PT  - JOURNAL ARTICLE
AU  - Hiromi Sakai
AU  - Yohei Masada
AU  - Hirohisa Horinouchi
AU  - Eiji Ikeda
AU  - Keitaro Sou
AU  - Shinji Takeoka
AU  - Makoto Suematsu
AU  - Masuhiko Takaori
AU  - Koichi Kobayashi
AU  - Eishun Tsuchida
TI  - 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
AID  - 10.1124/jpet.104.073049
DP  - 2004 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 874--884
VI  - 311
IP  - 3
4099  - http://jpet.aspetjournals.org/content/311/3/874.short
4100  - http://jpet.aspetjournals.org/content/311/3/874.full
SO  - J Pharmacol Exp Ther2004 Dec 01; 311
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 ml/kg) was equal to 2.5 times the whole blood volume (56 ml/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. The American Society for Pharmacology and Experimental Therapeutics