Protection against ischemia/reperfusion injury in cardiac and renal transplantation with carbon monoxide, biliverdin and both.
Both carbon monoxide (CO) and biliverdin, products of heme degradation by heme oxygenase, have been shown to attenuate ischemia/reperfusion (I/R) injury. We hypothesized in this study that dual-treatment with CO and biliverdin would induce enhanced protective effects against cold I/R injury. Heterotopic heart and orthotopic kidney transplantation were performed in syngeneic Lewis rats after 24-h cold preservation in UW solution. While monotherapy with CO (20 ppm) or biliverdin (50 mg/kg, ip) did not alter the survival of heart grafts, dual-treatment increased survival to 80% from 0% in untreated recipients, with a significant decrease of myocardial injury and improved cardiac function. Similarly, dual-treatment significantly improved glomerular filtration rates of renal grafts and prolonged recipient survival compared to untreated controls. I/R injury-induced up-regulation of pro-inflammatory mediators (e.g. TNF-alpha, iNOS) and extravasation of inflammatory infiltrates were significantly less with dual-treatment than untreated controls. In addition, dual-treatment was effective in decreasing lipid peroxidation and improving graft blood flow through the distinctive action of biliverdin and CO, respectively. The study shows that the addition of byproducts of heme degradation with different mechanisms of action provides enhanced protection against transplant-associated cold I/R injury of heart and kidney grafts.
Nakao
Atsunori
A
Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania, USA.
Neto
Joao Seda
JS
Kanno
Shinichi
S
Stolz
Donna B
DB
Kimizuka
Kei
K
Liu
Fang
F
Bach
Fritz H
FH
Billiar
Timothy R
TR
Choi
Augustine Mk
AM
Otterbein
Leo E
LE
Murase
Noriko
N
D000818:Animals; D001664:Biliverdine / Q000627:therapeutic use*; D002248:Carbon Monoxide / Q000627:therapeutic use*; D002465:Cell Movement / Q000502:physiology; D016027:Heart Transplantation; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics; D051547:Heme Oxygenase-1; D016030:Kidney Transplantation; D008264:Macrophages / Q000502:physiology; D008297:Male; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control*
D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D001664:Biliverdine; D010100:Oxygen