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Protection Against Ischemia/Reperfusion Injury in Cardiac and Renal Transplantation with Carbon Monoxide, Biliverdin and Both

  1. Atsunori Nakao1,2,
  2. Joao Seda Neto1,2,
  3. Shinichi Kanno2,
  4. Donna B. Stolz3,
  5. Kei Kimizuka1,2,
  6. Fang Liu4,
  7. Fritz H. Bach5,
  8. Timothy R. Billiar2,
  9. Augustine MK. Choi4,
  10. Leo E. Otterbein4,
  11. Noriko Murase1,2,*

Article first published online: 6 DEC 2004

DOI: 10.1111/j.1600-6143.2004.00695.x

Issue

American Journal of Transplantation

American Journal of Transplantation

Volume 5, Issue 2, pages 282–291, February 2005

Additional Information

How to Cite

Nakao, A., Neto, J. S., Kanno, S., Stolz, D. B., Kimizuka, K., Liu, F., Bach, F. H., Billiar, T. R., Choi, A. M., Otterbein, L. E. and Murase, N. (2005), Protection Against Ischemia/Reperfusion Injury in Cardiac and Renal Transplantation with Carbon Monoxide, Biliverdin and Both. American Journal of Transplantation, 5: 282–291. doi: 10.1111/j.1600-6143.2004.00695.x

Author Information

  1. 1

    Thomas E. Starzl Transplantation Institute

  2. 2

    Departments of Surgery

  3. 3

    Center for Biologic Imaging

  4. 4

    Pulmonary & Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

  5. 5

    Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

* *Corresponding author: Noriko Murase, Murase+@pitt.edu

Publication History

  1. Issue published online: 6 DEC 2004
  2. Article first published online: 6 DEC 2004
  3. Received 22 July 2004 and revised 3 September 2004 accepted for publication 24 September 2004

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Keywords:

  • Biliverdin;
  • carbon monoxide;
  • cardiac transplantation;
  • heme oxygenase;
  • ischemia/reperfusion injury;
  • renal transplantation

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.

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