title: Kupffer cell inactivation by carbon monoxide bound to red blood cells preserves hepatic cytochrome P450 via anti-oxidant and anti-inflammatory effects exerted through the HMGB1/TLR-4 pathway during resuscitation from hemorrhagic shock.
abstract: Red blood cell (RBC) transfusions for controlling hemorrhaging induce systemic ischemia reperfusion, resulting in a decrease in hepatic cytochrome P450 (CYP) levels. Carbon monoxide (CO), when bound to red blood cells (CO-RBC) has the potential to protect the hepatic CYP protein to produce a resuscitative effect in a hemorrhagic shock rat model. The aim of this study was to investigate the mechanism by which CO-RBC resuscitation from a massive hemorrhage protects against a decrease in hepatic CYP. In the early phase (∼1h) after a hemorrhage and RBC resuscitation, hepatic CYP protein levels were significantly decreased with increasing hepatic free heme levels, but were maintained by a pre-treatment of gadolinium chloride (GdCl3), a Kupffer cell inhibitor, and Trolox, an anti-oxidant agent, as well as CO-RBC resuscitation. Under these conditions, the production of reactive oxygen species (ROS) derived from activated Kupffer cells was increased, but this increase was suppressed by CO-RBC resuscitation. At a late phase (6∼24h), CYP mRNA levels decreased after hemorrhage and RBC resuscitation, but not in the case of CO-RBC resuscitation. The increases in plasma IL-6 and TNF-α levels were decreased by CO-RBC resuscitation via the suppression of the toll-like receptor-4 (TLR-4) and the expression of the high mobility group box-1 (HMGB-1). Hepatic CYP protection after a hemorrhage and CO-RBC resuscitation can be attributed to the inactivation of Kupffer cells, resulting in the suppression of ROS production in the early phase and the suppression of inflammatory cytokine production via the TLR-4/HMGB-1signal pathway in the late phase.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ogaki
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, 860-0082 Kumamoto, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Maeda
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan,; Center for Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan,; Center for Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan,; Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, 860-0082 Kumamoto, Japan,; DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, 860-0082 Kumamoto, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan,; Center for Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, 862-0973 Kumamoto, Japan,. Electronic address: tomaru@gpo.kumamoto-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D017707:Erythrocyte Transfusion / Q000009:adverse effects / Q000379:methods; D004912:Erythrocytes / Q000187:drug effects*; D005682:Gadolinium / Q000494:pharmacology; D024243:HMGB1 Protein / Q000378:metabolism*; D007728:Kupffer Cells / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000097:blood / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D002839:Chromans; D016207:Cytokines; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D005682:Gadolinium; C038958:gadolinium chloride; D008874:Midazolam; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
keywords: Carbon monoxide; Cytochrome P450; Hemorrhagic shock; High mobility group box-1; Kupffer cell; Reactive oxygen species; Toll-like receptor-4