| Project/Area Number |
13557132
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | Keio University |
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Principal Investigator |
SUEMATSU Makoto Professor and Chair, Department of Biochemistry and integrative Medical Biology, Keio University, 医学部, 教授 (00206385)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEOKA Shinji Associate Professor, Department of Applied Chemistry, School of Science and Engineering, Waseda University, 理工学部, 助教授 (20222094)
MORISAKI Hiroshi Assistant Professor, Department of Anesthesiology, School of Medicine, Keio University, 医学部, 専任講師 (60182226)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2002: ¥3,700,000 (Direct Cost: ¥3,700,000)
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| Keywords | heme oxygenase / Oxygen carrier / Hemoglobin / microcirculation / nitric oxide / bilirubin / carbon monoxide / Kupffer cells / NO / CO / 微小循環 / ヘモグロビン / バイオイメージング / ビリルビン / hme oxygenase / リポソーム / 一酸化炭素 / 酸素 / ヘムオキシゲナーゼ / シトクロームP450 / 肝臓 |
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| Research Abstract |
This study aimed to examine effects of liposome-encapsulated hemoglobin (HbV), a candidate artificial oxygn carrier, on hepatic microvascular hemodynamics under septic conditions, and roles of CO, the gaseous product of heme oxygenase (HO), in ameliorating hepatobiliary dysfunction during catabolism of heme molecules in endotoxemic livers. Vascular resistance and biliary flux of bilirubin-Ixα, an index of HO-derived CO generation, were monitored in perfused livers of endotoxemic rats. Livers were perfused with HbO_2 which captures NO and CO, or metHb, a reagent trapping NO but not CO. Effexts of HbV were also examined. In endotoxin-pretreated livers where inducible NO synthase and HO-1 overproduced NO and CO, HbO_2 caused marked vasoconstriction and cholestasis. These changes were not reproduced by the NO synthase inhibitor aminoguanidine alone, but by co-administration of zinc protoporphyrin-IX, an HO inhibitor. CO supplementation attenuated the events caused by aminoguanidine plus zinc protoporphyrin-IX, suggesting that simultaneous elimination of these vasorelaxing gases accounts for a mechanism for HbO_2-induced changes. This concept was supported by observation that metHb did not cause any cholestasis; the reagent captures NO but triggers CO overproduction through rapid degradation of the heme by HO-1. On the other hand, HbV exhibited only minor changes in sinusoidal patency without eliciting any notable reduction of sinusoidal blood supply. These results suggest protective roles of endogenous CO against hepatobiliary dysfunction caused by heme overloading under stress conditions, and thus extravasation of the candidate carrier should be limited to maintain optimal CO concentrations in the space of Disse.
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