Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both

Nakao, Atsunori; Kaczorowski, David J.; Wang, Yinna; Cardinal, Jon S.; Buchholz, Bettina M.; Sugimoto, Ryujiro; Tobita, Kimimasa; Lee, Sungsoo; Toyoda, Yoshiya; Billiar, Timothy R.; McCurry, Kenneth R.

doi:10.1016/j.healun.2009.10.011

« Previous Next »The Journal of Heart and Lung Transplantation
Volume 29, Issue 5 , Pages 544-553, May 2010

Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both

Atsunori Nakao, MD
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittburgh, Pennsylvania
- Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittburgh, Pennsylvania
- Reprint requests: Atsunori Nakao, MD, Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, E1551, Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213. Telephone: 412-648-9547. Fax: 412-624-6666
David J. Kaczorowski, MD
- Departments of Surgery, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittburgh, Pennsylvania
Yinna Wang, MD
- Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittburgh, Pennsylvania
Jon S. Cardinal, MD
- Departments of Surgery, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittburgh, Pennsylvania
Bettina M. Buchholz, MD
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittburgh, Pennsylvania
Ryujiro Sugimoto, MD
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittburgh, Pennsylvania
- Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittburgh, Pennsylvania
Kimimasa Tobita, MD
- Department of Pediatrics, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittburgh, Pennsylvania
Sungsoo Lee, MD
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittburgh, Pennsylvania
- Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittburgh, Pennsylvania
Yoshiya Toyoda, MD, PhD
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittburgh, Pennsylvania
- Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittburgh, Pennsylvania
Timothy R. Billiar, MD
- Departments of Surgery, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittburgh, Pennsylvania
Kenneth R. McCurry, MD
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittburgh, Pennsylvania
- Heart, Lung and Esophageal Surgery Institute, University of Pittsburgh, Pittburgh, Pennsylvania
- Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio

published online 25 December 2009.

Background

Recent advances in novel medical gases, including hydrogen and carbon monoxide (CO), have demonstrated significant opportunities for therapeutic use. This study was designed to evaluate the effects of inhaled hydrogen or CO, or both, on cold ischemia/reperfusion (I/R) injury of the myocardium.

Methods

Syngeneic heterotopic heart transplantation was performed in rats after 6 or 18 hours of cold ischemia in Celsior solution. Survival, morphology, apoptosis and marker gene expression were assessed in the grafts after in vivo inhalation of hydrogen (1% to 3%), CO (50 to 250 ppm), both or neither. Both donors and recipients were treated for 1 hour before and 1 hour after reperfusion.

Results

After 6-hour cold ischemia, inhalation of hydrogen (>2%) or CO (250 ppm) alone attenuated myocardial injury. Prolonged cold ischemia for 18 hours resulted in severe myocardial injury, and treatment with hydrogen or CO alone failed to demonstrate significant protection. Dual treatment with hydrogen and CO significantly attenuated I/R graft injury, reducing the infarcted area and decreasing in serum troponin I and creatine phosphokinase (CPK). Hydrogen treatment alone significantly reduced malondialdehyde levels and serum high-mobility group box 1 protein levels as compared with air-treated controls. In contrast, CO only marginally prevented lipid peroxidation, but it suppressed I/R-induced mRNA upregulation for several pro-inflammatory mediators and reduced graft apoptosis.

Conclusions

Combined therapy with hydrogen and CO demonstrated enhanced therapeutic efficacy via both anti-oxidant and anti-inflammatory mechanisms, and may be a clinically feasible approach for preventing cold I/R injury of the myocardium.

Keywords: hydrogen, carbon monoxide, ischemia/reperfusion, preservation, heart transplantation, rat