Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both.
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.
Nakao
Atsunori
A
Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittburgh, Pennsylvania 15213, USA. anakao@imap.pitt.edu
Kaczorowski
David J
DJ
Wang
Yinna
Y
Cardinal
Jon S
JS
Buchholz
Bettina M
BM
Sugimoto
Ryujiro
R
Tobita
Kimimasa
K
Lee
Sungsoo
S
Toyoda
Yoshiya
Y
Billiar
Timothy R
TR
McCurry
Kenneth R
KR
D000280:Administration, Inhalation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000494:pharmacology*; D050377:Cold Ischemia; D004359:Drug Therapy, Combination; D016027:Heart Transplantation / Q000473:pathology*; D006859:Hydrogen / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D018836:Inflammation Mediators / Q000032:analysis; D008264:Macrophages / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D015428:Myocardial Reperfusion Injury; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D018746:Systemic Inflammatory Response Syndrome / Q000473:pathology; D016042:Transplantation, Heterotopic
D018836:Inflammation Mediators; D008315:Malondialdehyde; D002248:Carbon Monoxide; D006859:Hydrogen