Patrolling Monocytes in Sickle Pain Crisis and following Transfusion

镰刀痛危象和输血后单核细胞的巡视 摘要 镰状细胞病(SCD)患者患有血管内溶血，与血管损伤和 功能障碍。疼痛的血管闭塞危象(VOC)，涉及镰刀状红细胞和 激活的白细胞损伤血管内皮细胞也是SCD的一个标志。输血使镰刀降下 (含血红蛋白(Hb S))红细胞质量，尽管其用于挥发性有机碳仍存在争议。在SCD，巡逻 单核细胞，通常清除血管系统中受损的细胞和碎片，表达更高水平的 抗炎血红素加氧酶1(HO-1)，一种具有抗细胞毒性和抗病毒作用的血红素降解酶 炎性物质。我们发现SCD患者有一个新的巡逻单核细胞亚群 表达非常高水平的HO-1(HO-1HI)，而在最近发生 VOC插曲。这个单核细胞亚群也负责摄取溶血损伤的内皮细胞。 作为SCD，但不是HD RBCs。在小鼠中，增加它们的数量降低了附着在SCD RBC上的 溶血-损伤血管内皮细胞。在这个提案中，我们将检验SCD巡逻的假设 单核细胞清除和清除受损的内皮细胞和内皮附着的镰刀状红细胞，导致 HO-1上调和抑制VOC。我们推测，当HO-1HI巡逻的单核细胞受到限制时， 血管损伤增加，内皮细胞上的镰刀状红细胞附着量增加，进而 增加了VOC的风险。我们进一步假设，输血可以提高HO-1HI巡视单核细胞的存活率， 使它们能够有效地清除受损内皮细胞中的血管系统，从而提供保护 对抗VOC。为了验证我们的假设，我们将确定巡逻单核细胞的机制 保护SCD血管系统(目标1)；在目标2中，我们将剖析HO-1在巡逻抗VOC活性中的作用 单核细胞，最后在目标3中，我们将研究巡逻单核细胞与HO-1HI亚群的关系 在I)急性VOC和II)慢性输血期间。总之，我们相信这些研究将会有所帮助。 建立HO-1HI巡视单核细胞在VOC病理生理学中的作用及其作为治疗的潜力 VOC的目标。

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.