Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway.
A direct role of carbon monoxide (CO), an effector-signaling molecule during heme oxygenase-1 (HO-1) catalysis of heme, in the protection against hepatic ischemia/reperfusion (I/R) injury needs to be established. This study was designed to determine the effects and downstream mechanisms of CO on cold I/R injury in a clinically relevant isolated perfusion rat liver model. After 24 hours of cold storage, rat livers perfused ex vivo for 2 hours with blood supplemented with CO (300 parts per million) showed significantly decreased portal venous resistance and increased bile production, as compared with control livers perfused with blood devoid of CO. These beneficial effects correlated with improved liver function (serum glutamic oxaloacetic transaminase levels) and diminished histological features of hepatocyte injury (Banff's scores). The CO-mediated cytoprotective effects were nitric oxide synthase- and cyclic guanine monophosphate-independent, but p38 mitogen-activated protein kinase (MAPK)-dependent. Moreover, adjunctive use of zinc protoporphyrin, a competitive HO-1 inhibitor, has shown that exogenous CO could fully substitute for endogenous HO-1 in preventing hepatic I/R insult. This study performed in a clinically relevant ex vivo cold ischemia model is the first to provide the evidence that HO-1-mediated cytoprotection against hepatic I/R injury depends on the generation of, and can be substituted by, exogenous CO. The p38 MAPK signaling pathway represents the key downstream mechanism by which CO prevents the I/R insult. In conclusion, regimens that employ exogenous CO should be revisited, as they may have potential applications in preventing/mitigating I/R injury, and thus expanding the liver donor pool for clinical transplantation.
Amersi
Farin
F
The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Shen
Xiu-Da
XD
Anselmo
Dean
D
Melinek
Judy
J
Iyer
Suhasani
S
Southard
Daniel J
DJ
Katori
Masamichi
M
Volk
Hans-Dieter
HD
Busuttil
Ronald W
RW
Buelow
Roland
R
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D003080:Cold Temperature; D006152:Cyclic GMP / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000494:pharmacology; D051547:Heme Oxygenase-1; D066298:In Vitro Techniques; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases
D009569:Nitric Oxide; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006152:Cyclic GMP