Comment on "The influence of hydroxyurea on oxidative stress in sickle cell anemia"

Sickle cell disease (SCD) is a monogenetic disorder caused by single amino acid change in the beta globin gene. This mutation facilitates the production of unstable sickle hemoglobin (Hb S) which upon deoxygenation forms higher order aggregates which cause erythrocyte rigidity. These rigid cells block the microvasculature resulting in vaso-occlusion, tissue ischemia, organ damage, pain and death. The rigid cells tend to lyse easily, releasing hemoglobin, a protein with oxidant properties related to its heme-bound iron. Therefore, the pathophysiology of SCD is driven by the molecular properties of Hb S, the amount of vaso-occlusion, and the rate of hemolysis. All of these three features are implicated in the induction of oxidative stress in SCD: The unstable Hb S has a high rate of spontaneous auto-oxidation inducing superoxide (1). Intravascular hemolysis results in high levels of free hemoglobin and free heme that have the potential to facilitate hydroxyl-radical formation (2) .Vaso-occlusion results in repeated ischemia-reperfusion cycles that likely strongly induce tissue oxidative stress throughout the body. High levels of xanthine oxidase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activities produce oxygen radicals as part of their normal activities (3). It also is possible that arginase-catalyzed depletion of the arginine substrate for nitric oxide synthase induces its uncoupling with consequent production of reactive oxygen species (4). Markers of oxidative stress such as advanced glycation end products are related to organ damage in SCD (5). Taken together there is no doubt that oxidative stress is prominent in the pathophysiology of SCD. Currently, hydroxyurea (HU) is the only disease-modifying therapy approved for SCD. Administration of HU increases the synthesis of fetal Hb (Hb F), which inhibits the polymerization of Hb S. In sickle cell mice, augmented Hb F expression reduces oxidant stress (6). In SCD patients higher Hb F reduces the number of painful vaso-occlusive crises and appears to reduce hemolysis (7,8). By reducing vaso-occlusion and hemolysis alone, administration of HU could have a major impact on total oxidative stress in SCD. However, there might also be direct effects of HU on the balance between oxidative stress and anti-oxidant capacity. For instance, it has been shown that HU induces glutathione peroxidase, an important anti-oxidant in sickle erythrocytes (9). Glutathione peroxidase activity plays a role in reducing membrane lipid peroxidation, promoting membrane stability and thereby likely reducing hemolysis. HU has both direct oxidant and indirect antioxidant properties. Its azide moiety can oxidize hemoglobin to methemoglobin …