Figures & data
Figure 1. Hb-based blood substitutes and the vascular system. (A) Under normal physiological conditions, NO acts as a vasodilator and antioxidant. There is more NO than O2·− (superoxide is kept at remarkably low levels by a high concentration of the enzyme superoxide dismutase) thus, any pro-oxidant effects of ONOO− and HOOH are suppressed by the anti-oxidant function of NO. (B) Cell-free Hb induces vasocostriction due to the scavenging of NO. In addition, the balance is disrupted, thus O2·− level exceeds NO formation resulting in the loss of the beneficial effects of NO and the concomitant formation of ONOO− and HOOH. The interactions between Hb and these oxidants may thus be detrimental to both Hb and the vasculature (adapted from reference Citation[[1]]).
![Figure 1. Hb-based blood substitutes and the vascular system. (A) Under normal physiological conditions, NO acts as a vasodilator and antioxidant. There is more NO than O2·− (superoxide is kept at remarkably low levels by a high concentration of the enzyme superoxide dismutase) thus, any pro-oxidant effects of ONOO− and HOOH are suppressed by the anti-oxidant function of NO. (B) Cell-free Hb induces vasocostriction due to the scavenging of NO. In addition, the balance is disrupted, thus O2·− level exceeds NO formation resulting in the loss of the beneficial effects of NO and the concomitant formation of ONOO− and HOOH. The interactions between Hb and these oxidants may thus be detrimental to both Hb and the vasculature (adapted from reference Citation[[1]]).](/cms/asset/33156f7d-6362-4f20-87ad-09266d200d72/ianb19_a_11116787_uf0001_b.gif)
Figure 2. Potential modulation of cell signaling by Hb-based blood substitutes. Oxidative stress and/or shear stress stimulates production of NO and O2· − in endothelial cells, which react together to form ONOO−. Scavenging of NO by oxyHb is predicted to increase H2O2 production from O2·−, a process catalyzed by superoxide dismutase (SOD). OxyHb can be oxidized to metHb by NO, ONOO−, and H2O2 (not shown for purposes of clarity). In turn metHb can modulate ONOO− and H2O2 concentrations by reactions that lead to ferryl Hb (Hb4+=O) production. Both reactive oxygen and nitrogen species can regulate transcription and translation processes. The downstream targets of reactive species remain poorly defined. Examples include regulation of sGC, JNK, NFκB, iron response element (IRE) activity and hypoxia-inducible factor (HIF-1). Examples of specific genes known to be regulated by reactive species includes the antioxidants heme oxygenase (HO-1) and glutathione, and the pro-inflammatory adhesion molecules VCAM-1 and ICAM-1 (adapted from reference Citation[[17]]).
![Figure 2. Potential modulation of cell signaling by Hb-based blood substitutes. Oxidative stress and/or shear stress stimulates production of NO and O2· − in endothelial cells, which react together to form ONOO−. Scavenging of NO by oxyHb is predicted to increase H2O2 production from O2·−, a process catalyzed by superoxide dismutase (SOD). OxyHb can be oxidized to metHb by NO, ONOO−, and H2O2 (not shown for purposes of clarity). In turn metHb can modulate ONOO− and H2O2 concentrations by reactions that lead to ferryl Hb (Hb4+=O) production. Both reactive oxygen and nitrogen species can regulate transcription and translation processes. The downstream targets of reactive species remain poorly defined. Examples include regulation of sGC, JNK, NFκB, iron response element (IRE) activity and hypoxia-inducible factor (HIF-1). Examples of specific genes known to be regulated by reactive species includes the antioxidants heme oxygenase (HO-1) and glutathione, and the pro-inflammatory adhesion molecules VCAM-1 and ICAM-1 (adapted from reference Citation[[17]]).](/cms/asset/8d3914e7-8462-44af-a107-c15837561fc5/ianb19_a_11116787_uf0002_b.gif)
Table 1. Biological Examples of Hb/Mb Redox Reactions
Table 2. Antioxidant Protective Strategies