For decades, it has been known that Hb is a highly efficient scavenger of NO in vitro. However, only in recent years has it become more widely appreciated that cell-free Hb scavenges NO in vivo in human disease and produces clinical manifestations (Figure ) (2
). The depletion of NO, a crucial endogenous antioxidant, is compounded by the oxidative stress induced by decomposition of Hb into heme and elemental iron, highly oxidative co-conspirators against vascular health. Indeed, not only does a canine model of intravascular hemolysis acutely demonstrate the induction of systemic and pulmonary hypertension but also impaired creatinine clearance, presumably due to decreased renal blood flow (4
). Overlapping syndromes have been observed in other human examples of acute hemoglobinemia (excess Hb in the blood plasma), such as the acute hemolytic transfusion reaction (abrupt hemolysis of transfused red blood cell), or following infusion of the first generation of cell-free blood substitutes (2
). The acute experimental canine vasculopathy is partially reversed by administration of NO (4
) or alternatively, as described in this issue by Boretti et al., by glucocorticoid-induced production of endogenous Hp (3
Model of pathologic and adaptive responses to intravascular hemolysis.
Sickle-cell disease has provided the most well-documented example of chronic hemolysis and clinical vasculopathy, with markers of hemolysis-induced NO scavenging statistically linked with pulmonary hypertension, leg ulceration, priapism, and cerebrovascular disease (5
). Reports also have begun to accumulate for these same exact complications, arising in other non-sickling, acute, and chronic hemolytic disorders, supporting a contributory role for hemolysis in the pathophysiology of this vasculopathy syndrome (5
). This growing list includes thalassemia, autoimmune hemolytic anemia, malaria, paroxysmal nocturnal hemoglobinuria, unstable hemoglobinopathy, and hereditary membranopathies (5
The biological importance of these pathways is emphasized by the redundant and overlapping mechanisms that have evolved to detoxify cell-free plasma Hb. First among these is Hp, a tetrameric plasma glycoprotein that binds cell-free plasma Hb and quickly escorts it to the CD163 protein, in which the Hp-Hb complex is avidly bound and cleared from plasma, depleting plasma Hp in the process (6
) (Figure ). Boretti et al. (3
) found that Hp binding to Hb is sufficient to prevent the generation of oxidant species from cell-free Hb that would otherwise mediate hypertension and other adverse vascular outcomes, perhaps in part by sequestering Hb in a high-molecular-weight complex that would not extravasate into the subendothelial space. Interestingly, Boretti et al. also show that Hp-bound Hb has a very high oxygen affinity, which should correspond to increased nitrite reductase activity (1
), potentially stimulating the activity of Hp-Hb complexes to produce the endogenous antioxidant NO from nitrite. As part of the teleological evidence of the biological influence of cell-free plasma Hb, additional Hb-binding pathways have evolved, including sequestration of Hb in HDL particles by Hp-related protein and the ability of CD163 scavenger receptor–1 to bind free Hb to some extent, even after Hp has been depleted (7
). In addition, the heme-binding protein hemopexin has evolved to mop up the toxic porphyrin heme ring released from decomposing cell-free Hb, and heme-metabolizing enzymes, such as heme oxygenase–1, provide a functional antioxidant effect that is protective to vascular health (8
) (Figure ). Finally, plasma transferrin protein sequesters and safely transports elemental iron released from the heme ring, one of the most oxidative substances in the human body.