Development of artificial oxygen carriers under consideration of microvascular homeostasis

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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.