Physiological capacity of the reticuloendothelial system for the degradation of hemoglobin vesicles (artificial oxygen carriers) after massive intravenous doses by daily repeated infusions for 14 days

Hiromi Sakai, Yohei Masada, Hirohisa Horinouchi, Eiji Ikeda, Keitaro Sou, Shinji Takeoka, Makoto Suematsu, Masuhiko Takaori, Koichi Kobayashi, Eishun Tsuchida

    Research output: Contribution to journalArticle

    51 Citations (Scopus)

    Abstract

    A hemoglobin vesicle (HbV; diameter 252 ± 53 nm) or liposome-encapsulated Hb is an artificial oxygen carrier developed for use as a transfusion alternative, and its oxygen-transporting capacity has been well characterized, although critical physiological compartments for the Hb degradation after a massive infusion of HbV and the safety outcome remain unknown. In this study, we aimed to examine the compartments for its degradation by daily repeated infusions (DRI) of HbV, focusing on its influence on the reticuloendothelial system (RES). Male Wistar rats intravenously received the HbV suspension at 10 ml/kg/day for 14 consecutive days. The cumulative infusion volume (140 mi/kg) was equal to 2.5 times the whole blood volume (56 mi/kg). The animals tolerated the DRI well and survived, and body weights continuously increased. One day after DRI, hepatosplenomegaly occurred significantly through the accumulation of large amounts of HbV. Plasma clinical chemistry was overall normal, except for a transient elevation of lipid components derived from HbV. These symptoms subsided 14 days after DRI. Hemosiderin deposition and up-regulation of heme oxygenase-1 coincided in the liver and spleen but were not evident in the parenchyma of these organs. Furthermore, the plasma iron and bilirubin levels remained unchanged, suggesting that the heme-degrading capacity of the RES did not surpass the ability to eliminate bilirubin. In conclusion, phospholipid vesicles for the encapsulation of Hb would be beneficial for heme detoxification through their preferential delivery to the RES, a physiological compartment for degradation of senescent RBCs, even at doses greater than putative clinical doses.

    Original languageEnglish
    Pages (from-to)874-884
    Number of pages11
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume311
    Issue number3
    DOIs
    Publication statusPublished - 2004 Dec

    Fingerprint

    Blood Substitutes
    Mononuclear Phagocyte System
    Oxygen
    Heme
    Bilirubin
    Hemosiderin
    Clinical Chemistry
    Heme Oxygenase-1
    Blood Volume
    Liposomes
    Wistar Rats
    Phospholipids
    Suspensions
    Hemoglobins
    Up-Regulation
    Spleen
    Iron
    Body Weight
    Lipids
    Safety

    ASJC Scopus subject areas

    • Pharmacology

    Cite this

    Physiological capacity of the reticuloendothelial system for the degradation of hemoglobin vesicles (artificial oxygen carriers) after massive intravenous doses by daily repeated infusions for 14 days. / Sakai, Hiromi; Masada, Yohei; Horinouchi, Hirohisa; Ikeda, Eiji; Sou, Keitaro; Takeoka, Shinji; Suematsu, Makoto; Takaori, Masuhiko; Kobayashi, Koichi; Tsuchida, Eishun.

    In: Journal of Pharmacology and Experimental Therapeutics, Vol. 311, No. 3, 12.2004, p. 874-884.

    Research output: Contribution to journalArticle

    Sakai, Hiromi ; Masada, Yohei ; Horinouchi, Hirohisa ; Ikeda, Eiji ; Sou, Keitaro ; Takeoka, Shinji ; Suematsu, Makoto ; Takaori, Masuhiko ; Kobayashi, Koichi ; Tsuchida, Eishun. / Physiological capacity of the reticuloendothelial system for the degradation of hemoglobin vesicles (artificial oxygen carriers) after massive intravenous doses by daily repeated infusions for 14 days. In: Journal of Pharmacology and Experimental Therapeutics. 2004 ; Vol. 311, No. 3. pp. 874-884.
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    abstract = "A hemoglobin vesicle (HbV; diameter 252 ± 53 nm) or liposome-encapsulated Hb is an artificial oxygen carrier developed for use as a transfusion alternative, and its oxygen-transporting capacity has been well characterized, although critical physiological compartments for the Hb degradation after a massive infusion of HbV and the safety outcome remain unknown. In this study, we aimed to examine the compartments for its degradation by daily repeated infusions (DRI) of HbV, focusing on its influence on the reticuloendothelial system (RES). Male Wistar rats intravenously received the HbV suspension at 10 ml/kg/day for 14 consecutive days. The cumulative infusion volume (140 mi/kg) was equal to 2.5 times the whole blood volume (56 mi/kg). The animals tolerated the DRI well and survived, and body weights continuously increased. One day after DRI, hepatosplenomegaly occurred significantly through the accumulation of large amounts of HbV. Plasma clinical chemistry was overall normal, except for a transient elevation of lipid components derived from HbV. These symptoms subsided 14 days after DRI. Hemosiderin deposition and up-regulation of heme oxygenase-1 coincided in the liver and spleen but were not evident in the parenchyma of these organs. Furthermore, the plasma iron and bilirubin levels remained unchanged, suggesting that the heme-degrading capacity of the RES did not surpass the ability to eliminate bilirubin. In conclusion, phospholipid vesicles for the encapsulation of Hb would be beneficial for heme detoxification through their preferential delivery to the RES, a physiological compartment for degradation of senescent RBCs, even at doses greater than putative clinical doses.",
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    AU - Sakai, Hiromi

    AU - Masada, Yohei

    AU - Horinouchi, Hirohisa

    AU - Ikeda, Eiji

    AU - Sou, Keitaro

    AU - Takeoka, Shinji

    AU - Suematsu, Makoto

    AU - Takaori, Masuhiko

    AU - Kobayashi, Koichi

    AU - Tsuchida, Eishun

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    AB - A hemoglobin vesicle (HbV; diameter 252 ± 53 nm) or liposome-encapsulated Hb is an artificial oxygen carrier developed for use as a transfusion alternative, and its oxygen-transporting capacity has been well characterized, although critical physiological compartments for the Hb degradation after a massive infusion of HbV and the safety outcome remain unknown. In this study, we aimed to examine the compartments for its degradation by daily repeated infusions (DRI) of HbV, focusing on its influence on the reticuloendothelial system (RES). Male Wistar rats intravenously received the HbV suspension at 10 ml/kg/day for 14 consecutive days. The cumulative infusion volume (140 mi/kg) was equal to 2.5 times the whole blood volume (56 mi/kg). The animals tolerated the DRI well and survived, and body weights continuously increased. One day after DRI, hepatosplenomegaly occurred significantly through the accumulation of large amounts of HbV. Plasma clinical chemistry was overall normal, except for a transient elevation of lipid components derived from HbV. These symptoms subsided 14 days after DRI. Hemosiderin deposition and up-regulation of heme oxygenase-1 coincided in the liver and spleen but were not evident in the parenchyma of these organs. Furthermore, the plasma iron and bilirubin levels remained unchanged, suggesting that the heme-degrading capacity of the RES did not surpass the ability to eliminate bilirubin. In conclusion, phospholipid vesicles for the encapsulation of Hb would be beneficial for heme detoxification through their preferential delivery to the RES, a physiological compartment for degradation of senescent RBCs, even at doses greater than putative clinical doses.

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