New insights into sickle cell disease: a disease of hypoxia

Sickle cell disease (SCD) is a devastating genetic disorder caused by a single amino acid substitution in β-globin. Although the condition was first described more than a 100 years ago, treatment options remain scarce and unsatisfactory. This review summarizes recent findings that may provide novel insight into therapeutic approaches to SCD treatment.

Because of insufficient numbers of erythrocytes for oxygen delivery, SCD patients constantly face hypoxia. Adenosine is well known as a key signaling nucleoside that orchestrates a multifaceted physiological response to hypoxia. Recent studies have revealed that adenosine concentrations are significantly elevated in SCD and contribute to disease pathology by activating adenosine receptors on red blood cells. Apart from adenosine, hypoxia also causes hemoglobin release via hemolysis. Studies on free hemoglobin in circulation have uncovered another two important molecules: nitric oxide and heme oxygenase-1.

The core of SCD pathology is erythrocyte sickling under hypoxic conditions, leading to vaso-occlusion and hemolysis. Deeper and more comprehensive understanding of SCD as a disease of hypoxia will provide us new therapeutic targets for SCD treatment.