Abstract
Sickle cell disease (SCD) is an inherited monogenic disorder and the most common severe hemoglobinopathy in the world. SCD is characterized by a point mutation in the β-globin gene, which results in hemoglobin (Hb) S production, leading to a variety of mechanistic and phenotypic changes within the sickle red blood cell (RBC). In SCD, the sickle RBCs are the root cause of the disease and they are a primary source of oxidative stress since sickle RBC redox state is compromised due to an imbalance between prooxidants and antioxidants. This imbalance in redox state is a result of a continuous production of reactive oxygen species (ROS) within the sickle RBC caused by the constant endogenous Hb autoxidation and NADPH oxidase activation, as well as by a deficiency in the antioxidant defense system. Accumulation of non-neutralized ROS within the sickle RBCs affects RBC membrane structure and function, leading to membrane integrity deficiency, low deformability, phosphatidylserine exposure, and release of micro-vesicles. These oxidative stress-associated RBC phenotypic modifications consequently evoke a myriad of physiological changes involved in multi-system manifestations. Thus, RBC oxidative stress in SCD can ultimately instigate major processes involved in organ damage. The critical role of the sickle RBC ROS production and its regulation in SCD pathophysiology are discussed here.
Highlights
Sickle cell disease (SCD) is a hereditary autosomal recessive red blood cell (RBC)disorder resulting from a point mutation in the β-globin gene, resulting in the production of the sickle hemoglobin (Hb S) due to substitution of valine for glutamic acid at the sixth amino acid position [1,2]
Sickle RBCs have a high level of Reactive oxygen species (ROS)-related PS exposure, suggesting that oxidative stress might play an important role in intravascular hemolysis [80,87]
Pre-apoptotic RBCs and other blood cells release damage-associated molecular patterns (DAMPs), such as adenosine triphosphate (ATP), heme, high-mobility group box 1 (HMGB1), and heat shock proteins, parameters of which are increased in SCD [195,196]
Summary
Sickle cell disease (SCD) is a hereditary autosomal recessive red blood cell (RBC). disorder resulting from a point mutation in the β-globin gene, resulting in the production of the sickle hemoglobin (Hb S) due to substitution of valine for glutamic acid at the sixth amino acid position [1,2]. The repeated polymerization of Hb S leads to a cyclic cascade inciting sickle RBC and other blood cell adhesion-promoting episodic vaso-occlusive events known as “pain crises” with subsequent ischemia-reperfusion injury [5,6,7], intravascular hemolysis, multiple organ damage, and short lifespan [8]. There is a balance between oxidant and antioxidant systems, preventing oxidative damage [9,10]. Oxidative stress results from the imbalance between oxidant and antioxidant systems, which triggers a cascade of reactions damaging membrane lipids, proteins, and DNA, causing a series of pathobiological events [11,12]. RBCs, affect interactions of these cells, with the vascular endothelium and other blood cells promoting vaso-occlusion, activation of coagulation, hemolysis-related anemia, activation of the complement system, endothelial dysfunction and tissue injury, and further inflammation, all of which promote SCD vascular pathology
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