Research Project
10204096
Patrolling Monocytes in Sickle Pain Crisis and following Transfusion Abstract Patients with sickle cell disease (SCD) suffer from intravascular hemolysis associated with vascular injury and dysfunction. Painful vaso-occlusive crisis (VOC) involving increased attachment of sickle erythrocytes and activated leukocytes to damaged vascular endothelium is also a hallmark of SCD. Transfusion lowers sickle (hemoglobin (Hb S)-containing) RBCs mass, although its use for VOC remains controversial. In SCD, patrolling monocytes, which normally scavenge damaged cells and debris from the vasculature, express higher levels of anti-inflammatory heme oxygenase 1 (HO-1), a heme degrading enzyme with anti-cytotoxic and anti- inflammatory properties. We have found that patients with SCD have a novel subset of patrolling monocytes expressing very high levels of HO-1 (HO-1hi) which are decreased in numbers in patients who had a recent VOC episode. This monocyte subset was responsible for uptake of hemolysis-damaged endothelium as well as SCD, but not HD RBCs. In mice, increasing their numbers lowered adherent SCD RBC attachment to the hemolysis-damaged vascular endothelium. In this proposal, we will test the hypothesis that SCD patrolling monocytes scavenge and remove damaged endothelium and endothelial-attached sickle RBCs, resulting in HO-1 upregulation and dampening of VOC. We postulate that when HO-1hi patrolling monocytes are limiting, there is a buildup of vascular damage and increased sickle RBC attachment to the endothelium, which in turn increases the risk of VOC. We further posit that transfusions improve survival of HO-1hi patrolling monocytes, enabling them to effectively clear the vasculature from damaged endothelial cells, thereby affording protection against VOC. To test our hypotheses, we will determine the mechanisms by which patrolling monocytes protect SCD vasculature (aim 1); in aim 2, we will dissect the role of HO-1 in anti-VOC activity of patrolling monocytes, and finally in aim 3, we will examine the association of patrolling monocytes and HO-1hi subset during i) acute VOC and ii) with chronic transfusions. Altogether, we believe that these studies will help establish the role of HO-1hi patrolling monocytes in VOC pathophysiology, and their potential as a therapeutic target for VOC.
