The proverbial chicken or the egg? Dissection of the role of cell-free hemoglobin versus reactive oxygen species in sickle cell pathophysiology

Abstract

SICKLE CELL PATHOPHYSIOLOGY comprises a complex interplay of episodic vasoocclusive events, ischemia-reperfusion injury, overproduction of reactive oxygen species (ROS), inflammation, endothelial activation, and hemolysis, all somehow driven by a single amino acid substitution in the -globin chain of hemoglobin. Hemolysis and oxidative stress act synergistically to promote vascular dysfunction in sickle cell disease (SCD). As a result of chronic hemolysis, levels of free plasma hemoglobin are increased at baseline and nitric oxide (NO) bioavailability is diminished, producing endothelial dysfunction that has been linked to chronic vasculopathic complications of SCD such as pulmonary hypertension, cutaneous leg ulceration, priapism, and sudden death (14, 18, 19, 22, 23, 25). NO regulates vasorelaxation and also possesses antioxidant, antiadhesive, and antithrombotic properties (33). NO is produced from the substrate L-arginine by endothelial nitric oxide synthase (eNOS) and mediates vasorelaxation through a paracrine action on vascular smooth muscle cells underlying the endothelium. Endothelial dysfunction, characterized by impaired vascular responsiveness resulting from decreased NO bioavailability, is associated with atherosclerosis, diabetes mellitus, hypertension, hypercholesterolemia, smoking, and obesity, illustrating the central importance of NO in the physiological regulation of vasomotor activity (3, 6).