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Haptoglobin halts hemoglobin’s havoc
Gregory J. Kato
Gregory J. Kato
Published July 20, 2009
Citation Information: J Clin Invest. 2009;119(8):2140-2142. https://doi.org/10.1172/JCI40258.
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Commentary

Haptoglobin halts hemoglobin’s havoc

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Abstract

Hemoglobin (Hb) is crucial to the function of the red blood cell. However, when it is released during intravascular hemolysis from the cell into blood plasma, it produces a state of NO depletion, oxidant stress, and vascular dysfunction, including hypertension. In their study reported in this issue of the JCI, Boretti and colleagues used canine and guinea pig models to demonstrate that pharmacological doses of glucocorticoid can increase the plasma levels of haptoglobin (Hp), the principal plasma-binding protein for free Hb (see the related article beginning on page 2271). Hp prevented Hb-induced hypertension and the generation of oxidant damage to the kidney. Neutralization of free Hb appears to be part of the downstream antiinflammatory properties of glucocorticoid.

Authors

Gregory J. Kato

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Figure 1

Model of pathologic and adaptive responses to intravascular hemolysis.

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Model of pathologic and adaptive responses to intravascular hemolysis.
A...
A variety of disease conditions can give rise to intravascular hemolysis, including hemolytic anemias such as sickle-cell disease, thalassemia, hereditary spherocytosis, and red blood cell enzymopathies and, to a less-appreciated extent, infection, inflammation, and diabetes mellitus. Extracellular Hb produces a set of pathological effects. It is oxidized to methemoglobin (MetHb) as it scavenges NO directly, depleting this endogenous vasodilator, antioxidant, and master regulator of vascular health. In addition, Hb releases heme and elemental iron (Fe), both of which are intensely oxidative. The net result of extracellular Hb release is oxidative stress, vasoconstriction, and vasculopathy. Glucocorticoids can increase the expression of CD163 and CD91 and, as shown in the study in this issue of the JCI by Boretti et al. (3), also Hp, potentially by either physiologic or pharmacologic stimulation. Hp avidly binds extracellular Hb and suppresses its oxidative consequences, as demonstrated by Boretti et al., largely by preventing its extravasation from the blood vessel lumen to the extraluminal interstitial space, in which some of these oxidative events appear to occur. Hp escorts Hb to the CD163 scavenger receptor on reticuloendothelial macrophages. These cells internalize the receptor-Hp-Hb complex, with consequent induction of heme oxygenase–1 and IL-10, providing antioxidant and antiinflammatory effects. CD163 also is capable, to some extent, of binding free Hb directly. Another adaptive protein, hemopexin, binds free heme and carries it to the macrophage receptor CD91, which also induces heme oxygenase–1. Transferrin transports non-heme iron in plasma, protecting against irons’s oxidative properties.

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