Abstract
People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80–102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.
Highlights
Sickle cell disease (SCD) is an autosomal recessive hemolytic anemia characterized by intermittent vaso-occlusion [1,2]
Weibel-Palade body degranulation can be assessed upon heme stimulation, we first investigated if cell surface P-selectin expression can be used as a readout in the presence of heme and various concentrations of hemopexin
human umbilical vein endothelial cells (HUVECs) were preincubated with various hemopexin concentrations for 5 min followed by 25 min stimulation with heme
Summary
Sickle cell disease (SCD) is an autosomal recessive hemolytic anemia characterized by intermittent vaso-occlusion [1,2]. Extracellular hemoglobin in plasma can deplete nitric oxide signaling between endothelial cells and vascular smooth muscle cells, leading to acute and chronic vaso-constriction [6]. As this hemoglobin becomes oxidized or denatured, it is prone to release extracellular free heme [7,8]. Heme induces exocytosis of Weibel-Palade bodies from endothelial cells, resulting in extensive endothelial cell surface exposure of P-selectin and von Willebrand factor. Both are known to play an important role in endothelial adhesiveness and vaso-occlusion [11]. The hemopexin and HO-1 pathways are associated with pronounced decreases in vascular inflammation and vaso-occlusion [15]
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