Haptoglobin, hemopexin, and related defense pathways-basic science, clinical perspectives, and drug development

Dominik J Schaer, Francesca Vinchi, Giada Ingoglia, Emanuela Tolosano, Paul W Buehler, Dominik J Schaer, Francesca Vinchi, Giada Ingoglia, Emanuela Tolosano, Paul W Buehler

Abstract

Hemolysis, which occurs in many disease states, can trigger a diverse pathophysiologic cascade that is related to the specific biochemical activities of free Hb and its porphyrin component heme. Normal erythropoiesis and concomitant removal of senescent red blood cells (RBC) from the circulation occurs at rates of approximately 2 × 10(6) RBCs/second. Within this physiologic range of RBC turnover, a small fraction of hemoglobin (Hb) is released into plasma as free extracellular Hb. In humans, there is an efficient multicomponent system of Hb sequestration, oxidative neutralization and clearance. Haptoglobin (Hp) is the primary Hb-binding protein in human plasma, which attenuates the adverse biochemical and physiologic effects of extracellular Hb. The cellular receptor target of Hp is the monocyte/macrophage scavenger receptor, CD163. Following Hb-Hp binding to CD163, cellular internalization of the complex leads to globin and heme metabolism, which is followed by adaptive changes in antioxidant and iron metabolism pathways and macrophage phenotype polarization. When Hb is released from RBCs within the physiologic range of Hp, the potential deleterious effects of Hb are prevented. However, during hyper-hemolytic conditions or with chronic hemolysis, Hp is depleted and Hb readily distributes to tissues where it might be exposed to oxidative conditions. In such conditions, heme can be released from ferric Hb. The free heme can then accelerate tissue damage by promoting peroxidative reactions and activation of inflammatory cascades. Hemopexin (Hx) is another plasma glycoprotein able to bind heme with high affinity. Hx sequesters heme in an inert, non-toxic form and transports it to the liver for catabolism and excretion. In the present review we discuss the components of physiologic Hb/heme detoxification and their potential therapeutic application in a wide range of hemolytic conditions.

Keywords: CD163; haptoglobin; hemolysis; hemopexin; sickle cell disease; transfusion; vascular diseases.

Figures

Figure 1
Figure 1
Sequence of renal plasma clearance of hemoglobin: The sequence represents sustained intravascular hemolysis in a guinea pig model. The red color of Hb in plasma during hemolysis suggests ferrous Hb accumulation. In the presence of haptoglobin free Hb is sequestrated within the Hb-Hp complex. Processes of Hb-Hp clearance are saturated during massive hemolysis and the complex remains in circulation for an extended period of time, leading to the brownish color or ferric heme in bound Hb dimers, which is a result of auto-oxidation or reaction with NO or other oxidants in plasma. Free hemoglobin readily dissociates into dimers in plasma, leading to extensive glomerular filtration, which is blocked by Hp. The filtration of Hb leads to renal tubule iron deposition (brown) and hemoglobinuria. This is not observed in control animals or when Hp is administered and Hb remains sequestered in the Hb-Hp complex.
Figure 2
Figure 2
Diastolic (A) and systolic (B) systemic arterial blood pressure response after bolus infusion of free Hb followed by a bolus infusion of purified human Hp in guinea pigs. (C) HPLC analysis of guinea pig plasma after infusion of free Hb followed by Hp. The traces show free Hb co-eluting with an Hb standard (red). The Hb-Hp complex has a larger molecular weight, as indicated by the earlier elution time. The Hb-Hp complex has a long circulation half-life with detectable levels up to 50 h after infusion in this species. (D) NO reactions with free Hb in the vascular wall. Ferrous Hb (Fe2+) can react with the vasodilator NO via two reactions: (1) NO dioxygenation of oxy-Hb that generates nitrate (NO−3) and ferric Hb (Fe3+), and (2) iron nitrosylation of deoxy-Hb that occurs by direct iron binding of NO to non-liganded ferrous Hb (Fe2+). Both reactions lead to depletion of NO and explain the acute vasoactivity of extracellular Hb, which is attenuated by Hp.
Figure 3
Figure 3
Summary of intravascular/extravascular Hb/heme clearance and cellular/tissue distribution. The main components of the Hb/heme detoxification system are haptoglobin (Hp), which sequesters Hb in the oxidatively protected Hb-Hp complex and hemopexin (Hx). The Hb-Hp complex is cleared and metabolized by CD163+ macrophages. Alternatively, during more severe hemolysis, free heme—after release from ferric Hb—can be detoxified by the hemopexin (Hx) rescue pathway. In all scenarios heme is finally detoxified by the heme oxygenases, which provide free iron for export by ferroportin or, alternatively, storage in the ferritin complex. The physiologic clearance and detoxification organs for Hb/heme are the liver and spleen, respectively, while the primary targets of Hb/heme toxic activities are the vascular endothelium and the kidney.

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