title: Carbon monoxide-bound red blood cell resuscitation ameliorates hepatic injury induced by massive hemorrhage and red blood cell resuscitation via hepatic cytochrome P450 protection in hemorrhagic shock rats.
abstract: Red blood cell (RBC) transfusions are the gold standard in cases of massive hemorrhage, but induce hepatic ischemia-reperfusion injury, a serious complication associated with hemorrhage and RBC resuscitation. Thus, the development of a novel resuscitable fluid that is not associated with hepatic ischemia-reperfusion injury would be desirable. It was reported that exogenous carbon monoxide (CO) treatment ameliorated hepatic ischemia-reperfusion injury accompanying liver transplantation. This suggests that transfusions with CO-bound RBC (CO-RBC) might protect against hepatic ischemia-reperfusion injury following massive hemorrhage and resuscitation compared with RBC resuscitation. To investigate this, we created a hemorrhagic shock model rat, followed by resuscitation with RBC and CO-RBC. Hepatic ischemia-reperfusion injury and the destruction of hepatic cytochrome P450 (CYP) were significantly ameliorated in the CO-RBC resuscitation group compared with the RBC resuscitation group. The free heme derived from the destruction of hepatic CYP was correlated with hepatic oxidation and injury, suggesting that CO-RBC was a major factor in the amelioration of hepatic ischemia-reperfusion injury induced by hemorrhage and resuscitation via hepatic CYP protection. These results indicate that CO-RBC has potential for use as a resuscitative fluid in blood transfusion and does not suffer from the limitations associated with the RBC transfusions that are currently in use.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ogaki
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan; DDS Research Institute, Sojo University, Kumamoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: tomaru@gpo.kumamoto-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000097:blood*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003622:Dapsone / Q000097:blood / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D017707:Erythrocyte Transfusion / Q000009:adverse effects* / Q000379:methods; D004912:Erythrocytes / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000150:complications / Q000201:enzymology / Q000628:therapy*
chemical_list: D017382:Reactive Oxygen Species; D006418:Heme; D002248:Carbon Monoxide; D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System
keywords: cytochrome P450; drug effects; drug transport; hepatic metabolism; pharmacokinetics