Oxidative stress in sickle cell disease

In the 18th century, Priestley, Scheele and Lavoisier discovered oxygen and reported its critical role and toxic effects in living organisms. In the last century, several studies highlighted the importance of biological oxidation for energy production by aerobic organisms, in defense and the elimination of drugs. Oxidation is mediated by oxidants and free radicals, generically called reactive oxygen species (ROS), are formed as a byproduct of the oxygen metabolism. Antioxidant enzymatic and non-enzymatic molecules play a crucial role in maintaining the balance of ROS; an imbalance may lead to attack on all the components of the cell, including proteins, lipids and DNA. Collectively, oxidative stress is described as an imbalance between oxidants/free radicals and antioxidants (1-3). Recently, several reports have suggested that oxidative stress is a complex mechanism rather than a simple imbalance between the production and elimination of ROS. Oxidants and free radicals are continuously produced in living organisms with endogenous and external sources such as oxygen and nitric oxide [reactive nitrogen species (RNS)]. An increase in the normal redox state of a cell causes toxic effects that may lead to cell and tissue damage. Furthermore, a decrease in free radicals may be harmful, due to their critical role in microbial defense, cell proliferation, apoptosis, migration, inflammatory gene expression and vascular matrix regulation. In addition, free radicals are increasingly recognized as vital messengers in cellular signal transduction in several organisms (3-5). Sickle cell anemia is an inherited blood disorder affecting approximately 5% of the world's population. This disease results from a mutation in the beta globin chain inducing the substitution of Val for Glu at position 6, shifting the isoelectric point of the protein (6). This single mutation induces the production of hemoglobin S (Hb S), which is abnormal and insoluble. Sickle cell disease promotes harmful pathological effects that includes sickling of erythrocytes, vaso-occlusion and ischemia-reperfusion injury. Increasing evidence points towards an oxidative stress response responsible for increased pathophysiology of secondary dysfunctions in sickle cell patients (7,8). Several molecular mechanisms have been proposed to contribute towards a high oxidative burden in sickle cell patients. Some of the mechanisms that disturb the redox state include, the excessive levels of free hemoglobin that catalyze the Fenton reaction (9) , the recurrent ischemia-reperfusion injury promoting the activation of the xanthine-xanthine oxidase system (10) and higher autoxidation of Hb S generating superoxide anion radicals and hence hydrogen peroxide (11). Furthermore, a chronic proinflammatory …