Protection against ischemia/reperfusion injury in cardiac and renal transplantation with carbon monoxide, biliverdin and both

Atsunori Nakao, Joao Seda Neto, Shinichi Kanno, Donna B. Stolz, Kei Kimizuka, Fang Liu, Fritz H. Bach, Timothy R. Billiar, Augustine M.K. Choi, Leo E. Otterbein, Noriko Murase

Research output: Contribution to journalArticlepeer-review

208 Scopus citations


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-α, 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.

Original languageEnglish (US)
Pages (from-to)282-291
Number of pages10
JournalAmerican Journal of Transplantation
Issue number2
StatePublished - Feb 2005


  • Biliverdin
  • Carbon monoxide
  • Cardiac transplantation
  • Heme oxygenase
  • Ischemia/reperfusion injury
  • Renal transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)


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