flow, maximum (+dP/dt) and minimum (-dP/dt) rate of contraction were analyzed in Lewis rat hearts rinsed with bilirubin prior to reperfusion on a Langendorff apparatus after 12 h of cold ischemia. In vivo, isogenic C57Bl/6 mouse hearts rinsed with bilirubin were transplanted after 12 h of cold ischemia. Cardiac function and apoptosis were assessed 24 h after reperfusion. Heart lysates recovered 15 min after reperfusion were probed for the total and the phosphorylated forms of extracellular signal-related protein kinases (ERK), JNK, p38-MAPK, and Akt. In isolated perfused hearts, bilirubin rinse resulted in significantly lower LVEDP and improved LVDevP, RPP, coronary flow, +dP/dt and -dP/dt. In vivo, after reperfusion, all mitogen-activated protein kinases (MAPKs) were suppressed significantly by bilirubin pretreatment. Bilirubin rinse improved cardiac scores (3.4 ± 0.5 vs. 2.0 ± 1.0 in controls, P < 0.05) and significantly suppressed apoptosis. Ex vivo administration of bilirubin to heart grafts prior reperfusion ameliorates IRI and provides a simple and effective tool to ameliorate outcome in heart transplantation.
Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria; Department of Surgery, Ludwig-Maximilians University Munich, Munich, Germany.
Florian
F
Bösch
Michael
M
Thomas
Pamela
P
Kogler
Rupert
R
Oberhuber
Robert
R
Sucher
Felix
F
Aigner
Severin
S
Semsroth
Dominik
D
Wiedemann
Kenichiro
K
Yamashita
Jakob
J
Troppmair
Katja
K
Kotsch
Johann
J
Pratschke
Robert
R
Öllinger
D000818:Animals; D017209:Apoptosis; D001663:Bilirubin / Q000627:therapeutic use*; D052279:Creatine Kinase, MB Form / Q000097:blood; D016027:Heart Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D016277:Ventricular Function, Left
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D052279:Creatine Kinase, MB Form; D001663:Bilirubin
apoptosis; experimental transplantation; heart transplantation; heme oxygenase; ischemia reperfusion injury; molecular diagnostic